OW'
`
`WiNgfir"".
`
`NIA? 2001 Voiume 120 • Number 6
`
`astro
`
`•
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`e 7fl (cid:9)
`
`I
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`•
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`It
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`lo
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`,
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`•••••••••••ft
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`.
`
`L iv con'
`ivied tf.).-p (cid:9)
`L Car iac K+ Channel-KCNQ1 and
`Gastric Acid Secretion-
`
`UC
`
`I
`
`MDR3 and Cholestatic Disorders
`Fe Transajorters, Iros Deficiency,
`and IrorMverload
`
`I
`
`Ex. 1023 - Page 1
`
`

`

`Gastroenterology (cid:9)
`
`Official Journal of the American Gastroenterological Association
`
`
`
`Editor
`Daniel K. Podolsky
`Massachusetts General Hospital
`Boston, Massachusetts
`
`Senior
`Associate Editor
`J. Thomas Lalsioni
`Beth Israel Deaconess
`Medical Center
`Boston, Massachusetts
`
`Richard S. Blumberg
`Brigham & Women's Hospital
`Boston, Massachusetts
`Michael Camilleri
`Mayo Clinic
`Rochester, Minnesota
`Jules L. Dienstag
`Massachusetts General Hospital
`Boston, Massachusetts
`Fred S. Gorelick
`West Haven VA Medical Center
`West Haven, Connecticut
`Neil Kaplowitz
`USC School of Medicine
`Los Angeles, California
`
`Associate Editors
`
`T. Jake Liang
`National Institutes of Health
`Bethesda, Maryland
`Jeffrey B. Matthews
`Beth Israel Deaconess Medical Center
`Boston, Massachusetts
`Ann Ouyang
`Penn State College of Medicine
`Hershey, Pennsylvania
`Anil K. Rustgi
`University of Pennsylvania
`School of Medicine
`Philadelphia, Pennsylvania
`
`Editorial Staff
`
`ikoorali
`Nrkoleta Dineen. Snout ,gansimpt Caninfave
`Gilbert Ebner, Ssnive Mansampt Co/4mm
`Thoba Khumalo..‘1,0manpr Coordinator
`Eon Loughran, Al.pociarpr Gaiiarrop
`Axel Morales, hisnusurrpt
`Leah Passfield, Motrurrim iV'afihdligf
`fibanna Karugiannis, EditertaI Assistant
`
`:area
`
`Guido N. J. Tyrgat
`Academic Medical Center
`Amsterdam, The Netherlands
`Timothy C. Wang
`University of Massachusetts Media.
`\Von:ester. Massa( huserts
`Associate Editor for Nutrition
`Samuel Klein
`Washington Universiry School of Medicine
`Sr Louis. Missouri
`Consulting Biostatisticians
`Entiti join' Oras
`Boston, Massachusetts
`YuChiao Chang
`Boston, Massachusetts
`
`This Month in Karen E. Kim
`GASTROENTEROLOGY Chicago, Illinois
`
`Image of the Month Sanjiv Chopra
`Boston, Massachusetts
`
`Special Section Editors
`vtcrylog) And K. Rusrgi
`Naci Philadelphia, Pennsylvania
`Print and Media Review Lawrence S. Friedmil .
`Boston, Massachusetts
`
`Selected Summaries Henry J. Binder (cid:9)
`New Haven, Connecticut
`Editorial Board
`
`Nezham Afdhal, Boston, Massachusen.
`Guido Adler, Ulm, Germany
`James M. Anderson, New Haven, Cannes Lll llr
`John Baillie, Durham, North Carolina
`Laurence M. Blendis, Tel Aviv, Israel
`Robert S. Bresalier, Detroit, Michigan
`Markus W. Biichler, Bern, Switzerland
`Alan Charney, New York, New York
`Tsutomu Chiba, Kyoto, Japan
`Ray E. Clouse, St. Louis, Missouri
`Stephen Collins, Hamilton, Ontario, Canada
`Fabio Cominelli, Charlottesville, Virginia
`Nicholas Davidson, St. Louis, Missouri
`Joanne Donovan, Boston, Massachusetts
`Douglas A. Drossman, Chapel Hill, North Carolina
`J. Greg Fitz, Denver, Colorado
`Eileen Friedman, Syracuse, New York
`Richard Grand, Boston, Massachusetts
`Peter C. Hayes, Edinburgh, Scotland, United Kindgom
`Gail Hecht, Chicago, Illinois
`Toshifumi Hibi, Tokyo, Japan
`Jay H. Hoofnagle, Bethesda, Maryland
`Stephen P. James, Bethesda, Maryland
`Richard A. Kozarek, Seattle, Washington
`Officers of the American Gastroenterological Association
`President Jon I. Isenberg (cid:9)
`San Diego, California
`Vice President Martin Brotman
`San Francisco, California
`
`Strraary Joanne A. P. Wilson
`Trearorer Mark S. McPhee
`Durham, North Carolina
`Kansas City, Missouri
`Published by W. 9. Saunders Company. The Curtis Center. Independence Square West. Philadelphia, Pennsylvania 19106-3399
`
`Ernst J. Kuipers, Rotterdam, The Netherlands
`Nicholas F. LaRusso, Rochester, Minnesota
`Didier Lebrec, Clichy, France
`Adrian Lee, Sydney, Australia
`Daniel Louvard, Paris, France
`James L. Madara, Atlanta, Georgia
`Gabriel Makhlouf, Richmond, Virginia
`Peter Malferrheiner, Magdeburg, Germany
`Emeran A. Mayer, Los Angeles, California
`Juanita Merchant, Ann Arbor, Michigan
`Howard Mertz, Nashville, Tennessee
`Kunio Okuda, Chiba, Japan
`Henry P. Parkman, Philadelphia, Pennsylvania
`Charalabos Pothoulakis, Boston, Massachusetts
`Lawrie W. Powell, Brisbane, Australia
`Linda Rabeneck, Houston, Texas
`Daniel Rachmilewitz, Jerusalem, Israel
`Robert Riddell, Hamilton, Ontario, Canada
`Nobuhiro Saro, Tokyo, Japan
`Jurgen Scholmerich, Regensburg, Germany
`Lloyd R. Sutherland, Calgary, Alberta, Canada
`Jan Tack, Leuven, Belgium
`Peter G. Traber, Philadelphia, Pennsylvania
`
`President-Elect Vacant
`
`Ex. 1023 - Page 2
`
`

`

`GASTROENTEROLOGY 2001:120'1330-1338
`
`An Engineered Human Antibody to TNF (CDP571) for
`Active Crohn's Disease: A Randomized Double-blind
`Placebo-Controlled Trial
`
`WILLIAM J. SANDBORN,* BRIAN G. FEAGAN,' STEPHEN B. HANAUER,§ DANIEL H. PRESENT,'
`LLOYD R. SUTHERLAND,411 MICHAEL A. KAMM," DOUGLAS C. WOLF,** JEFFREY P. BAKER,“
`CHRISTOPHER HAWKEY,§t ANDRE ARCHAMBAULT, CHARLES N. BERNSTEIN,Il
`CLAIRE NOVAK,## PATRICIA K. HEATH," and STEPHAN R. TARGAN***
`for the CDP571 CROHN'S DISEASE STUDY GROUP
`*Mayo Clinic, Rochester. Minnesota: qJniversity of Western Ontario, London, Ontario, Canada; tUniverslty of Chicago. Chicago. Illinois:
`lMount Sinai School of Medicine. New York, New York; 1University of Calgary, Calgary, Alberta, Canada; 'St. Marks Hospital. London.
`England; **Atlanta Gastroenterology Associates, Atlanta, Georgia; "University of Toronto, Toronto, Ontario, Canada; ssUniversity Hospital.
`Nottingham, England; I lUniversity of Montreal, Montreal, Quebec, Canada; IlUniversity of Manitoba. Winnipeg, Manitoba. Canada;
`"Celltech Therapeutics Ltd., Slough, England; and ***Cedars Sinai Medical Center. Los Angeles. California
`
`Background & Aims: We evaluated CDP571, a human-
`ized antibody to tumor necrosis factor, for the treatment
`of active Crohn's disease. Methods: One hundred sixty-
`nine patients with moderate-to-severe Crohn's disease
`were enrolled in a 24-week placebo-controlled trial. Pa-
`tients were initially randomized to a single dose of 10 or
`20 mg/kg CDP571 or placebo to assess dose response.
`Patients were then retreated with 10 mg/kg CDP571 or
`placebo every 8 or 12 weeks to assess subsequent
`dosing intervals. The primary endpoint was clinical re-
`sponse at week 2, defined as a decrease in the Crohn's
`70 points. Results: At
`Disease Activity Index score (cid:9)
`week 2. clinical response occurred in 45% of CDP571-
`treated patients compared with 27% of patients in the
`placebo group (P = 0.023). Patients appeared to benefit
`from retreatment with CDP571 over 24 weeks, but not
`all of the results for secondary endpoints were statisti-
`cally significant. The frequency of severe or serious ad-
`verse events was similar among all groups. Conclusions:
`CDP571 at an initial dose of 10 or 20 mg/kg is safe and
`effective for treatment of patients with moderate-to-
`severe Crohn's disease. Preliminary evidence suggests
`that retreatment with 10 mg/kg CDP571 at dose inter-
`vals of 8 or 12 weeks may also be beneficial, but
`additional studies are needed.
`
`Tumor necrosis factor (TNF)-oz concentration is
`in-
`_IL (cid:9)
`creased in the serum, intestinal tissue, and stool of
`patients with Crohn's disease'-3 and plays a pivotal role
`in the disease pathogenesis.4.' The mouse/human chi-
`meric monoclonal antibody to TNF-ct, intliximab, is
`effective for short-term treatment of patients with mod-
`erately to severely active Crohn's disease or draining
`
`enterocutaneOuS fistulas,' and preliminary data Suggest
`sustained benefit with retreatment every 8 weeks." How-
`ever, iniliximab therapy has been associated with adverse
`events including formation of human antichirneric anti-
`bodies, infusion reactions, delayed hypersensitivity reac-
`tions, and formation of anti-DNA antibodies leading in
`some cases to drug-induced lupus.'-"
`Protein engineering techniques have been used to
`decrease the amount of murine protein in monoclonal
`antibodies. In one process, the antigen-binding regions
`(complementarity-determining regions, or CDRs) of the
`murine variable domain are transplanted to a human
`antibody." The resulting "humanized" monoclonal anti-
`body (-95% human residues) is potentially less immu-
`nogenic than chimeric antibodies. A humanized moan-
`clonal antibody to human TNF-a, CDP571, was
`constructed by linking the CDR of a mouse anti-human
`TNF monoclonal antibody to a human immunog lobnlin
`(Ig) G4 antibody.'" A placebo-controlled trial of a single
`infusion of CDP571 at a dose of 5 mg/kg in 30 patients
`with mildly to severely active Crohn's disease refractory
`to medical therapy demonstrated a beneficial effect on
`disease activity in a short-term trial." Based on These
`results, we conducted a 24-week trial in which patients
`with active Crohn's disease received a single dose of i()
`
`Abbreviations used in this paper. CDAI. Cronrfs Disease Acii°'
`tory
`Index; CDR. complimentarity-determining region: IBDQ, Inflamma
`Bowel Disease Questionnaire: IV. intravenous; TNF. tumor riecr°66
`tactor.
`
`2001 by the American Gastroenterological Association
`0016-5085/01/$35.00
`doi:10.1053/gast.2001.24042
`
`Ex. 1023 - Page 3
`
`

`

`May 2001
`
`CDP571 FOR CROWS DISEASE 1331
`
`mg/kg CDP571, 20 mg/kg CDP517, or placebo to assess
`the dose response, followed by retreatment with 10
`mg/kg CDP571 or placebo every 8 or 12 weeks to assess
`subsequent dosing intervals.
`
`Materials and Methods
`
`Selection of Patients
`
`The study was performed between June 1998 and June
`1999. Eligible patients were at least 18 years of age and had
`moderately to severely active Crohn'S disease, as defined by a
`score of 220-450 on the Crohn's Disease Activity Index
`(CDAI).' 2
`Eligible patients had Crohn's disease confirmed by radio-
`logic, endoscopic, or histologic criteria. The following patients
`were not eligible: those with an ileostomy or colostomy; those
`with a serious intercurrent infection or other clinically impor-
`tant active diseases (such a renal or hepatic disease); those with
`bowel perforation, fixed stenosis at endoscopy or by radio-
`graphic study within 6 months, or obstructive symptoms
`within 3 months (unless imaging studies showed the absence
`of significant mechanical obstruction); and those who had
`undergone resection of more than 100 cm of the small bowel
`and/or more than the right side of the colon. Patients with a
`history of cancer other than cervical dysplasia or basal cell
`carcinoma within 5 years, dysplasia of the colon within 5 years,
`or clinically significant hematologic or biochemical values
`were also ineligible, as were pregnant or breast-feeding
`women, patients with multiple drug allergies, and patients
`with a positive stool culture for enteric pathogens, recent drug
`or alcohol abuse, and known hepatitis or human immunode-
`ficiency virus. The institutional review board at each center
`approved the study, and all participants gave written informed
`consent.
`
`Concomitant Medications
`
`Patients who had previously received anti-TNF thera-
`pies were ineligible. No patient received other antibodies or
`cytokines within 3 months or immune modifier drugs (except
`as specified below) or antibiotics within 1 month preceding
`randomization. Patients receiving prednisone or budesonide
`for a least 4 weeks with a stable prednisone dose of 10-30
`mgiday or a budesonide dose of 9 mg for at least 2 weeks were
`eligible, whereas patients treated with parenteral corticoste-
`raids or corticotrophin within 4 weeks and those in whom
`torticosteroid treatment was discontinued within 2 weeks were
`not eligible. Patients receiving stable doses of azathioprine (at
`least 1.5 mg • kg-' • day-l) or 6-mercaptopurine (at least 0.75
`mg ' kg-' • day -') for at least 4 months, or methotrexate (at
`least 15 mg/week) for at least 3 months, were eligible, whereas
`iPaattelse:s who discontinued these medications within 1 month
`were not eligible. Continued treatment with 5-aminosalicy-
`as allowed provided the dose had been stable for at least
`3 months.
`
`IL
`
`Study Medication
`
`Pharmacists at each center prepared the intravenous
`(IV) infusions (CDP571 or placebo). Placebo was 5% (wc/vol)
`dextrose. CDP571 at a dose of 10 or 20 mg/kg body wt or
`placebo was administered to patients as a 2-hour IV infusion
`using a 0.2-µm filter. Both CDP571 and placebo had a similar
`clear and colorless appearance.
`
`Study Design
`
`The 24-week study was a randomized, double-blind,
`placebo-controlled trial performed at 21 centers in the United
`States, Canada, and Great Britain. The study was designed to
`initially assess the dose response for CDP571 at doses of 10 and
`20 mg/kg, and subsequently to assess the retreatment dose
`intervals of 8 and 12 weeks at a CDP571 dose of 10 mg/kg.
`Patients were stratified according to concomitant treatment
`with corticosteroids and/or azathioprine, 6-mercaptopurine, or
`methocrexate or no concomitant treatment. After stratification,
`patients were randomized separately to 1 of 6 treatment groups
`(Figure 1). It was planned that patients randomized to 8 or 12
`weekly dosing would be pooled by dose into 3 groups (placebo,
`10 mg/kg CDP571, and 20 mg/kg CDP571) for assessment of
`the primary outcome measure at week 2. Subsequently, it was
`planned that patients randomized to placebo, 10 mg/kg
`CDP571, or 20 mg/kg CDP571 dosing would be pooled by
`dose interval into 4 groups (placebo 8 weekly, 10 mg/kg
`CDP571 8 weekly, placebo 12 weekly, and 10 mg/kg CDP571
`12 weekly) for assessment of secondary outcome measures
`during retreatment. An unblinded statistician using a com-
`puter-generated randomization scheme performed the random-
`ization centrally.
`At entry, each patient's demographic characteristics, medi-
`cal history, and current medications were recorded. Disease
`activity was assessed at the baseline visit and after 2, 4, 8, 10,
`16, 18, and 24 weeks in the 8 weekly dosing group or 2, 4, 8,
`12, 14, 20, and 24 weeks in the 12 weekly dosing group.
`Patients recorded on diary cards the frequency of loose stools,
`the extent of their abdominal pain, and general well-being
`during the 7 days before each visit. At each visit, a physical
`examination, fistula evaluation, quality-of-life assessment, lab-
`oratory tests, and a global evaluation were conducted and
`patients were asked whether any adverse events had occurred.
`No medications for Crohn's disease other than the study drug,
`antidiarrheals (loperamide, diphenoxylate, opiates), and stable
`doses of prednisone, budesonide, azathioprine, 6-mercaptopu-
`rine, methotrexate, and 5-aminosalicylates were allowed.
`Patients were assessed at each visit for the presence of
`perianal or enterocutaneous fistulas (defined as either sponta-
`neous drainage or the ability to express drainage with gentle
`compression).' Fistula closure was defined as the absence of
`drainage with gentle compression. Quality of life was assessed
`with the self-administered Inflammatory Bowel Disease Ques-
`tionnaire (IBDQ), a previously validated instrument with 4
`parts (bowel function, emotional status, systemic symptoms,
`and social function).';
`
`Ex. 1023 - Page 4
`
`

`

`1332 5ANDSORN ET AL.
`
`GASTROENTEROLOGY Vol. 120. No. 6
`
`Weeks (cid:9)
`
`0
`
`2 (cid:9)
`
`4 (cid:9)
`
`8 (cid:9)
`
`8-Week Repeat Dosing
`18
`16 (cid:9)
`10 (cid:9)
`
`Treatment groups (cid:9)
`1. Active (CDP571) (cid:9)
`2. Active (CDP571) (cid:9)
`5. Placebo (cid:9)
`
`Weeks-2 or -1
`
`First dose
`20 mg/kg
`10 mg/kg
`Placebo
`
`Second dose
`10 mg/kg
`10 mg/kg
`Placebo
`
`Third dose
`10 mg/kg
`10 mg/kg
`Placebo
`
`24
`
`Final
`assessment
`
`Screen
`Patients stratified
`(± steroidslazathioprinel
`6-mercaptopurine/methotrexate)
`and randomized
`Treatment groups (cid:9)
`3. Active (CDP571) (cid:9)
`
`4. Active (CDP571) (cid:9)
`6. Placebo (cid:9)
`
`
`First dose
`20 mg/kg
`10 mg/kg
`Placebo
`
`0 1 2
`
`12-Week Repeat Dosing
`12 14
`4 8 (cid:9)
`
`20
`
`24
`
`Second dose
`10 mg/kg
`10 mg/kg
`Placebo
`
`24-Week Treatment Period
`
`Final
`assessment
`
`(cid:9)1
`
`Figure 1. Schematic diagram showing stratification and subsequent randomization to 1 of 6 treatment groups. Patients were divided into 2 strata
`to balance the treatment groups for concomitant therapy: (1) those receiving concomitant corticosteroids and/or immune modifiers and )2) those
`not receiving concomitant treatment.
`
`Blood samples were taken for hematologic and biochemical
`assessments and for measurement of antinuclear antibody,
`anti-DNA antibody, and anticardiolipin antibody. Blood was
`also obtained for measurement of plasma anti-CDP571 anti-
`body concentrations (immunogenicity assay).
`All adverse events were recorded and graded according to
`Costart dictionary criteria. Infusion reactions were defined as
`any adverse events occurring within 2 hours of infusion of the
`study medication. Treatment of infusion reactions thought to
`be potentially related to the study medication (itchy rash
`lurticaria), dyspnea, cold swear, chill, rigor) were treated on a
`case-by-case basis, with potential treatments including stop-
`ping or slowing the infusion and/or administration of 50 mg
`diphenhydramine IV or 10-20 mg chlorpheniramine maleate.
`Similarly, the decision to continue the study and administer
`additional infusions of the study medication was made on a
`case-by-case basis by individual investigators.
`
`Outcomes and Statistical Analysis
`
`The intention-to-treat population included all patients
`who had received at least one infusion of study medication and
`had at least one efficacy evaluation after the first infusion. All
`primary and secondary outcome measures detailed below were
`predefined. The primary measure of clinical response was de-
`fined as a decrease in baseline CDAI score 70 points at week
`2.6 Secondary outcome measures were (1) rate of patients with
`a decrease in baseline CDAI score (cid:9)
`100 points at week 2; (2)
`rate of fistula closure (defined as closure of
`.-501% of open
`fistulas in patients with open fistulas maintained for at least 2
`visits'); (3) time to withdrawal from the study; (4) rates of
`clinical remission (CDAI score < 150 points) ar each visit; and
`(5) median IBDQ scores at each visit. Safety outcome measures
`were (I) frequency of anti-CDP571 antibodies over the 24-
`week study; (2) frequency of new antinuclear antibodies, anti-
`A, and anticardiolipin antibodies over the 24-week study;
`
`and (3) and adverse events. Patients receiving the same initial
`dose were combined for the primary outcome measure and for
`the secondary outcome measure of the rate of patients with a
`decrease in baseline CDAI score a 100 points at week 2, as
`discussed above. Similarly, data from patients assigned to the
`same dose interval during retreatment were combined for the
`secondary outcome measures of time to withdrawal from the
`study, rate of clinical remission (CDAI score < 150 points) at
`each visit, median CDAI scores and median change from
`baseline CDAI scores at each visit, and median IBDQ scores at
`each visit.
`The rates of clinical response were compared using the
`Mantel—Haenszel x 2 test adjusting for concomitant corticoste-
`roid and/or immune modifier ins,... Stratification for concomi-
`tant therapy with corticosteroids and/or immune modifiers was
`used to ensure adequate representation across treatment groups
`and to determine whether concomitant therapy is required to
`prevent formation of anti-CDP571 antibodies and infusion
`reactions with repeat dosing of CDP571. The extended Man-
`tel—Haenszel test was used when more than 2 rates were
`compared. The Mantel—Haenszel test was also used to compare
`the rates of clinical remission. All patients in the intention-
`to-treat population were used to calculate response and remis-
`sion rates. The rates of fistula closure and the frequencies of
`anti-CDP571 antibodies, new antinuclear antibodies, anti-
`DNA and anticardiolipin antibodies, and adverse events were
`compared using the Fisher exact test. A nonparametric analysis
`of variance was used to compare the medians for CDAI scores,
`change from baseline CDAI scores, and IBDQ scores. Kaplan`
`Meier survival analysis was used to compare time to with-
`drawal from the study. For the analyses of CDAI scores, change
`in CDAI scores and IBDQ scores, data on patients who were
`lost to follow-up or withdrawn from the study because of
`deterioration in their condition, or adverse events were cen-
`sored at the time of the last study visit (a last value carried
`
`Ex. 1023 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`May 2001
`
`CDP571 FOR CROHN'S DISEASE 1333
`
`Table 1. Baseline Characteristics of the Patients
`
`Variable
`
`Sex (M/F)
`Age at entry (yr)
`Median
`Range
`Weight (kg)
`Median
`Range
`Duration of disease (yr)
`Median
`Range
`Disease site (no. of patients)
`Ileum
`Ileocolon
`Colon
`No. of open perianal or enterocutaneous fistulas
`Previous intestinal resection (no. of patients)
`CDAI
`Median
`Range
`IBDO
`Median
`Range
`Concomitant medications
`Corticosterolds and/or immunosuppressive
`Corticosterolds
`Azathioprine or 6-mercaptopurine
`Methotrexate
`5-Aminosalicylates°
`
`Placebo
`
`CDP571 10 mg/kg
`
`CDP571 20 mg/kg
`
`8 Weekly
`(n = 27)
`
`12 Weekly
`(n = 31)
`
`8 Weekly
`= 29)
`
`12 Weekly
`(n = 25)
`
`8 Weekly
`(n = 28)
`
`12 Weekly
`(n = 29)
`
`14/13
`
`34
`20-66
`
`71
`47-124
`
`11.3
`1-32
`
`6
`11
`9
`3
`13
`
`15/16
`
`31
`18-62
`
`66
`41-99
`
`7.9
`0-33
`
`7
`21
`3
`10
`18
`
`16/13
`
`13/12
`
`12/16
`
`16/13
`
`28
`18-71
`
`68
`44-89
`
`4.7
`0-32
`
`4
`17
`8
`7
`7
`
`38
`24-57
`
`70
`54-108
`
`13.8
`1-31
`
`7
`12
`6
`6
`15
`
`33
`22-76
`
`60
`44-139
`
`8.2
`0-24
`
`8
`10
`10
`5
`13
`
`32
`23-67
`
`67
`40-127
`
`7.7
`0-26
`
`8
`15
`6
`6
`17
`
`320
`223-449
`
`343
`216-466
`
`327
`226-473
`
`319
`240-462
`
`289
`222-438
`
`304
`217-486
`
`112
`75-164
`
`111
`42-155
`
`121
`69-180
`
`133
`58-178
`
`124
`56-192
`
`128
`77-170
`
`18
`9
`10
`2
`17
`
`20
`18
`10
`3
`16
`
`20
`18
`5
`0
`17
`
`17
`13
`8
`1
`13
`
`19
`14
`7
`1
`17
`
`20
`17
`7
`2
`12
`
`5-Aminosalicylates indicates mesalamine, sulfasalazine, and olsalazine.
`
`forward approach was not used for these analyses). All rests
`were 2-sided. P values of <0.05 were considered to indicate
`statistical significance.
`
`Sample Size
`We estimated that 50 patients were needed in each of
`the 3 groups (placebo, 10 mg/kg CDP571, and 20 mg/kg
`CDP571) to detect a true difference in the primary outcome
`measure between placebo and an active treatment arm, assum-
`ing clinical response rates of 45% with CDP571 compared
`with 17% with placebo, and 80% power. We planned to
`recruit a total of 150 patients.
`
`Results
`A total of 193 patients were screened and ran-
`domized. Of those, 169 patients received the IV study
`medication and are included in the safety analysis. Fifty-
`eight received placebo initially and as maintenance 8
`weekly (n = 27) or 12 weekly (n = 31); 54 received 10
`mg/kg CDP571 initially and as maintenance 8 weekly
`(11 --= 29) or 12 weekly (n = 25); and 57 received 20
`mg/kg CDP571 initially and then 10 mg/kg as mainte-
`nance 8 weekly (n = 28) or 12 weekly (n = 29). Two
`
`patients in the 12 weekly placebo group did not undergo
`a least one efficacy evaluation after receiving the study
`medication. Thus, the intention-to-treat population con-
`sists of 167 patients. The baseline characteristics of the 6
`groups of patients were similar (Table 1). The disposition
`of all patients who entered the trial is shown in Table 2.
`Thirty-six of 111 patients (32%) in the CDP571 groups
`
`Table 2. Disposition of Patients Enrolled in the Trial
`
`Disposition
`
`Completed study
`Withdrawal for adverse event
`Withdrawal due to progression of
`Crohn's disease
`Withdrawal due to patient request
`Withdrawal due to decision of
`investigator
`Lost to follow-up
`
`CDP571
`(n = 111)
`
`36 (32%)
`3 (3%)
`
`52 (47%)
`7 (6%)
`
`9 (8%)
`4 (4%)
`
`Placebo
`(n = 58)
`
`11 (19%)
`0 (0%)
`
`26 (45%)
`14 (24%)
`
`5 (9%)
`2 (3%)
`
`NOTE. For patients who did not complete the study for more than one
`reason, only one reason is included in the table, according to the
`following hierarchy: lost to follow-up > non-Crohn's disease—asso-
`ciated adverse event > progression of Crohn's disease > withdrawal
`due to patient request > withdrawal due to decision of investigator.
`
`Ex. 1023 - Page 6
`
`

`

`C
`
`100 -
`
`69.
`
`50 -
`
`a
`
`Closure (no.)
`Total
`
`Placebo (cid:9)
`
`2
`13
`
`Pallettl groups
`
`P.0.074
`
`CDP571
`
`12
`24 (cid:9)
`
`25
`
`20
`
`Is
`
`10
`
`,°
`
`9i d
`
`weekly
`dose
`
`8 (cid:9)
`weakly
`nose
`4,
`
`2
`Remission (no.) I t, •
`Total (cid:9)
`
`27173144
`
`8
`
`10
`
`4
`• • 4 0
`
`12
`91
`
`14 (cid:9)
`
`16
`1I1
`
`18
`6
`
`24
`20 (cid:9)
`11 (cid:9) 14 1 1
`
`1011411427171•441113
`
`,114
`
`3114 3167
`
`7347
`
`1114 31131114
`
`1334 SANDBORN ET AL.
`
`GASTROENTEROLOGY Vol. 120. No. 6
`
`50 -
`
`P=0-005 (cid:9)
`
`P.--0 256
`
`P=0.023
`
`25 -
`
`P=0_087
`
`P4.026
`
`P=0 026
`
`Placebo (cid:9)
`
`1 (cid:9)
`
`CDP571 (cid:9)
`10 mg/kg (cid:9)
`
`1
`
`CDP57
`20 mg/kg
`
`Response (no.)
`Total
`
`is
`56
`
`21
`29
`54
`57
`Patient groups
`
`
`
`All
`CDP571
`doses
`50
`111
`
`Placebo (cid:9)
`
`CDP571
`10 mgikg
`
`CDP571 (cid:9)
`20 mgikg (cid:9)
`
`Response (no )
`
`Total
`
`8
`56
`
`18
`15
`54
`57
`Patinni groups
`
`All
`CDP571
`dotes
`33
`111
`
`CI Placebo() week'
`MCDP571 9 weekly
`13 Placebo 12 weary
`CDP571 12 weekly
`
`Weeks of Ires1ment
`
`Figure 2. Percentages of patients with Crohn's disease with clinical response at 2 weeks, fistula closure, or clinical remission according to
`treatment group. All significant differences are indicated on the figure. (A) Clinical response (decrease in CDAI score from baseline z 70 points):
`(8) clinical response (decrease in CDAI score from baseline w 100 points); (C) fistula closure (closure of a5096 of fistulas in patients with open
`fistulas at baseline maintained for at least 2 visits); (D) clinical remission (CDAI score < 150 points).
`
`and 11 of 58 patients (19%) in the placebo group (P =
`0.098) completed the scheduled 24 weeks of treatment
`and follow-up.
`
`Clinical Efficacy
`
`The rate of clinical response at 2 weeks was
`significantly higher in patients treated with CDP571
`(50/111, 45%) compared with placebo (15/56, 27%;
`P = 0.023) (Figure 2A). For the 10-mg/kg CDP571
`close, the clinical response rate at 2 weeks (29/54,
`54%) was significant compared with placebo (P =
`0.003); the response rate for the 20-mg/kg dose (21/
`57, 37%) was greater than placebo, but the difference
`was not significant (P = 0.248; Figure 2A ). The
`proportion of patients with a decrease in baseline
`CDAI score (cid:9)
`100 points at week 2 was also signif-
`icantly greater in patients treated with CDP571 (33/
`111, 30%) than with placebo (8/56, 14%; P = 0.026)
`(Figure 2B). For the 10-mg/kg CDP571 dose, there
`was a trend toward an increased rate of patients with
`a decrease in the CDAI score (cid:9)
`100 points at 2 weeks
`(15/54, 28%) compared with placebo (8/56,14%; P
`0.087); the difference was significant for the 20-mg/kg
`dose (18/57, 32%) vs. placebo (8/56, 14%; P = 0.026)
`(Figure 2B). A trend toward an increased rate of fistula
`closure was also noted for CDP571 (12/24, 50%)
`
`compared with placebo (2/13, 15%; P = 0.074 (Fig-
`ure 2C). At most scheduled visits, the rates of clinical
`remission (CDAI score < 150 points) in patients
`treated with 10 or 20 mg/kg CDP571 initially and
`then retreated with 10 mg/kg 8 weekly or 12 weekly
`were greater than the rates of clinical remission in
`patients treated with placebo, but the differences were
`not significant (Figure 2D). The placebo and CDP571
`clinical remission rates at 24 weeks were 4% and 11%,
`respectively, for the 8 weekly dosing group and 3%
`and 11%, respectively, for the 12 weekly dosing group
`(differences nor significant) (Figure 2D). The median
`time to withdrawal from the study was significantly
`greater in the CDP571 12 weekly dosing group (56
`days) than with placebo (18 days; P = 0.01), and there
`was a trend toward a greater median time to with-
`drawal from the study for the 8 weekly dosing group
`(35 days; P = 0.06) (Figure 3A ). The median CDAI
`scores, change in baseline CDAI scores, and IBDQ
`scores are shown in Figure 3B, C, and a No signif-
`icant differences in the outcome of any of the primary
`or secondary outcome variables were observed accord-
`ing to the stratification criteria (concomitant therapy with
`immunosuppressive and/or corticosteroid therapy). Mul-
`tivariate analyses identified no interactions between the
`
`Ex. 1023 - Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`CDP571 FOR CROHN'S DISEASE 1335
`
`• CDP571 8 weekly
`o Placebo S weekly
`• CDP571 12 weekly
`o Placebo 12 weekly
`
`...
`6 8 10 12 14 16 18 20 22 24
`Weeks of treatment
`
`I' (cid:9)
`
`I
`
`O 2 4
`
`• CDP571 B weakly
`o placebo 8 weekly
`• CDP671 12 weekly
`o Placebo 12 weakly
`4111.1.111411111111111111111141—
`p.m•IkAMEMPOS (cid:9)
`•
`•
`of
`• •
`8 weekly 12 weekly (cid:9)
`InItlel dose dose 4 (cid:9)
`dose 41 (cid:9)
`
`8 weekly
`4 dose
`O 2 4 6 8 10 12 14 16 18 20 22 24
`Weeks of trealmme
`
`B
`
`350
`
`300 •
`
`a 250
`
`200
`
`150
`
`D
`
`190
`leo
`170
`160
` 150
`140
`130
`120
`110
`100
`
`bi
`
`07
`
`• ...... (cid:9)
`
`••• .. ... (cid:9)
`
`Placebo
` CDP571 8•week doe log
` CDP571 12.week dosing
`
`1:::0.171 (cid:9)
`
`p.0.06
`
`2 4 6 8 10 12 14 16 18 20 22 24
`
`Weeks
`
`• CDP571 8 weekly
`o Placebo 8 weekly
`• CDP571 12 weekly
`e, Placebo 12 weekly
`
`May 2001
`
`A
`
`I0
`
`0.8
`
`0.6
`
`D4 •
`
`0.2
`
`0.0
`
`Survival mailmen•
`
`C
`
`0
`
`-so.
`
`o .100.
`
`-150
`
`u
`
`O 2 4 6 e 10 12 14 16 16 20 22
`
`24
`
`Weeks of treatment
`
`Figure 3. Time to withdrawal over 24 weeks or median scores at each study visit, according to treatment group. All significant differences are
`indicated on the figure. (A) Survival analysis; (B) CDAI; (C) change from baseline in CDAI; (D) IBDQ quality-of-life index.
`
`treatment response and any of the baseline characteristics
`of the patients. The likelihood of response to CDP571
`was not influenced by the baseline characteristics of the
`patients.
`
`Adverse Events
`
`The proportion of patients with any adverse event
`was greater in the combined CDP571 group than in
`those receiving placebo, but the proportions of patients
`with severe or serious adverse events were similar (Table
`3). The most frequent adverse events (frequency a: 5%)
`and adverse events potentially associated with anti-TNF
`antibody therapy were similar in the 2 treatment groups
`(Table 3). The frequency of anti-idiorype antibodies to
`CDP71 was 7% in the combined CDP571 group. This
`was not influenced by concomitant use of immune mod-
`ifier therapy (data nor shown). The frequency of new
`antinuclear antibodies and anti-DNA antibodies was low
`in both the placebo (0%) and combined CDP571 (5.3%)
`groups. Fluctuations in the frequency of anticardiolipin
`antibodies occurred over rime, but no relationship to
`CDP571 could be demonstrated. There were no clini-
`cally significant changes between the treatment groups
`in laboratory assessments.
`
`Discussion
`We found CDP571 to be effective for inducing a
`clinical response at 2 weeks in patients with mildly to
`severely active Crohn's disease, using a decrease in base-
`
`line CDAI score of either a' 70 points or (cid:9)
`100 points
`as the definition or response. In further support of these
`results, trends toward efficacy for CDP571 at 2 weeks as
`measured by the rate of clinical remission (CDAI score <
`150), decrease in CDAI score from baseline, and in-
`creased quality of life were also observed. Although the
`study was not powered to directly compare the 2
`CDP571 doses (which would have required a much
`larger study), the clinical response rates (decrease in
`baseline CDAI of 70 points or a 100 points) for the
`CDP571 doses of 10 and 20 mg/kg were similar. In the
`secondary statistical analyses, the response rates for both
`doses were greater than placebo (the 10-mg/kg dose was
`significant using the 70-point definition, and the 20-
`mg/kg dose was significant using the 100-point defini-
`tion). This latter finding is probably due to chance. The
`clinical response in patients treated with CDP571 who
`received concomitant immune modifier therapy (cortico-
`steroids, azathioprine, 6-mercaptopurine, methotrexate)
`and those not receiving immune modifiers also appeared
`similar. The study population can be classified as both
`moderately to severely active and refractory to standard
`therapy based on a minimum entry CDAI score of 220
`points, median entry CDAI scores ranging from 289 to
`343, and concomitant therapy with immune modifiers in
`67% of patients.
`We also found preliminary evidence suggesting that
`retreatment with 10 mg/kg CDP571 at dose intervals of
`8 or 12 weeks, after initial treatment with CDP571 at a
`
`Ex. 1023 - Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`II
`
`1336 (cid:9) SANDBORN ET AL.
`
`Table 3. Adver