The Open Rheu matology Journal, 20 l 0, 4, 15-22
`
`15
`
`Tolerability and Patient/Phys ician Satisfaction with Subcutaneously
`Administered Methotrexate Provided in Two Formulation s of Different
`Drug Concentr ations in Patients with Rheumatoid Arthritis
`
`Ulf Milller-Ladner"'·1, Karin Rockwitz2, Jan Brandt -Jilrgens 3, Roland Haux3, Peter Kastner4,
`
`
`, Uwe Pichlmeier 7 and
`JUrgen Braun5, Winfried Demary6, Ceci le Guimbal -Schmolck 7
`Andreas Brandt7 for the MC-MTX . l 0/RH Study Group
`
`I Kerckhojf-Klinik , Bad Nauheim, Germany
`1 Practising Rheumatologist, Goslar, Germany
`3 Practising Rheumatologist, Berlin, Germany
`•Practising Rheumatologist , Etfurt, Germany
`5 Rheumazentrum Ruhrgebiet, Herne, Germany
`6 Practising Rheumatologist, Hildesheim , Germany
`7Medac Gesellschaftfur klinische Spezialpraparate mbH, Hamburg, Germany
`
`Abstr act: Objectives: To determine preference, satisfaction, usability and local tolerability by patients, physicians and
`study nurses of two subcutaneously administered methotrexate (MTX) formulations of different concentrations.
`
`Methods: This was an open-label, comparative, within-patient controlled, multicentre study of 132 patients with
`rheumatoid arthritis (RA). MTX treatment consisted of20 mg/week administered as a medium-concentration formulation
`(MC) (2.0 ml of IO mg/ml solution in prefilled syringe; separate needle) compared to a novel high-concentration
`fonnulation (HC) (0.4 ml of 50 mg/ml in prefilled syringe; pre-attached needle). Each treatment was given for three
`weeks. Questionnaires and visual analogue scales were used to measure outcomes.
`
`Results: At the end of the study, 93% of the patients preferred HC over MC as further treatment. Overall assessment of
`HC was "good" or "very good" in 90.6% vs 34.4% in MC-treated patients. Physician's and patients global assessment of
`syringe usability showed highly statistically significant differences (P < 0.000 I) in favour of HC. Overall assessment by
`study nurses' and investigators' was ·'good" (18.8%) or "very good" (81.2%) for HC and "good" in 31.3% or "very good"
`in 12.5% for MC, and no preference in 50%. Local tolerability improved slightly also with I-IC.
`
`Conclusions: The total smaller volume of administered drug and the improved usability of a pre-attached needle in
`combination with a smaller prefilled syringe resulted in preference of the patients of HC over MC. The slightly improved
`local tolerability may also have added to this preference. This assessment was confirmed by similar assessments made by
`healthcare professionals.
`
`Eudra-CT number: 2007-003591- 19.
`
`Keyw or ds: Methotrexate , subcutaneo us injection, prefilled syringe, rhe umatoid arthritis.
`
`INTRODUCTION
`
`(MTX) has
`low-dose methotrexate
`In the past decade,
`become the disease-modifying
`anti rhe umatic drug of choice
`in
`the
`treatment
`of
`rheumatoid
`arthritis
`(RA).
`Subcutaneously
`(SC) administered MT X is well absorbed,
`appears
`to overcome
`the problems
`associated w ith ora l
`adm inistration,
`including variable absorpt ion and sat uration
`of the absorption mechanism wit h increasing doses, and is
`
`* Address correspondence to this author at the Kerckhoff-Klinik GmbH,
`Department ofRheumatology and Clinical Immunology , 8enekestrasse 2-8,
`D-61231 Bad Nauheim, Gennany; Tel: + 49-6032-9962101 ; Fax: + 49-
`6032-9962104; E-mail: u.mueller-ladner @kerckhofT-klinik.de
`
`well to lerated [ l ]. Recent studies have also confirmed
`the
`improved
`usability
`and
`tolerabil ity
`of
`subcutaneous
`application
`[2-4],
`in
`part icular
`in
`comparison
`to
`intramuscular
`injectio n [2]. However, several patients sti ll
`exper ience prob lems
`to app ly several mi llilitres of liquid
`MTX eve ry week and report also local s ide effects associated
`with the injected volume.
`
`double-dummy
`randomized,
`A 6-month , prospective,
`trial compared
`the eff icacy and safety of SC versus oral
`adm inistratio n of MTX in 384 patients with RA [5]. Patients
`to receive 15 mg/week of MTX
`were randomly assigned
`either orally (two 7.5 mg tablets) or SC (prefilled syringe
`contain ing IO mg/ml) . After 6 months, significantly more
`
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`
`Muller-Lad11er et al.
`
`patients treated with SC MTX than with oral MTX showed
`ACR20 (78% vs 70%) and ACR70 (41% vs 33%) responses.
`Patients with disease duration ;;:: 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
`IO 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 Cmax was
`different with higher Cmax 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 mg/ml and two
`with the concentration of IO mg/ml). 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 treatm ent
`with either the medium-concentration formulation (MC) (2.0
`ml of IO mg/ml solution ; need to apply needle) or the high(cid:173)
`concentration formulation (HC) (0.4 ml of 50 mg/ml pre(cid:173)
`filled syringe ; pre-attached needle) by repeated SC inject(cid:173)
`ions.
`Secondary objectives included satisfaction, usability and
`local tolerability assessed by patients, physicians and study
`nurses.
`
`Study Design
`
`controlled,
`comparative , within-patient
`This open,
`multicentre study enrolled 132 patients at 16 centres
`in
`Germany between No vember 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 ( I st and
`4th injection within the study) , the following two injections
`of every type of syringe were performed by the patients
`themse lves (211d, 3'd, 5•h and 6th 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.
`
`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 > 1.5 x ULN); liver function test abnormalities
`(AST or ALT> 2 x ULN, bilirubin > 5 mg/di); impaired
`haematopoiesis (platelets< 100 x 109/1, leukocytes< 3.5 x
`I 09/ 1), anaemia (haemoglobin < IO 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(cid:173)
`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 adminis(cid:173)
`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(cid:173)
`roids were permitted during the study: combination therapy
`with one or more DMARDs or a biological
`immuno(cid:173)
`modulator (e.g. TNF-« blockers) ; drugs causing folate defic(cid:173)
`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.
`
`Assessment of Patient-Reported, Physician-Reported and
`Study Nurse/Physician-Reported Outcomes
`
`Table 1 summarises questions and answers concerning
`patient-reported , physician-reported and study nurse/physi(cid:173)
`cian-reported outcomes.
`
`Assessment of Safety
`
`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(cid:173)
`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 (IO mg/m I solution; need
`to apply a needle; metex® in Germany, metoject® in other
`countries, manufacturer: medac Gesellschaft
`flir klin ische
`Spezialpraparate mbH, Hamburg, Germany) and a prefilled
`
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`Compariso n of Two MTX Prefilled Sy ringes fo r S.C llljec tion i11 RA
`
`Tlte Ope11 R fleumatology Jou ma l, 2010, Volume 4 17
`
`Table I.
`
`Preference and Usability Ou tcomes*
`
`Patie nt-Report ed O utcomes
`
`Ove ra ll pr eference (primary endpoint)
`
`"Which of the pre-filled syringes would you prefer from now on?··
`
`Patie nt satisfactio n
`
`"How would you assess . in summary. the small/large syringe at the end of the study? "
`
`Five categories were suggested: "very poor", "poor", "no preference ", "g ood" and "very good" .
`
`Syri nge with or with out pre-a tt ache d need le
`
`"'How do you like the pre-al/ached needle (small syringe) in comparison to one that still has to be attached (large syringe)?··
`
`Five categories were suggested: "great disadvantage", "disadvantage", "no d ifference", "advantage", and "g reat advantage" .
`
`Usability of syrin ge volum e
`
`''Do you feel comfortable with the fact that the injection liquid is jive times less in the small syringe than in the large syringe?"
`
`Five possible answers were suggested: "fully disagree" , "disagree", "ind ifferent", "agree" and "fully agree".
`
`Loca l tolera bility
`
`Occurrence of erythema, swelling, itching, pain and haematoma assessed as "none", " mild", " moderate" or "seve re".
`
`Usab ility of th e IO mg/ml syri nge at the 2n" and 3•• injec tion (MC for mulat ion) and of th e 50 mg/ml syri nge at th e 5•• an d 61
`formul at ion)
`
`• injection (HC
`
`Rated on a visual sca le from O (not convenient = 0 mm) to 10 (very convenient= 100 mm).
`
`Physician-Repor ted Outco mes
`
`l lsability of th e IO mg/ml syr inge at the I'' inj ection (MC for mulation) and of the 50 mg/ml syrin ge at th e 4'" injec tion (HC formul at ion)
`
`Rated on a visual sca le rrom O (not convenient = 0 mm) to 10 (very convenient= 100 mm) .
`
`Local tolerab ility
`
`Occurrence of erythema, swelling , itching, pain and haematoma assessed as "none", "mild", "moderate" or "severe" .
`
`Study Nurse/Ph ysician- Reported O utco mes
`
`Sy ringe wit h or with out pr e-a ttache d needle
`
`., How do you like the pre-attached needle (small syringe) in comparison to the one which still has to be al/ached (large syringe)? "
`
`Five categor ies were suggested: "g reat disadvantage ", "disadvantage", "no difference", "advantage", and "great advantage".
`
`Usability of syringe volume
`
`''Do you feel comfortable with the fact that the injection liquid is.five limes less in the small syringe than in the large syringe?"
`
`Five possible answers were suggested: "fully disagree", "disagree" , "indifferent" , "agree" and "fully agree".
`
`Ove rall ass essment of the sma ll prefilled syr inge
`
`Five categories were suggested: "very poor'', "poor'', "no preference", "good" and "very good".
`
`Overa ll assess ment of the large pre lilled syri nge
`
`Five categories were suggested: "very poor", " poor", "no preference", "good" and "very good".
`*Ortgmal III Gennan.
`
`(50 mg/ml
`formulation
`syringe MTX high-concentration
`solution; pre-attached needle) (Fig. 1); both formulations
`were provided by medac Gmb H, Germany .
`
`Stat istica l Ana lysis
`
`i.e. the proportion of patients
`The primary objective,
`deciding in favour of the HC syringe, was subjected to
`statistica l testing by apply ing a two-sided one-group chi(cid:173)
`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
`
`level wou ld have 90% power to detect the
`significance
`difference between the null hypothes is rate of 55% and the
`alternat ive rate of70% w ith a sample size of 110 patients.
`To assess the local tolerabi lity at the site of injection,
`frequency distr ibutions of mi ld, moderate and severe s igns
`and symptoms of swell ing, itching, erythema, haematoma
`and pain were presen ted. Treatment-specific differences
`between ordinal data were evaluated using Wilcoxo n signed (cid:173)
`rank tests on an explorative perspect ive. All other parameters
`were analysed desc riptively using robust measures of
`location and dispersion such as medians and 1st (Q l ) and 3rd
`quartiles (Q3).
`
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`Miiffer-Latf11er et al .
`
`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: I
`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.l % 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).
`
`Efficacy
`
`Patient-Reported Outcomes
`
`the
`The primary efficacy variable was to quantify
`decision of the patient for future MTX treatment (50 mg/ml
`syringe vs IO mg/ml 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 statistica lly
`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).
`89 .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.
`Using
`a visual
`analogue
`scale, patient's
`global
`assessment of syringe usability was 63.5 mm (Ql-Q3: 49-
`92) after MC administrations which increased significantly
`to 95.0 mm (Q J-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 usabi I ity was 82.0 mm (Q l -Q3: 59-
`100) at the time of administration of the MC formulation . A
`significant
`increase in to 96.0 mm (Ql-Q3: 86-100) was
`observed at time of HC administration (P < 0.0001) .
`Study Nurse/Physician-Reported 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 mg/ml
`
`MTX 50 mg/ml
`
`the methotrexate prefilled syringe
`(1). Compari son of
`Fig.
`10 mg/ml and 50 mg/ml true to scale. MTX=methotre xate.
`
`Ethics
`
`The study was performed in accordance with the Good
`Clinical
`Practice
`guidelines
`recommended
`by
`the
`International Conference on Harmonization (!CH) of
`Technical Requirements. Ethics committees relevant to the
`respective study sites approved the study protocol. Written
`informed consent was obtained from all patients.
`
`Fun ding
`
`The study was supported by medac Gesellschaft fur
`klinische Spezialpraparate mbH, Hamburg, Germany .
`
`RESULTS
`
`Patient Characteristics
`
`Of the 132 patients enrolled , one was excluded from the
`
`safety-analysis set (due to missing study visits (1 5', 2"d and
`4th injection) and lack of any source data) and additional 3
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`The Ope11 Rlzeumawlogy Joumal , 2010, Volume 4 19
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10 %
`
`0%
`
`I
`
`Very good
`
`Good
`
`No
`preference
`
`D MTX 10 mg/ml
`• MTX 50 mg/ml
`
`n I -Poor
`
`[L
`
`Very Poor
`
`[II
`
`Missing
`
`Fig. (2 ). Patients' overall assessment of methotrexate prefilled syringe 10 mg/m I and 50 mg/ml.
`
`D MTX 10 mg/ml
`• MTX 50 mg/ml
`
`100%
`
`90%
`
`80%
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Very good
`
`No preference
`
`Fig. (3). Study nurses ' and physicians' overall assessment of methotrexate prefilled syringe IO mg/m l and 50 mg/ml.
`
`in the HC
`the smaller volume
`that
`87.5% found
`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).
`
`Safety
`
`Adverse events were coded according to the Medical
`Dictionary
`for Regulatory Affairs
`(MedDRA) . Adver se
`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(cid:173)
`related . The most frequent adverse events and drug-related
`adverse events were gastrointestinal disorders
`(6.1 %),
`investigations
`(3.8%)
`and
`genera l
`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
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`Miiller-l ad11er et al.
`
`T able 2. Adverse Events
`
`MedDRA System Orga n Class/Pr eferr ed Term s
`
`Number or patients with adverse events
`
`Gastrointestinal disorders
`
`Abdominal pain
`
`Abdominal pain upper
`
`Diarrhoea
`
`Mouth ulceration
`
`Nausea
`
`Investigations
`
`Alanine aminotransferase increased
`
`Aspartate aminotransferase increased
`
`Gamma-glutamyltransferase increased
`
`White blood cell count decreased
`
`0 (0.D}
`
`0 (0.0)
`
`0 (0.0)
`
`2 (1.5)
`
`I (0.8)
`
`3 (2.3)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`0 (0.0)
`
`General disorders and administration site conditions
`
`3 (2.3)
`
`Fatigue
`
`Feeling abnormal
`
`Injection site irritation
`
`Mucosal dryness
`
`MTX Medium
`Concentrat ion
`o=13 1
`n (%)
`
`14 ( 10.7)
`
`5 (3.8)
`
`MTX High
`Concentr ation
`n=l 31
`n (%)
`
`15(11.5)
`
`4 (3.1)
`
`Tota l
`n=J31
`n (%)
`
`25 (19.1)
`
`8 (6. 1)
`
`2 (1.5)
`
`I (0 8)
`
`2 (l.5)
`
`I (0.8)
`
`4 (3.1)
`
`2 (1.5)
`
`I (0.8)
`
`0 (0.0)
`
`0 (0.0)
`
`I (0.8)
`
`5 (3.8)
`
`5 (3.8)
`
`5 (3.8)
`
`2 ( l.5)
`
`I (0.8)
`
`I (0.8)
`
`5 (3.8)
`
`2(1.5)
`
`I (0.8)
`
`0 (0.0)
`
`2 ( 1.5)
`
`4 (3.1)
`
`0 (0.0)
`
`0 (0.0)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`Pain
`
`Skin and subcutaneous tissue disorders
`
`2 ( 1.5)
`
`Alopecia
`
`Erythema
`
`0 (0.0)
`
`2 ( 1.5)
`
`0 (0.0)
`
`1 (0.8)
`
`I (0.8)
`
`I (0.8)
`
`3 (2.3)
`
`0 (0.0)
`
`I (0.8)
`
`2 ( 1.5)
`
`I (0.8)
`
`Musculoskeletal and connective tissue disorders
`
`I (0.8)
`
`2 (1.5)
`
`2 (1.5)
`
`Musculoskeletal pain
`
`Myalgia
`
`Pain in extremity
`
`Rheumatoid arthritis (worsening)
`
`Nervous system disorders
`
`Cervical root pain
`
`Dizziness
`
`Respiratory, thoracic and mediastinal disorders/ Cough
`
`Infections and infestations/Oral herpes
`
`Ear and labyrinth disordersNertigo
`
`Injury, poisoning and procedural complications/Facial bones fracture
`
`Metabolism and nutrition disorders/Anorexia
`
`Vascular disorders Extremity necrosis
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`I (0.8)
`
`0 (0.o)
`
`I (0.8)
`
`I (0.8)
`
`l (0.8)
`
`I (0.8)
`
`0 (0.0)
`
`I (0.8)
`
`1 (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`2 (1.5)
`
`I (0.8)
`
`0 (0.0)
`
`I (0.8)
`
`I (0.8)
`
`0 (0.0)
`
`0 (0.0)
`
`I (0.8)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`2 (1.5)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`2 (1.5)
`
`I (0.8)
`
`0 (0.0)
`
`I (0.8)
`
`I (0.8)
`
`I (0.8)
`
`invest igations occurring during HC
`system organ c lass
`treatment compared to no cases during MC treatment.
`Three serious adverse events were
`reported: One
`occurred during RC-treatment phase two days after the 51
`h
`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 invest igato r.
`
`Three subjects disconti nued study part ic ipation due to
`adverse events. These
`included coughing, dizziness and
`nausea/s icca symptoms/pain. All events were non-ser ious
`and considered as possi bly related to study med ication .
`
`Page 6 of 8
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`KOIOS Exhibit 1011
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`

`Compariso11 of Two MTX Preji/led Syringes.for S.C /11jectio11 i11 RA
`
`The Ope11 RJ,eumatology Joumal, 2010, Volume 4 21
`
`including
`tolerability
`local
`to overall
`With regard
`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 BC 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.
`
`and
`(haematology
`categories
`laboratory
`all
`For
`biochemistry), mean parameter
`changes were minor
`including those of liver function tests. Except for a mean
`decrease in CRP by 4 mg/I, mean changes were ofno clinical
`relevance.
`
`DISCUSS ION
`
`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 prefilled 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 usab ility showed also
`highly statistically significant differences (P < 0.0001) in
`favour of the 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 with in patient-controlled design was considered the
`most appropriate approach to determine whether the switch
`to the newly available HC treatment has the ability
`to
`increase patient's
`satisfaction
`of
`subcutaneous MTX
`treatment
`compared
`to
`the previously
`available 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 BC 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,
`
`trial in
`multicenter, randomized, double-blind, controlled
`comparison to oral MTX in 384 MTX-naYve patients with
`active RA (5), similar clinical results can be expected for the
`novel HC formulation. Parenteral MTX
`treatment
`is in
`accordance with
`current
`practice
`guidelines which
`recommend to consider a switch to the intramuscular or SC
`route
`in patients with poor compliance,
`inadequate
`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 mg/ml 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 tolerability.
`
`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 HC treatment
`quality and quantity of adverse events did in general not
`differ between the two formulations.
`
`ACKNOWLEDGSMENTS
`
`The authors wish to thank a ll 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-Jilrgens, Berlin; R. Haux ,
`Berlin; P. Kastner, Erfurt; J. Braun, Herne; W. Demary,
`Hildesheim; K. Karberg, Berlin; M. Leidert, Ltineburg; U.
`MUiier-Ladner, Bad Nauheim; H. Schulze-Koops, Milnchen;
`C. Fiehn, Baden-Baden; B. Heilig, Heidelberg; C. Baerwald ,
`Leipzig; M. Fleck, Bad Abbach; J. Kuipers, Bremen; G.
`Gauler, Osnabrtick.
`The authors also wish to thank Sonja Bohm, medac
`GmbH, for her excellent monitoring of the study and Martin
`Bornemann, who provided medical writing support on behalf
`of medac GmbH.
`
`FlNANClAL DlSCLOSURES/CONFLICTS OF INTEREST
`
`UML has received consulting and speaker fees (less than
`I 0.000 USD) from medac GmbH. CGS , UP and AB are
`employees of medac GmbH . All other authors have declared
`no conflicts of interest.
`
`KEY MESSAGES
`
`Patients, physic ians and nursing staff prefer a high(cid:173)
`concentration prefilled syr inge over a medium-concentration
`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.
`
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`22 Tlte Open Rlte111natology Journal, 2010, Volume 4
`
`REF ER ENCES
`
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`
`[2)
`
`(3)
`
`(4]
`
`(5]
`
`Balis FM, Mirro J, Jr, Reaman GH, et al. Phannacokinetics of
`subcutaneous methotrexate. J Clin Oncol 1988; 6: 1882-6.
`Brooks PJ, Spruill WJ, Parish RC, Birchmore DA.
`Phannacokinetics of methotrexate administered by intramuscular
`and subcutaneous injections in patients with rheumatoid arthritis.
`Arthritis Rheum 1990; 33: 91-4.
`Sander 0 , Hilbner G, Rau R. Subcutaneous MTX • a reasonable
`addition of established modes of administration. Z Rheumatol
`1996; 55(Suppl I): 11 I.
`Zackheim HS. Subcutaneous administration ofmethotrexate. J Am
`Acad Denna to I 1992; 26: I 008.
`Braun J, Kastner P, Flaxenberg P, et al. Comparison of the clinical
`efficacy and safety of subcutaneous versus oral administration of
`methotrexate in patients with active rheumatoid arthritis: Results of
`
`(6)
`
`[7]
`
`[8]
`
`(9)
`
`Miiller-Lad11er et al.
`
`a six-month, multicenter, randomized, double-blind, controlled,
`phase IV trial. Arthritis Rheum 2008; 58: 73-81.
`Arnett FC, Edworthy SM, Bloch DA, et al. The American
`Rheumatism Association 1987 revised criteria for the classification
`ofrheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.
`Wollenhaupt J, Alten R, Backhaus M, el al. Recommendations for
`the treatment of rheumatoid arthritis. Results from a German
`consensus conference: Update 2009. Akt R.heumatol 2009; 34: 234-
`9.
`Pavy S, Constantin A, Pham T, el al. Methotrexate therapy for
`rheumatoid arthritis: Clinical practice guidelines based on
`published evidence and expert opinion. Joint Bone Spine 2006; 73:
`388-95.
`IH, Manger B, Fleck M, et al. Evidence-based
`Tamer
`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
`
`© MUiier-Ladner el al.; Licensee Bentham Open.
`This is an open access article licensed under the tenns of the Creative Commons Attribution Non-Commercial License (httpJ/creativecommons.org/licenses/by-nc/
`3.0/) which pennits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
`
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