WI BRE•25F
`v.34 (cid:9)
`NO.4 (cid:9)
`1:995
`C.01 (cid:9)
` SEO: B35530000
`TI: BRITISH JOURNAL OF
`RILE W1ATOLOG Y
`
`Volume
`Number
`
`Editorials:
`Diag
`
`turned
`
`ankylosing
`abstract
`
`Dougados
`spondylitis
`Kingsley
`
`levels
`e oligomeric matrix protein
`T. Saxne,
`of the knee joint M. Sharif,
`Dieppe
`Heinegard and P. A.
`molecule-1
`
`patients
`
`unaltered
`in
`sys emic
`lupus
`
`blood
`peripheral
`Rose,
`L. M.
`
`mononuP ear
`Latchman
`
`Original Spientific
`Papers:
`Fie.lationshiip between
`disease progression in
`L. Shepstone, J. R. Kirwan,
`Le (cid:9)
`s of circulating intercellular
`circa ating endothelial
`with rhematoid
`A. f Zwinderman,
`Sq.-2
`cells in
`and D.
`Interleukin-6
`presence of
`Y. Ohsugi
`Cyy:kine mRNA expression
`with primarySjogreri's syndrome
`H. M. Moutsopoulos
`
`salivary
`labial
`F.
`D. Boumba,
`
`patients
`
`from
`and
`
`Origina
`The therarteutic
`*the antibody
`E. H. S. Choy,
`and G. S. finayl
`
`engineered h man
`rheumatoid arthritis
`Sopwith,
`G. H. ings/e , M.
`
`factor
`
`Isenberg
`
`remissions
`J.if./.
`M.
`
`arthritis patients starting
`placebo-controlled trial
`de
`L. B. A. (cid:9)
`
`Is bridge therapy
`sral gold. AT:iihdomized
`van Gestel, R. F. J. M.
`C. M. (cid:9)
`Riel
`Africans with
`stress proteinstin West
`the 65 kDa mycobacterial
`G. Williams,
`malaria A. 0. Adebajo, D.
`arthlitis, tuberculais and
`and R. N. Magi
`strength
`
`recent-onset
`
`patients
`In
`Hannonen
`lupus
`systemic
`and
`Kausman
`course
`normal plain
`iliopsoas bursae
`enlarged
`O'Connell
`S. Sant; R.
`L Flanagan,
`Ferri,
`Berrettini,
`ulinaemia patients (cid:9)
`mixed cryo. (cid:9)
`Inner ear involvement in
`F. Lombardir17, P. Bruschini, G. Longomb"rdo and
`L La CivilaMgnini,
`S. SellriiFFranceschini
`
`significance
`
`Continued'on inside back cover
`•
`Thi'S ater.0 v.; As copied ..
`:At xhe.14(LM:And rrlayp#
`
`Ex. 1025 - Page 1
`
`(cid:9)
`(cid:9)
`

`

`BRITISH JOURNAL OF RHEUMATOLOGY
`
`Official Journal of the British Society for Rheumatology
`
`Editor
`H. A. Bird
`
`Editorial Assistant
`J. Gilson
`
`Assistant Editors
`D. L. Scott
`King's College Hospital
`London
`
`Editorial Board
`
`M. Bayliss, London, UK
`C. Black, London, UK
`F. Breedveld, Leiden, Netherlands
`F. Brennan, London, UK
`P. Brooks, Darlinghurst, Australia
`H. Capell, Glasgow, UK
`F. Cavalcanti, Pernambuco, Brazil
`M. Cawley, Southampton, UK
`R. Clague, Isle of Man, UK
`P. Davis, Alberta, Canada
`P. Dawes, Stoke -on - Trent, UK
`J-M. Dayer, Geneva, Switzerland
`A. M. Denman, London, UK
`M. Dougados, Paris, France
`
`Ex -officio
`A. Mowat (BSR President)
`
`Editorial Office
`Chapel Allerton ,Hospital
`Chapeltown Road
`Leeds LS7 4SA
`Tel 0113 292 4727 Fax 0113 292 4726
`
`M. Walport
`Hammersmith Hospital
`London
`
`F. Wollheim
`University Hospital of Lund
`Sweden
`
`C. Eastmond, Aberdeen, UK
`P. Emery, Birmingham, UK
`T. Gibson, London, UK
`R. Grahame, London, UK
`I. Griffiths, Newcastle upon Tyne, UK
`D. Haskard, London, UK
`E. Hess, Cincinnati, OH, USA
`M. Hochberg, Baltimore, MD, USA
`D. Isenberg, London, UK
`R. Jubb, Birmingham, UK
`A. Keat, London, UK
`R. N. Maini, London, UK
`G. Mody, Congella, South Africa
`A. Mowat, Oxford, UK
`
`G. Murphy, Cambridge, UK
`G. Panayi, London, UK
`E. Pascual, Alicante, Spain
`J. J. Rasker, Enschede, Netherlands
`P. van Riel, Nijmegen, Netherlands
`Y. Scharf, Haifa, Israel
`D. G. I. Scott, Norwich, UK
`P. Sheldon, Leicester, UK
`A. Silman, Manchester, UK
`J. Smolen, Vienna, Austria
`M. Snaith, Sheffield, UK
`K. Whaley, Leicester, UK
`B. Williams, Cardiff, UK
`P. Woo, London, UK
`
`M. Webley (BSR Honorary Treasurer) D. V. Doyle (BSR Honorary Secretary)
`
`The journal is listed in Current Contents'Life Sciences 'Clinical Practice • Index Medicus • Medline • Excerpta Medica lExcerpta Medica
`EMBASE
`
`SUBSCRIPTIONS
`A subscription to British Journal of Rheumatology comprises 12 issues, with an Annual Author and Subject Index. Subscriptions are
`entered on a calendar year basis only. Prices include air-speeded delivery to Australia, Canada, India, Japan, New Zealand and the USA.
`Delivery elsewhere is by surface post.
`Annual subscription rate (Volume 34, 1995):
`Institutional rate: Europe £190; rest of World, USS335. Subscribers in Europe (EC) please either send details of sales tax (VAT)
`registration/exemption or add local sales tax to the prices quoted. Subscribers in Canada please add 7% GST to the prices quoted.
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`
`© British Society for Rheumatology 1995
`
`All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means,
`electronic, mechanical, photocopying, recording, or otherwise without either the prior written permission of the Publishers, or a licence
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`Special requests, such as copying for general distribution, or for advertising or promotion purposes, should be addressed to the Production
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`
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`
`P- i= 'a7arialwaz
`att- "AVE'3
`
`Ex. 1025 - Page 2
`
`

`

`Volume 34
`Number 4
`April 1995
`
`ritish Journal of
`
`Editorials:
`Diagnostic features of ankylosing spondylitis M. Dougados
`They turned down my abstract again... G. Kingsley
`
`Original Scientific Papers:
`Relationship between serum cartilage oligomeric matrix protein levels and
`disease progression in osteoarthritis of the knee joint M. Sharif, T. Saxne,
`L. Shepstone, J. R. Kirwan, C. J. Elson, D. Heinegird and P. A. Dieppe
`Levels of circulating intercellular adhesion molecule-1 and -3 but not
`circulating endothelial leucocyte adhesion molecule are increased in patients
`with rheumatoid vasculitis A. E. Voskuyl, S. Martin, I. Melchers,
`A. H. Zwinderman, I. Weichselbraun and F. C. Breedveld
`BcL-2 expression is unaltered in unfractionated peripheral blood mononuclear
`cells in patients with systemic lupus erythematosus L. M. Rose, D. S. Latchman
`and D. A. Isenberg
`Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the
`presence of soluble IL-6 receptor M. Mihara, Y. Moriya, T. Kishimoto and
`Y. Ohsugi
`Cytokine mRNA expression in the labial salivary gland tissues from patients
`with primary Sj6gren's syndrome D. Boumba, F. N. Skopouli and
`H. M. Moutsopoulos
`
`Original Clinical Papers:
`The therapeutic effects of an engineered human anti-tumour necrosis factor
`alpha antibody (CDP571) in rheumatoid arthritis E. C. C. Rankin,
`E. H. S. Choy, D. Kassimos, G. H. Kingsley, A. M. Sopwith, D. A. Isenberg
`and G. S. Panayi (cid:9)
`Human leucocyte antigen phenotypes and gold-induced remissions in patients
`with rheumatoid arthritis S. ten Wolde, B. A. C. Dijkmans, J. J. van Rood,
`F. H. J. Claas, R. R. P. de Vries, J. M. W. Hazes, P. L. C. M. van Riel,
`A. van Gestel and F. C. Breedveld (cid:9)
`Oral steroids as bridge therapy in rheumatoid arthritis patients starting with
`parenteral gold. A randomized double-blind placebo-controlled trial
`A. M. van Gestel, R. F. J. M. Laan, C. J. Haagsma, L. B. A. van de Putte and
`P. L. C. M. van Riel (cid:9)
`Antibodies to the 65 kDa mycobacterial stress protein in West Africans with
`rheumatoid arthritis, tuberculosis and malaria A. 0. Adebajo, D. G. Williams,
`B. L. Hazleman and R. N. Maini (cid:9)
`Muscle strength in healthy people and in patients suffering from recent-onset
`inflammatory arthritis A. Hakkinen, P. Hannonen and K. Hfikkinen (cid:9)
`Thyroid autoimmunity in systemic lupus erythematosus: the clinical significance
`of a fluctuating course D. Kausman and D. A. Isenberg (cid:9)
`Symptomatic enlarged iliopsoas bursae in the presence of a normal plain hip
`radiograph F. L. Flanagan, S. Sant, R. J. Coughlan and D. O'Connell (cid:9)
`Inner ear involvement in mixed cryoglobulinaemia patients S. Berrettini, C. Ferri,
`L. La Civita, G. Segnini, F. Lombardini, P. Bruschini, G. Longombardo and
`S. Sellari -Franceschini
`
`301
`303
`
`306
`
`311
`
`316
`
`321
`
`326
`
`334
`
`343
`
`347
`
`352
`
`355
`
`361
`
`365
`
`370
`
`Thiz "EtEeiEN.EZ
`E."
`
`=:t LE
`
`Ex. 1025 - Page 3
`
`

`

`Contents continued
`
`Clinical Practice:
`Assessing clinical competence: recognition of case descriptions of rheumatic
`diseases by general practitioners A. A. M. Blaauw, L. W. T. Schuwirth,
`C. P. M. van der Vleuten, F. Smits and Sj. van der Linden (cid:9)
`Role of prophylactic antibiotics in the prevention of late infection of prosthetic
`joints. Results of a questionnaire and review of the literature H. L. Averns and
`R. Kerry (cid:9)
`
`Case Reports:
`Sulphasalazine-induced lupus in psoriatic arthritis D. J. Veale, M. Ho and
`K. D. Morley (cid:9)
`Steroid myopathy induced by epidural triamcinolone injection S. Boonen,
`G. Van Distel, R. Westhovens and J. Dequeker (cid:9)
`Multiple joint avascular necrosis: beware of tuberculosis and human
`immunodeficiency virus—a rare but important cause N. T. Cheung, J. Saklatvala
`and P. T. Dawes (cid:9)
`
`Letters to the Editor:
`Lyme borreliosis presenting as a polymyalgia rheumatica-like syndrome
`M. Schwartzberg, C. A. Weber and J. Musico (cid:9)
`Musculoskeletal complaints in patients with hyperlipoproteinaemia
`D. J. Careless, M. G. Cohen and F. Lepre (cid:9)
`Antigen specificity of ANCA in systemic vasculitis D. A. Collins and
`B. E. Bourke (cid:9)
`Reply D. G. I. Scott and R. A. Watts (cid:9)
`A further possible cause of diarrhoea caused by oral gold N. J. Cook,
`E. T. Owen and J. B. Donlon (cid:9)
`Staphylococcal arthritis in human immunodeficiency virus infection F. Medina,
`C. Hermida, L. J. Jara, L. Barile, 0. Vera and J. M. Miranda (cid:9)
`Minocycline-related lupus D. Y. Bu/gen (cid:9)
`
`Calendar (cid:9)
`
`Announcements (cid:9)
`
`375
`
`380
`
`383
`
`385
`
`387
`
`392
`
`393
`
`394
`394
`
`395
`
`397
`398
`
`399
`
`399
`
`this mats,121,..
`attKe (cid:9)
`..1a., __
`Subje :t (cid:9)
`LFors.
`
`Ex. 1025 - Page 4
`
`

`

`British Journal of Rheumatology 1995;34:334-342
`
`THE THERAPEUTIC EFFECTS OF AN ENGINEERED HUMAN
`ANTI-TUMOUR NECROSIS FACTOR ALPHA ANTIBODY (CDP571) IN
`RHEUMATOID ARTHRITIS
`E. C. C. RANKIN,* E. H. S. CHOY,t D. KASSIMOS,t G. H. KINGSLEY4 A. M. SOPWITH,§
`D. A. ISENBERG* and G. S. PANAYIt
`tploomsbury Rheumatology Unit, Division of Rheumatology, Department of Medicine University College London,)
`Arthur Stanley House, Tottenhain Street, London W1P 9PG, t Rheumatology Unit, Floor 4, Hunt's House, Guy's
`Hospital, London Bridge, London SE1 9RT, t Lewisham Hospital, Lewisham High Street, London SE13 6LH and
`§Celltech Therapeutics Ltd, 216 Bath Road, Slough SL1 4EN
`
`SUMMARY
`Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFa) have been implicated in the pathogenesis of
`rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that
`neutralizes human TNFa was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA
`(n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open
`continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions
`in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was
`confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal
`in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects
`of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant
`at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active
`RA. In conclusion CDP571, an engineered human anti-TNFa antibody, is well tolerated and, after a single dose of 10 mg/kg,
`provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.\
`
`KEY WORDS: Rheumatoid arthritis, Tumour necrosis factor, Therapeutics, Monoclonal antibody.
`
`RHEUMATOID arthritis (RA) is a systemic inflammatory
`disease of unknown cause characterized by an erosive,
`proliferative synovitis. It is the commonest chronic
`inflammatory disease of the western world with a
`prevalence of 0.5-1.0% [1]. Not only does the joint
`inflammation lead to pain, loss of function, systemic
`ill-health and costly treatments including orthopaedic
`surgery, but the disease also leads to a shortening of life
`expectancy [2]. At present, drug treatment of RA is
`limited by toxicity and/or ineffectiveness with, for
`example, half of all patients who are prescribed one of
`the slow-acting anti-rheumatic drugs (SAARDs) gold,
`penicillamine or hydroxychloroquine discontinuing the
`drug at 2 yr [3]. The precise mechanisms of action of
`this class of drug remains unknown. Thus, there is a
`need for a more effective and less toxic drug therapy
`which has its basis in an improved understanding of the
`pathophysiology of the disease.
`It appears that pro-inflammatory cytokines are
`central in maintaining the inflammatory process [4].
`One candidate for this role in tumour necrosis factor
`alpha (TNFa) since it stimulates fibroblast growth [5],
`collagenase release from synovial cells [6] and induces
`resorption of bone and cartilage [7]. These actions
`could lead in vivo to inflammation and cartilage
`
`Submitted 21 December 1994; revised version accepted 4 January
`1995.
`Correspondence to: D. A. Isenberg, Bloomsbury Rheumatology
`Unit, Arthur Stanley House, Tottenham Street, London WI P 9PG.
`
`destruction. TNFa has therefore become a therapeutic
`target. Attempts have been made to inhibit its activity
`by the parenteral administration of a chimeric anti-
`TNFa antibody in patients with RA [8, 9]. Results
`were encouraging but the initial study [8] was not
`placebo controlled and the subsequent study [9],
`though placebo controlled, had a follow-up period of
`only 4 weeks.
`In this paper we present the findings from the first
`placebo-controlled, dose-finding trial of an engineered
`human anti-TNFa antibody, CDP571, in patients with
`RA. The follow-up period was 8 weeks. In addition, we
`include data from a proportion of patients who sub-
`sequently entered an open phase of the study in which
`a single infusion of CDP571 was administered at 1.0
`and 10 mg/kg.
`
`MATERIALS AND METHODS
`
`Patients
`Thirty-six patients with RA, who satisfied the revised
`1987 criteria of the American College of Rheumatology
`[10], were recruited from the out-patient clinics of the
`Middlesex, Lewisham and Guy's Hospitals, London
`(Table I). The characteristics of the patients entered
`into the study were age 18-72 yr, 10 yr or less since the
`onset of RA, active disease and failure of one or more
`SAARDs due to ineffectiveness or side-effects. Active
`disease was defined as the presence of at least three of
`the following: six or more joints painful to tender on
`motion, three or more swollen joints, 45 min or longer
`of early morning stiffness (EMS) and an erythrocyte
`
`© 1995 British Society for Rheumatology
`
`334
`
`This
`attr•E (cid:9)
`
`E'LL (cid:9)
`
`_ _
`
`Ex. 1025 - Page 5
`
`

`

`RANKIN ET AL.: ANTI-TNFa IN RA (cid:9)
`
`335
`
`TABLE I
`Characteristics of patients with RA
`
`No. of patients
`Sex (male/female)
`Age (mean, yr)
`S.D.
`Duration of RA (mean, yr)
`S.D.
`No. of failed slow-acting drugs (mean)
`Range
`No. of patients on steroids
`
`Placebo
`
`12
`1/11
`51.0
`11.87
`7.5
`2.27
`3.8
`1-6
`0
`
`sedimentation rate (ESR) of 28 mm or more in the
`first hour. A modified disease activity score (DAS)
`was derived for each patient at each time point, as
`follows [11]:
`
`DAS = 0.555V(No. of tender joints)
`+ 0.284V(No. of swollen joints) + 0.7 loge ESR
`+0.0142 (patient's global assessment score).
`
`SAARDs were discontinued for at least 1-month
`before administration of the drug/placebo. Patients
`could remain on stable doses of oral prednisolone
`7.5 mg per day, and doses of non-steroidal anti-
`inflammatory drugs were stabilized. Exclusion criteria
`were pregnancy or lactation, intercurrent infection,
`other serious disease, atopic disposition, surgery in the
`previous 1 month or antibody administration in the
`previous year. The study was approved by the local
`ethics committees and patients gave written informed
`consent. In women of child-bearing age, contraception
`was used and a pregnancy test carried out before
`administration of antibody.
`
`Engineered human antibody
`The antibody CDP571 (Celltech Therapeutics Ltd,
`Slough) is a recombinant antibody in which the short
`hypervariable regions derived from a mouse mono-
`clonal antibody have been grafted into an otherwise
`virtually human immunoglobulin (IgG4, kappa light
`chain). CDP571 neutralizes human TNFa in vitro and
`in vivo. Phase one studies indicated a plasma half-life
`of at least 1 week [12].
`Human serum albumin was chosen as the placebo
`so that the appearances of the placebo and active
`solutions were similar.
`
`Study design
`Patients were initially divided into three dosage
`groups and were studied sequentially. In each group,
`eight patients were randomized to receive CDP571
`and four patients received placebo. Within each centre,
`six patients were assigned to a dosage level and two
`patients at each dosage level were randomly selected to
`receive placebo. Patient groups received 0.1, 1.0 and
`10 mg/kg of CDP571, respectively. Patients and clinical
`assessors were blinded to which patients received active
`
`att
`
`0.1
`
`8
`1/7
`53.2
`13.61
`5.2
`3.68
`2.9
`1-5
`2
`
`CDP571 dose (mg/kg)
`1.0 (cid:9)
`8
`3/5
`56.4
`11.76
`5.6
`2.30
`3.4
`1-7
`1
`
`10.0
`8
`0/8
`53.3
`15.34
`5.5
`3.38
`3.9
`1-6
`1
`
`drug or placebo. The treatment was given as a single
`intravenous infusion over 1 h, with measurement of
`vital signs half-hourly during treatment and hourly for
`2 h after treatment. Patients who had not experienced
`any untoward effects in the placebo-controlled part of
`the trial were invited to enter a continuation phase.
`This phase was open and patients received either 1.0 or
`10 mg/kg. The time interval between completion of the
`placebo-controlled phase of the trial and the adminis-
`tration of the second infusion ranged from 5 to 28 days
`(mean 9 days). After each infusion, patients were
`followed for 8 weeks.
`Disease activity was measured using the European
`League Against Rheumatism core criteria for disease
`assessment [11]. In brief, these included the duration
`of EMS, visual analogue scales of pain (10 cm) and
`of the patient's global assessment of disease activity
`(expressed as a ratio), the number of tender and
`swollen joints (maximum 28) and ESR and C-reactive
`protein (CRP). The method of assessment was stand-
`ardized between assessors before the trial. Patients were
`assessed 1-3 weeks before administration of the first
`infusion and at weeks 0, 1, 2, 4 and 8 after each
`infusion. Urinalysis was performed at each visit and
`other measurements included full blood count, pro-
`thrombin time, activated partial thromboplastin time,
`renal and liver function tests.
`
`Statistical analysis
`The first placebo-controlled phase was an explora-
`tory dose-finding study. No formal sample size calcu-
`lations were performed and sample size was based on
`clinical judgement. The analysis was based on an intent
`to treat population, defined as all patients who received
`the study medication and who had post-baseline evalu-
`ations. All patients received the medication to which
`they were randomly allocated. At each timepoint, the
`Kruskal—Wallis test was used to compare the median
`changes from pre-infusion between the four groups for
`the parameters measured. If this overall test showed
`significant or borderline significant differences between
`the groups, then the Mann—Whitney U test was used to
`compare the median changes from pre-infusion in each
`CDP571 group to the placebo group and only these
`results are presented. The Bonferroni method was used
`to adjust the P-values to take into account the multiple
`comparisons.
`
`Ex. 1025 - Page 6
`
`

`

`336 (cid:9)
`
`BRITISH JOURNAL OF RHEUMATOLOGY VOL. 34 NO. 4
`
`RESULTS
`The maximum response to CDP571 was seen in
`those patients who received 10 mg/kg. Median absolute
`values for the pain and patient global assessment of
`disease activity visual analogue scales, tender joints,
`swollen joints, CRP and DAS in the placebo, 1 and
`10 mg/kg groups are shown in Table II.
`In all patients receiving CDP571 there was a fall in
`the pain scale at week 1 which was dose related (Fig. 1).
`After 10 mg/kg CDP571, the pain score was reduced
`by a maximum of 40% by 2 weeks, with evidence
`of improvement still present at 8 weeks (Fig. 1). At
`week 2, the 10 mg/kg CDP571 group had significantly
`less pain {median change from pre-infusion -2.6 cm
`[interquartile (IQ) range -5.4 to -0.85 cm]} com-
`pared to the placebo group [median change 0.95 cm
`(IQ -0.6-1.75 cm)], P = 0.024 adjusted. The improve-
`ment in pain scale values was paralleled by the tender
`joint count which was markedly reduced at week 1 in
`patients who received 1.0 and 10 mg/kg (Fig. 2). After
`10 mg/kg CDP571 the median tender joint score was
`reduced from 16.5 to between 10 and 11 at weeks 1-4;
`and by week 8 the median score was still reduced at
`12 joints. The 10 mg/kg CDP571 group had signifi-
`cantly fewer tender joints at 2 weeks [median change
`from pre-infusion -4.0 (IQ range -11.5 to -1.0)]
`compared to the placebo group [median change 0.5
`(IQ range - 1.0-2.5)], P = 0.048 adjusted (Fig. 2).
`On the visual analogue scale of patient global
`assessment of disease activity, patients in the placebo
`group documented little change. The median score
`after 1 week in the 1.0 mg/kg group was 0.36 (IQ range
`0.18-0.79) and in the 10 mg/kg group was 0.28
`(IQ range 0.31-0.79) compared to 0.90 (IQ range
`0.62-1.0) in the placebo group (P = 0.099 and 0.153,
`respectively).
`The median number of swollen joints in the 10 mg/kg
`dosage group was reduced by between two and five
`joints for up to 4 weeks (Fig. 3), but there were no
`statistically significant differences between the groups
`at any of the visits.
`Of the changes in laboratory parameters, the fall in
`CRP was the most marked. At doses of 1.0 and
`10 mg/kg, median CRP concentrations were reduced
`at week 1 to virtually within the normal range
`(0-12 mg/1). These reductions in CRP appeared to be
`sustained for up to 8 weeks in the 10 mg/kg group
`(Fig. 4). The median change in the 10 mg/kg group was
`- 37.5 mg/1 (IQ range - 66.5 to - 20 mg/1) at week 1
`compared to - 3.5 mg/1 (IQ range - 20-2 mg/1) in the
`placebo group and this difference was of borderline
`significance (P = 0.057, adjusted). After 2 weeks the
`median change was - 37.5 mg/1 (IQ range - 64.5 to
`- 25 mg/1) in the 10 mg/kg group compared to
`-9.0 mg/1 (IQ range -27-4.5 mg/1) in the placebo
`group (P = 0.093, adjusted). In the 1.0 and 10 mg/kg
`groups, median ESR values were reduced at week 1 and
`the fall was sustained for 0-8 weeks. In the 10 mg/kg
`group the fall in ESR [median change - 19 mm/h
`(IQ range - 30.5 to - 6 mm/h)] was statistically signifi-
`
`cant at week 2 (P = 0.015) when compared to the
`placebo group [median change 1 mm/h (IQ range
`- 5-8 mm/h)]: the median absolute values were 6.5 and
`75 mm/h for the placebo group and 76.5 and 39 mm/h
`for the 10 mg/kg group pre-infusion and 2 weeks
`post-infusion, respectively.
`There was a fall in the platelet count, another marker
`of RA disease activity, in patients who received the
`active drug. This was a trend and was not statistically
`significant. No patient became thrombocytopenic
`( < 150 x 109/1).
`The patients' reports of duration of EMS were the
`most scattered of the variables, and varied most widely
`from visit to visit. No clear trends to treatment effect
`could be discerned although proportionately the great-
`est changes seen after study medication occurred after
`1 and 2 weeks in the 10 mg/kg dosage group.
`The median change in DAS in the placebo group at
`2 weeks was 0.05 (IQ range -0.139-0.239) and the
`10 mg/kg group was -0.45 (IQ range -1.752 to
`-0.167). This reduction in the treated group was
`significant (P = 0.015, adjusted).
`There were 59 adverse events, 24 of which occurred
`in the placebo group. Six of the 24 in the placebo group
`and 2 of the 28 in the 0.1 and 1.0 mg/kg groups were
`classified as severe and involved worsening of disease.
`No worsening of RA was reported in the patients who
`received 10 mg/kg CDP571. The single serious adverse
`event, worsening RA requiring admission to hospital,
`occurred in a patient who had received placebo. Two
`patients withdrew from the study because of disease
`progression; one had received placebo and one had
`received 1.0 mg/kg CDP57 I . Skin rashes and infusion
`site reactions were as frequent in placebo-treated
`patients as in those who received CDP571. There was
`no change in vital signs during or after the infusion.
`One patient who received 10 mg/kg felt dizzy and
`unwell toward the end of the first infusion, but was able
`to complete the infusion. There was no increase in
`allergic events in the treatment groups compared to the
`placebo group, although one patient with a history of
`drug rashes and who received 1.0 mg/kg developed a
`rash during the infusion. This patient was not allowed
`to enter the continuation phase. Urinalysis and
`measurement of routine haematological and bio-
`chemical variables showed no untoward change in any
`group.
`The continuation phase of the trial was not double
`blind. Thirty of the initial 36 patients entered and 22
`completed the continuation phase. Eight patients there-
`fore withdrew from this phase; two had received
`10 mg/kg and six had received 1.0 mg/kg. All eight
`withdrew because of disease progression.
`The data were pooled for the continuation phase into
`two group, those who received either 1.0 or 10 mg/kg
`(Table III). The data must be interpreted in the
`knowledge of the lack of a placebo group, the different
`doses of CDP571 given to the patients in the
`placebo-controlled phase of the trial and the smaller
`numbers of patients in the continuation phase of the
`trial compounded by patient withdrawal during the
`
`Ex. 1025 - Page 7
`
`

`

`TABLE II
`Absolute values (median and range) of the pain and relief of symptoms visual analogue scales, numbers of tender and swollen joints, CRP and DAS during double-blind phase
`Placebo
`1 mg/kg group
`10 mg/kg group
`Symptom
`Symptom
`Symptom
`CRP
`CRP
`CRP
`relief
`Tender Swollen
`relief
`Tender Swollen
`relief
`Pain
`Tender Swollen
`Pain
`DAS
`(mg/1)
`(mg/1)
`(ratio)
`DAS N
`(mg/1)
`DAS Nt
`joints (cid:9)
`joints
`(ratio)
`joints (cid:9)
`joints
`(ratio)
`joints (cid:9)
`joints
`(cm)
`(cm)
`(cm)Pain
`5.8
`8
`6.5
`6.0
`8
`12.5
`17.5
`16.0
`15.0 - 37.0
`16.5
`16.5 - 50.5
`5.5
`8.4
`80.0
`6.2
`(3-118) (4.5-7.4)
`(6-142) (4.7-7.5)
`(3.2-8.0) (7-28) (7-24)
`(4.1-8.3) (3-28) (6-22)
`(13-116) (4.6-7.0)
`(2.9-9.9) (10-28) (8-25)
`0.28
`0.36
`16.5
`10.5
`5.8
`4.3
`11.0
`11.5
`11.0
`5.3
`68.5
`5.8
`0.90
`5.7
`13.0
`17.0
`4.2
`17.0
`(0.6-9.7) (3-28) (7-25) (0.08-1)
`(2-22)
`(4.2-7.5)
`(1.7-7.8) (7-28) (5-25) (0.35-1) (4-135) (4.2-7.6)
`(1.6-6.3) (0-24) (7-20) (0.16-1)
`(2-61) (3.4-6.8)
`12.5
`4.7
`16.0
`0.69
`12.5
`11.0
`11.5
`0.29
`7.9
`14.5
`16.0
`0.96
`59.0
`6.2
`5.0
`14.0
`5.7
`3.6
`(0.9-9.9) (3-28) (10 -25) (0.07-1)
`(1-30)
`(4.0-7.3)
`(2.0 -8.3) (0 -27) (1 0 -23) (0.27-1)
`(3-62)
`(2.7-7.1)
`(0.8-9.5) (9-28) (7-25) (0.46-1) (2-104) (4.5-7.5)
`6.0
`5.7
`10.0
`14.0
`0.75
`19.0
`5.1
`20.0
`0.97
`55.0
`6.3
`7.8
`15.0
`17.0
`0.92
`41.0
`5.5
`16.0
`(0.2-9.9) (2-28) (6-25) (0.04-1)
`(1-30)
`(4.1-7.6)
`(1.4-8.6) (1-21) (2-24) (0.20 -1) (4 -128) (2.6-6.9)
`(1.4-9.1) (4 -28) (0 -26) (0.29-1) (3-118) (3.2-7.6)
`0.78
`27.5
`5.7
`6.2
`8.3
`13.0
`17.0
`0.90
`37.0
`5.7
`7.2
`12.0
`14.5
`8.5
`20.0
`19.0
`0.99
`31.0
`(1-47) (4.0-7.6)
`(6.6-9.7) (4-26) (6-23) (0.37-1) (11-152) (4.7-7.2)
`(0.6-9.5) (2-28) (8-24) (0.05-1)
`(2-115) (3.0-7.6)
`(0-9.9)
`(2-28) (2-25)
`(0-1)
`*CRP was based on 12 patients at all the timepoints for the placebo group.
`fDAS was based on seven patients at week 8 for the 10 mg/kg group.
`
`Week 1
`
`Week 2
`
`Week 4
`
`Week 8
`
`° 31\11-IINV :7J/ i? NDINIVII
`
`VII NI 7
`
`12
`
`12
`
`11
`
`11
`
`8
`
`8
`
`7
`
`7
`
`8
`
`8
`
`8
`
`8
`
`Visit
`N*
`Pre-infusion 12
`
`Ex. 1025 - Page 8
`
`

`

`338 (cid:9)
`
`BRITISH JOURNAL OF RHEUMATOLOGY VOL. 34 NO. 4
`
`5.5 -
`
`4.5
`
`3.5
`
`2.5
`
`1.5
`
`0.5
`
`E
`
`(1) -0.5
`
`-1.5
`
`- 2.5
`
`- 3.5
`
`- 4.5
`
`
`
`-5.5 (cid:9)
`P e-
`infusion
`
`2
`
`TIME SINCE THE START OF INFUSION (weeks)
`
`8
`
`FIG. 1.—Changes from pre-infusion in visual analogue scale of pain (cm). Medians and interquartile ranges are presented for treatment and
`placebo groups. Key to figure: q placebo; A 0.1 mg/kg CDP571; 0 1 mg/kg CDP571; x 10 mg/kg CDP571.
`
`13
`
`11
`
`9
`
`7
`
`5 -
`
`3
`
`- 3
`
`- 5
`
`- 9 -
`
`TENDER JOINTS
`
`Pre- (cid:9)
`infusion
`
`1 (cid:9)
`
`2 (cid:9)
`
`4
`
`8
`
`TIME SINCE THE START OF INFUSION (weeks)
`
`FIG. 2.—Changes from pre-infusion in number of tender joints. Medians and interquartile ranges arc presented for treatment and placebo groups.
`Key to figure: q placebo; A 0.1 mg/kg CDP571; 0 1 mg/kg CDP571; x 10 mg/kg CDP571.
`
`This .-nat'iEl
`att-.E (cid:9)
`
`_
`
`Ex. 1025 - Page 9
`
`(cid:9)
`

`

`RANKIN ET AL.: ANTI-TNFtx IN RA (cid:9)
`
`339
`
`•
`
`---------------------
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`-2
`
`-4
`
`- 6
`
`- 8
`
`SWOLLEN JOINTS
`
`
`
`10 (cid:9)
`P e- (cid:9)
`infusion
`
`1 (cid:9)
`
`2
`
`TIME SINCE THE START OF INFUSION (weeks)
`
`FIG. 3.—Changes from pre-infusion in number of swollen joints. Medians and interquartile ranges are presented for treatment and placebo
`groups. Key to figure: E] placebo; Q 0.1 mg/kg CDP571; 0 1 mg/kg CDP571; x 10 mg/kg CDP57I.
`
`50
`
`30
`
`10
`
`-
`rn
`E
`z
`
`
`Ce- -10
`0
`
`tr
`I -30
`
`- 50
`
`- 70 (cid:9)
`P e- (cid:9)
`infusion
`
`1 (cid:9)
`
`2
`
`
`
`TIME SINCE THE START OF INFUSION (weeks)
`
`FIG. 4.---Changes from pre-infusion in CRP values (mg/1). Medians and interquartile ranges are presented for treatment and placebo groups.
`Key to figure: q placebo; Q 0.1 mg/kg CDP571; 0 1 mg/kg CDP571; x 10 mg/kg CDP571.
`
`This .-nat'iEl
`att-.E (cid:9)
`
`_
`
`Ex. 1025 - Page 10
`
`

`

`BRITISH JOURNAL OF RHEUMATOLOGY VOL. 34 NO. 4
`
`TABLE III
`Absolute values (median and range) of the pain and relief of symptoms visual analogue scales, numbers of tender and swollen joints, CRP and DAS during the continuation
`phase
`
`Visit
`Pre-infusion
`
`N*
`17
`
`1 mg/kg group
`Symptom
`relief
`(ratio)
`
`Nt
`12
`
`12
`
`12
`
`12
`
`12
`
`10 mg/kg group
`Symptom
`relief
`(ratio)
`
`Tender
`Pain
`Swollen
`joints
`(cm)
`joints
`7.60
`19.5
`20.0
`(3-24)
`(4-28)
`(0.5-9.7)
`14.0
`7.0
`3.15
`0.29
`(1-28)
`(0.0-7.5)
`(2-22)
`(0.02-1)
`2.15
`6.5
`0.14
`13.5
`(2-28)
`(0.2-9.1)
`(5-24)
`(0.02-1)
`1.65
`13.0
`4.0
`0.14
`(3-23)
`(0 -28)
`(0.4-9.8)
`(0.01-1)
`7.20
`11.0
`0.88
`19.5
`(0-28)
`(0.2-9.9)
`(0-25)
`(0.01-1)
`on 15 patients at week I for the 1 mg/kg group.
`for the 10 mg/kg group.
`
`CRP
`(mg/1)
`40.0
`(2-120)
`5.0
`(1-125)
`11.5
`(1-107)
`13.5
`(1-192)
`44.5
`(2-111)
`
`DAS
`6.4
`(3.8-7.6)
`5.1
`(3.0-7.2)
`5.0
`(3.5-7.6)
`4.9
`(3.0-7.6)
`5.8
`(2.8-7.4)
`
`Pain
`Tender
`Swollen
`CRP
`(cm)
`joints
`joints
`(mg/I)
`DAS
`8.3
`13.0
`18.0
`6.2
`48.0
`(0.8-9.8)
`(2-28)
`