The
`New England
`Journal of Medicine
`
`Established in 1812 as THE NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 337 (cid:9)
`
`OCTOBER 9, 1997
`
`NUMBER 15
`
`Emergency Contraception — Expanding
`Opportunities for Primary Prevention (cid:9)
`D.A. GRIMES
`
` 1078
`
`CLINICAL IMPLICATIONS
`OF BASIC RESEARCH
`The Genetics of Dilated Cardiomyopathy —
`Emerging Clues to the Puzzle (cid:9)
`J.M. LEIDEN
`
`SOUNDING BOARD
`The Tobacco Settlement (cid:9)
`D.A. KESSLER
`
`CORRESPONDENCE
`
` 1080
`
` 1082
`
` 8084
`Putting Patients First? (cid:9)
`Thalidomide for Aphthous Ulcers in 11W Infection 1086
`High-Dose Intravenous Immune Globulin
`and the Response to Splenectomy in Patients
`with Idiopathic Thrombocytopenic Purpura (cid:9)
`Conventional versus Laparoscopic Surgery
`for Inguinal-Hernia Repair (cid:9)
`Aluminum Toxicity in Preterm Infants (cid:9)
`Physician-Assisted Death and Pharmacy Practice
`in the Netherlands (cid:9)
`
` 1087
`
` 1089
` 1090
`
` 1091
`
`BOOK REVIEWS (cid:9)
`BOOKS RECEIVED (cid:9)
`NOTICES (cid:9)
`CORRECTION
`The Relation of Virologic and Immunologic Markers
`to Clinical Outcomes after Nucleoside Therapy in
`HIV-Infected Adults with 200 to 500 CD4 Cells
`per Cubic Millimeter (cid:9)
`
`ORIGINAL ARTICLES
`All-trans-Retinoic Acid in Acute Promyelocytic
`Leukemia (cid:9)
` 1021
`
`M.S. TALLMAN AND OTHERS
`A Short-Term Study of Chimeric Monoclonal
`Antibody cA2 to Tumor Necrosis Factor a
`for Crohn's Disease (cid:9)
`S.R. TARGAN AND OTHERS
`Posteroventral Medial Pallidotomy in Advanced
`Parkinson's Disease (cid:9)
` 1036
`A.E. LANG AND OTHERS
`
` 1029
`
`IMAGES IN CLINICAL MEDICINE
`Pathologic Fracture (cid:9)
` 1043
`G.M. DORES AND M.E. MILLER
`
`SPECIAL ARTICLES
`The Effect of Enforcing Tobacco-Sales Laws
`on Adolescents' Access to Tobacco
`and Smoking Behavior (cid:9)
`N.A. RIGOTTI AND OTHERS
`The Health Care Costs of Smoking (cid:9)
`J.J. BARENDREGT, L. BONNEUX,
`AND P.J. VAN DER MAAS
`
`REVIEW ARTICLE
`Drug Therapy: Emergency Postcoital
`Contraception (cid:9)
`
`A. GLASIER
`
`
`1044
`
` 1052
`
` 1058
`
`CASE RECORDS OF THE
`MASSACHUSETTS GENERAL HOSPITAL
`A 67-Year-Old Renal-Transplant Recipient with
`Anemia, Leukopenia, and Pulmonary Lesions 1065
`R.M. STONE, E.J. MARK, AND J.A. FERRY
`
` 8093
` 8095
` 1096
`
` 1097
`
` 1098
`
` 1104
`
`EDITORIALS
`Differentiation Therapy for Acute
`Promyelocytic Leukemia (cid:9)
`P. FENAUX AND L. DEGOS
`Owned, published, and C copyrighted, 1997, by THE MASSACHUSETTS MEDICAL SOCIETY
`
` 1076
`
`INFORMATION FOR AUTHORS (cid:9)
`
`LEGAL ISSUES IN MEDICINE
`The Bell Tolls for a Constitutional Right
`to Physician-Assisted Suicide (cid:9)
`G.J. ANNAS
`
`4 Mini
`
`P
`E
`R
`I
`0
`D
`
`A
`L
`S
`
`0026
`
`THE NEW ENGLAND JOURNAL OF MEDICINE (ISSN 0028-4793) is published weekly
`from editorial offices at 10 Shattuck Street, Boston, MA 02115-6094. Subscription price:
`$119.00 per year. Periodicals postage paid at Boston and at additional mailing offices.
`POSTMASTER Send address changes to P.O. Box 803, Waltham, MA 02254-0803.
`
`N
`E
`
`S
`P
`A
`P
`E
`R
`
`Ex. 1052 - Page 1
`
`(cid:9)
`

`

`Zithromax
`
`azithromycin for injection
`
`
`.t.,F4-,,,.-.•,-,0,,z
`The onI.V. advanced-generation macrolide for
`4,0,1;n1AW41.:-;7....
`10-..kar,.44,...:,,fic.,-,-..-,......r,4,:-..:-.,,,g., ex,,,,..,
`.--,1 ..-.400wAt
`.....-. (cid:9)
`community-acquired pneumontat,In adult hospitalized patien
`•
`, 4.16 it.,--, (cid:9)
`',O*04:,(Otliiilf (cid:9)
`
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`v....VE -• - -.OW., '•••• (cid:9)
`1,,,,,,,s,,,ty, . (cid:9)
`ens of community-acquire
`Targeted, coverage of the
`iii,
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`'
`'4•2 4r4 Z' '
`neumonia
`
`
`
`.. ._,
`
`- (cid:9)
`
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`
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`
`Typical
`Streptococcui pneumoniae (cid:9)
`HaemOphilusjnfluenzae: (cid:9)
`StaphylodOin aureus (cid:9)
`Moraxella catarrhalis
`........
`
`Atypical
`Legionella pneumophila
`Chlamydia pneumoniae
`M coplasma pneumoniae
`
`,.,...:.
`
`
`
`*
`
`Proven efficacy
`-,4drie.46.fer-tie.f4P. .:.s
`
`In ' a controlled clinical .trial,, once-daily' Zithromax 1.y; demonstrated
`4, success comparable' With cefurOxime ± erythromycin in hospitalized
`••-•fr„,,,,--• .• r•,••••, (cid:9)
`
`,. .-, :......"-••-•-iir :* (cid:9)
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`patients with community ac uired pneurnonia!"
`. n (cid:9)
`i'•-;4‘ • ,...
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`• ' XI
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`r Early step-down therapy. to oral Zithrornax,
`_*,_-..,04,9#4,ii.v. ItAx4simvewr-S,,.-41+414%÷, (cid:9)
`Patients 4,witFo comrnunitY;acqu!rect prieumoria; should:: receive
`by orals '
`Zithrorna>i 1.V. pa.: 76:1Onci'daily). fori2 to*Tdays' for (cid:9)
`‘..4 00 Frig OnCe-dailyy to comji.lete74,to 10 days' of therapy ,,
`(cid:9) ave"rige"duratiOnOf INI.th; -•1was 3.3 days.
`In 7clinical trials,
`•"*.;,,,t-;
`al (cid:9)
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`ery,well tolerate
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`The, most common side effects associated ,With 'titalMent , in adu 014,..st.0,,,=A4-•
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`patientS'Whoecived I.VJP0-,.Zrtlir:oma.x in studies of;.• community=.
`
`"45 t"
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`acquired pneumonia were"diarrhealloole stools (4.3%), nausea (3.9%). (cid:9)
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`he injection site. (6.5A)
`and JoCal;:inflarnmation J3.1%)..1Approximately: I 2%!,of,„th riSatients ..4%,4f.-rites
`• discontinued intravenous 'i ZithrornaxItherapy,= and iai„totitl„pf .72.4% i_li"0,..4:,...,,,,,
`44.1. 4-A.A.Z.-LS!.
`diSContipued azithromycin theri-apy by, either; the intravenous or: oral
`; tt. .,(t'i,v4V
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`'.i.:7,?,,p;iatqiii-alhitogitrw.giv*Itvi..,-1,-6-140,0%.-k.,
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`
`Ex. 1052 - Page 2
`
`(cid:9)
`

`

`azithromycin for injection
`
`The only I.V. advanced-generation macrolide for
`community-acquired pneumonia* in adult hospitalized patients
`
`Targeted coverage of the key pathogens of community-acquired
`pneumonia
`
`Streptococcus pneumoniae
`Haemophilus influenzae
`Staphylococcus aureus
`Moraxella catarrhalis
`
`Legionella pneumophila
`Chlamydia pneumoniae
`Mycoplasma pneumoniae
`
`Proven efficacy
`In a controlled clinical trial, once-daily Zithromax I.V. demonstrated
`success comparable with cefuroxime ± erythromycin in hospitalized
`patients with community-acquired pneumonia.'
`
`Early step-down therapy to oral Zithromax
`Patients with community-acquired pneumonia should receive
`Zithromax I.V. (500 mg once daily) for 2 to 5 days followed by oral
`Zithromax (500 mg once daily) to complete 7 to 10 days of therapy.
`In clinical trials, the average duration of I.V. therapy was 3.3 days.
`
`Very well tolerated
`The most common side effects associated with treatment in adult
`patients who received I.V./P0 Zithromax in studies of community-
`acquired pneumonia were diarrhea/loose stools (4.3%), nausea (3.9%),
`abdominal pain (2.7%), and vomiting (1.4%).The most common side
`effects related to I.V. infusion included pain at the injection site (6.5%)
`and local inflammation (3.1%). Approximately 1.2% of the patients
`discontinued intravenous Zithromax therapy, and a total of 2.4%
`discontinued azithromycin therapy by either the intravenous or oral
`route because of clinical or laboratory side effects.
`
`Zithromax is contraindicated in patients with known7;enosasit,iyto
`lycis.
`azithmycin, erythromycin, or any macrolide antibiotic.
`ro (cid:9)
`
`zitli)nce daily
`
`OCI 1
`
`(azithromycin for inif pjjpnl)
`The Power of Z in I.V.
`
`Please see brief summary of prescribing information on last page of this advertisement.
`
`Ex. 1052 - Page 3
`
`

`

`Introducing once-daily
`Zithromax® I.V.
`
`(azithromycin for injection)
`
`The only I.V. advanced-generation macrolide for
`community-acquired pneumonia* in adult hospitalized patients
`
`Targeted coverage of the key pathogens of community-acquired
`pneumonia
`
`Typical
`
`Atypical
`
`Streptococcus pneumoniae
`Haemophilus influenzae
`Staphylococcus aureus
`Moraxella catarrhalis
`
`Legionella pneumophila
`Chlamydia pneumoniae
`Mycoplasma pneumoniae
`
`Proven efficacy
`In a controlled clinical trial, once-daily Zithromax I.V. demonstrated
`success comparable with cefuroxime ± erythromycin in hospitalized
`patients with community-acquired pneumonia.'
`
`Early step-down therapy to oral Zithromax
`Patients with community-acquired pneumonia should receive
`Zithromax I.V. (500 mg once daily) for 2 to 5 days followed by oral
`Zithromax (500 mg once daily) to complete 7 to 10 days of therapy.
`In clinical trials, the average duration of I.V. therapy was 3.3 days.
`
`Very well tolerated
`The most common side effects associated with treatment in adult
`patients who received I.V./P0 Zithromax in studies of community-
`acquired pneumonia were diarrhea/loose stools (4.3%), nausea (3.9%),
`abdominal pain (2.7%), and vomiting (1.4%). The most common side
`effects related to I.V. infusion included pain at the injection site (6.5%)
`and local inflammation (3.1%). Approximately 1.2% of the patients
`discontinued intravenous Zithromax therapy, and a total of 2.4%
`discontinued azithromycin therapy by either the intravenous or oral
`route because of clinical or laboratory side effects.
`
`Zithromax is contraindicated in patients with known hypersensitivity to
`azithromycin, erythromycin, or any macrolide antibiotic.
`
`Once daily
`
`. .
`azithromycin for injection I
`The Power of Z in I.V.
`
`for IV infusion only
`
`Please see brief summary of prescribing information on last page of this advertisement.
`
`Ex. 1052 - Page 4
`
`(cid:9)
`

`

`CHIMERIC MONOCLONAL ANTIBODY cA2 TO TUMOR NECROSIS FACTOR a FOR CROHN'S DISEASE
`
`A SHORT-TERM STUDY OF CHIMERIC MONOCLONAL ANTIBODY cA2 TO
`TUMOR NECROSIS FACTOR a FOR CROHN'S DISEASE
`
`STEPHAN R. TARGAN, M.D., STEPHEN B. HANAUER, M.D., SANDER J.H. VAN DEVENTER, M.D., PH.D., LLOYD MAYER, M.D.,
`DANIEL H. PRESENT, M.D., TANJA BRAAKMAN, M.D., KIMBERLY L. DEWOODY, M.S., THOMAS F. SCHAIBLE, PH.D.,
`AND PAUL J. RUTGEERTS, M.D., PH.D., FOR THE CROHN'S DISEASE CA2 STUDY GROUP
`
`requiring glucocorticoid treatment.2 Immunomod-
`ulatory agents, including azathioprine or mercapto-
`purine,3 methotrexate,4,3 and cyclosporine,6-9 may be
`used to treat severe, persistent disease that is refrac-
`tory to treatment with corticosteroids, or symptoms
`that recur on tapering of the dose of corticosteroids.
`In animal models, antibodies to tumor necrosis
`factor a (anti—TNF-a) prevent or reduce inflamma-
`tion,l°44 suggesting that therapy with such antibod-
`ies may be useful for disorders in which chronic in-
`flammation may be due to an increase in cytokines
`produced by the T helper 1 subclass of T cells. In
`vitro studies have shown that the production of
`TNF-a is increased in the mucosa of patients with
`Crohn's diseaseis,i6 and that the mucosal inflamma-
`tory process reflects a shift in the balance of cytokine
`production by T cells toward the T helper 1 sub-
`class.17,18 Similar findings were reported in the syn-
`ovia of patients with rheumatoid arthritis,19 and
`anti—TNF-a reduces clinical signs and symptoms of
`this disease.2°,21 The role of TNF-a in the pathogen-
`esis of Crohn's disease and the successful use of anti—
`TNF-a in the treatment of rheumatoid arthritis
`stimulated an open-label trial of chimeric monoclon-
`al antibody cA2 (infliximab, Centocor, Malvern, Pa.)
`for Crohn's disease. In that preliminary trial, clinical
`remission occurred after one infusion of cA2 in eight
`of nine patients with Crohn's disease.22 We report
`the results of a multicenter randomized, placebo-
`controlled, double-blind trial of cA2 for the treat-
`ment of active Crohn's disease.
`
`METHODS
`
`Patients
`
`To be eligible for the study, patients had to have had Crohn's
`disease for six months,' with scores on the Crohn's Disease Activ-
`ity Index23 between 220 and 400. The Crohn's Disease Activity
`Index incorporates eight variables related to the disease: the num-
`ber of liquid or very soft stools, the severity of abdominal pain or
`cramping, general well-being, the presence of extraintestinal man-
`
`From the Cedars—Sinai Medical Center, Los Angeles (S.RT.); the Uni-
`versity of Chicago, Chicago (S.B.H.); Academisch Medisch Centrum, Am-
`sterdam (S.J.H.D.); Mt. Sinai Medical Center, New York (L.M., D.H.P.);
`Centocor, Inc., Malvern, Pa. (T.B., K.L.D., T.F.S.); and Academisch Zie-
`kenhuis Gasthuisberg, Leuven, Belgium (P.J.R.). Address reprint requests
`to Dr. Targan at Cedars—Sinai Medical Center, Division of Gastroenterol-
`ogy and Inflammatory Bowel Disease Center D4063, 8700 Beverly Blvd.,
`Los Angeles, CA 90048.
`
`Volume 337 Number 15 • 1029
`
`1,1a6 1/4.r. (cid:9)
`
`s
`
`••• • .• • (cid:9) • .
`
`ABSTRACT
`Background Studies in animals and an open-
`label trial have suggested a role for antibodies to tu-
`mor necrosis factor a, specifically chimeric mono-
`clonal antibody cA2, in the treatment of Crohn's
`disease.
`Methods We conducted a 12-week multicenter,
`double-blind, placebo-controlled trial of cA2 in 108
`patients with moderate-to-severe Crohn's disease
`that was resistant to treatment. All had scores on the
`Crohn's Disease Activity Index between 220 and 400
`(scores can range from 0 to about 600, with higher
`scores indicating more severe illness). Patients were
`randomly assigned to receive a single two-hour in-
`travenous infusion of either placebo or cA2 in a dose
`of 5 mg per kilogram of body weight, 10 mg per kil-
`ogram, or 20 mg per kilogram. Clinical response, the
`primary end point, was defined as a reduction of 70
`or more points in the score on the Crohn's Disease
`Activity Index at four weeks that was not accompa-
`nied by a change in any concomitant medications.
`Results At four weeks, 81 percent of the patients
`given 5 mg of cA2 per kilogram (22 of 27 patients),
`50 percent of those given 10 mg of cA2 per kilogram
`(14 of 28), and 64 percent of those given 20 mg of
`cA2 per kilogram (18 of 28) had had a clinical re-
`sponse, as compared with 17 percent of patients in
`the placebo group (4 of 24) (P<0.001 for the compar-
`ison of the cA2 group as a whole with placebo). Thir-
`ty-three percent of the patients given cA2 went into
`remission (defined as a score below 150 on the
`Crohn's Disease Activity Index), as compared with
`4 percent of the patients given placebo (P=0.005). At
`12 weeks, 41 percent of the cA2-treated patients (34
`of 83) had had a clinical response, as compared with
`12 percent of the patients in the placebo group (3 of
`25) (P=0.008). The rates of adverse effects were sim-
`ilar in the groups.
`Conclusions A single infusion of cA2 was an ef-
`fective short-term treatment in many patients with
`moderate-to-severe, treatment-resistant Crohn's dis-
`ease. (N Engl J Med 1997;337:1029-35.)
`©1997, Massachusetts Medical Society.
`
`Cj
`
` ROHN'S disease is a chronic inflammato-
`
`ry disorder characterized by patchy granu-
`lomatous inflammation of any part of the
`gastrointestinal tract.' Patients have a spec-
`
`trum of clinical features, with great variation in the
`course of the disease. Mesalamine is considered first-
`line therapy. The majority of patients have relapses
`
`Ex. 1052 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`The New England Journal of Medicine
`
`ifestations, abdominal mass, use of antidiarrheal drugs, hemato-
`crit, and body weight. These items yield a composite score rang-
`ing from 0 to approximately 600. Higher scores indicate greater
`disease activity. Scores below 150 indicate remission, whereas
`scores above 450 indicate severe illness. Patients were eligible for
`the study if they had been receiving any of the following: me-
`salamine for eight or more weeks, with the dose remaining stable
`during the four weeks before screening; a maximum of 40 mg of
`corticosteroids per day for eight or more weeks, with the dose re-
`maining stable during the two weeks before screening; and mer-
`captopurine or azathioprine for six or more months, with the
`dose remaining stable during the eight weeks before screening.
`Patients were excluded from the study if they had received treat-
`ment with cyclosporine, methotrexate, or experimental agents
`within three months before screening. Patients were also excluded
`if they met any of the following criteria: symptomatic stenosis or
`ileal strictures; proctocolectomy or total colectomy; stoma; a his-
`tory of allergy to murine proteins; prior treatment with murine,
`chimerk:, or humanized monoclonal antibodies; or treatment
`with parenteral corticosteroids or corticotropin within four weeks
`before screening.
`Patients were enrolled at 18 centers in North America and Eu-
`rope. The protocol was approved by the institutional review
`boards and ethics committees at all sites, and all patients gave
`written informed consent before enrolling in the trial. The study
`began on June 21, 1995, and concluded on March 12, 1996. A
`total of 203 patients were screened for the study, 95 of whom
`were excluded. The most common reasons for exclusion were a
`requirement for contraindicated medications, refusal to give in-
`formed consent, or disease activity that did not meet the study
`criteria.
`
`Protocol
`
`Subjects were screened one week before the administration of
`cA2 to establish base-line scores on the Crohn's Disease Activity
`Index and the Inflammatory Bowel Disease Questionnaire,24 and
`base-line C-reactive protein concentrations. The Inflammatory
`Bowel Disease Questionnaire, a 32-item questionnaire, evaluates
`quality of life with respect to bowel function (e.g., loose stools
`and abdominal pain), systemic symptoms (fatigue and altered
`sleep pattern), social function (work attendance and the need to
`cancel social events), and emotional status (angry, depressed, or
`irritable). The score ranges from 32 to 224, with higher scores
`indicating a better quality of life. Patients in remission usually
`score between 170 and 190.24
`Patients were randomly assigned to receive a single dose of ei-
`ther placebo or 5 mg of cA2 per kilogram of body weight, 10 mg
`of cA2 per kilogram, or 20 mg of cA2 per kilogram in an intra-
`venous infusion, administered over a two-hour period. The cA2
`monoclonal antibody is a chimeric mouse—human IgG1 that
`binds to both soluble25 and transmembranem human TNF-a with
`high affinity and specificity. It neutralizes the functional activity
`of TNF in a variety of bioassays by blocking the binding of the
`factor to the p55 and p75 receptors.27 The placebo preparation
`contained 0.1 percent human serum albumin instead of cA2 and
`was identical in appearance to the cA2 solution. Patients were en-
`rolled from June 21, 1995, to October 31, 1995. Randomization
`was performed centrally by an independent organization (PPD
`Pharmaco, Austin, Tex.). The cA2 and placebo solutions were
`prepared by a pharmacist at each site who was aware of the treat-
`ment assignments. The investigators, all other study personnel,
`and the patients were blinded to the treatment assignments.
`The primary end point was defined before the initiation of the
`trial as a reduction of 70 points or more in the score on the
`Crohn's Disease Activity Index at the four-week evaluation that
`was not accompanied by a change in any concomitant medica-
`tions. Patients who did not have a clinical response at that time
`were enrolled in a parallel, open-label study and received a single
`infusion of 10 mg of cA2 per kilogram and were followed for 12
`additional weeks. Patients who were receiving mesalamine, corti-
`
`1030 • October 9, 1997
`
`costeroids, azathioprine, or mercaptopurine before the study con-
`tinued to receive a stable dose during the trial period. The dose
`of corticosteroids could be tapered beginning eight weeks after
`the initiation of the study. Treatment with these drugs or with
`methotrexate or cyclosporine could not be initiated during the
`trial. After all patients had completed 12 weeks of the trial and
`the data were finalized, the treatment assignments were revealed.
`
`Immunologic Investigations
`Serum samples were obtained at base line and at 12 weeks for
`the evaluation of antinuclear antibodies and human anti-cA2. An-
`tinuclear antibodies were detected by immunofluorescence on
`Hep-2 cells. Serum samples positive by immunofluorescence for an-
`tinuclear antibodies were tested for antibodies to double-stranded
`DNA by an enzyme-linked immunosorbent assay (North Ameri-
`can centers) or by Crithidia immunofluorescence (European cen-
`ters). Human anti-cA2 was measured by a double-antigen enzyme-
`linked immunosorbent assay.
`
`Statistical Analysis
`An adaptive stratified design was used to assign patients to a
`treatment group, with investigational site and corticosteroid use
`as the strata. We calculated that approximately 25 patients were
`needed in each treatment group to detect a difference in the
`number of patients who responded with 80 percent power
`(a =0.05), assuming a response rate of 30 percent in the placebo
`group, 80 percent in the cA2 group with the greatest response,
`and 55 percent in the remaining cA2 groups. The original study
`protocol did not specify the use of intention-to-treat analysis.
`Two patients were assigned to a treatment but did not receive it:
`one declined to participate and one did not meet eligibility crite-
`ria. No further data were collected on these two patients, and
`they are not included in the analysis. Otherwise, all patients were
`analyzed according to the treatment to which they were assigned.
`When we assessed the response or remission rates in all evaluation
`periods after the initial blinded infusion, patients who received an
`open-label infusion or those with a change in concomitantly ad-
`ministered medications were considered to have had no response.
`Categorical variables (clinical response and remission) were
`compared with use of the Mantel—Haenszel chi-square test for
`general association stratified according to investigational site."
`Analyses comparing each of the cA2 treatment groups with pla-
`cebo were performed only when the treatment effect was con-
`sidered significant (P<0.05). The changes from base line in
`continuous variables (Crohn's Disease Activity Index score, In-
`flammatory Bowel Disease Questionnaire score, and C-reactive
`protein concentration) were compared with use of analysis of van-
`ance, with the van der Waerden normal scores blocked according
`to center.29 If the treatment effect was significant, the cA2 treat-
`ment groups were compared with the placebo group with linear
`contrasts. All P values are two-sided.
`
`RESULTS
`
`Base-Line Characteristics of the Study Patients
`A total of 108 patients were studied, with 25 to
`28 patients in each group. There were no significant
`differences in age, weight, race (all patients were
`white), sex, duration of disease, scores on the Crohn's
`Disease Activity Index and Inflammatory Bowel Dis-
`ease Questionnaire, or C-reactive protein concen-
`trations at base line among the groups, although
`patients in the placebo group had a lower mean con-
`centration of C-reactive protein (Table 1). Signifi-
`cantly more patients had ileal disease alone in the
`placebo group than in the other three groups
`(P = 0.02), but there were no significant differences
`
`Ex. 1052 - Page 6
`
`

`

`CHIMERIC MONOCLONAL ANTIBODY cA2 TO TUMOR NECROSIS FACTOR a FOR CROHN'S DISEASE
`
`TABLE 1. BASE-LINE CHARACTERISTICS OF THE 108 PATIENTS.*
`
`CHARACTERISTIC
`
`Duration of disease — yr
`Involved intestinal area — no. of
`patients (%)
`Ileum only
`Ileum and colon
`Colon only
`Previous segmental resection —
`no. of patients (%)
`Age — yr
`Male sex — no. (%)
`Weight — kg
`Height — cm
`Medications — no. of patients
`Prednisone equivalent
`<20 mg/day orally
`w20 mg/day orally
`Mercaptopurine
`Azathioprine
`Oral aminosalicylates
`Score on Crohn's Disease Activity Index
`Score on Inflammatory Bowel Disease
`Questionnaire
`C-reactive protein — mg/liter
`
`PLACEBO
`(N=25)
`
`5 mg OF
`cA2/kg
`(N=27)
`
`10 mg OF
`cA2/kg
`(N=28)
`
`20 mg OF
`cA2/kg
`(N=28)
`
`10.4±7.7
`
`12.5±10.3
`
`11.5±9.6 13.5±8.8
`
`8 (32)t
`10 (40)
`7 (28)
`13 (52)
`
`3 (11)
`15 (56)
`9 (33)
`12 (44)
`
`4 (14)
`14 (50)
`10 (36)
`14 (50)
`
`2 (7)
`19 (68)
`7 (25)
`14 (50)
`
`38.5±11.0
`15 (60)
`71.4±14.4
`172±11
`
`37.0±11.8
`14 (52)
`68.1±17.7
`169±8
`
`39.3±10.6 36.0±9.7
`13 (46)
`13 (46)
`74.2±19.5 68.4±16.0
`171±10
`171±9
`
`10 (40)
`6 (24)
`4 (16)
`7 (28)
`17 (68)
`288±54
`128±29
`
`8 (30)
`7 (26)
`4 (15)
`5 (19)
`16 (59)
`312±56
`122±29
`
`8 (29)
`8 (29)
`4 (14)
`4 (14)
`18 (64)
`318±59
`116±23
`
`10 (36)
`7 (25)
`4 (14)
`8 (29)
`13 (46)
`307±50
`118±28
`
`12.8±13.9
`
`22.1±23.6
`
`23.2±34.2 22.4±23.9
`
`"Plus—minus values are means ±SD. Higher scores on the Crohn's Disease Activity Index indicate
`greater disease activity, and higher scores on the Inflammatory Bowel Disease Questionnaire indicate
`better quality of life.
`tP= 0.02 for the comparison with the other three groups.
`
`in the number who had undergone previous seg-
`mental resections among the groups. Similar num-
`bers of patients in each group had been treated with
`oral corticosteroids, mercaptopurine, azathioprine,
`and oral mesalamine at base line. All treatment groups
`had a mean score on the Crohn's Disease Activity
`Index of approximately 300, despite concurrent treat-
`ment with drugs other than cA2; thus, the patients
`had moderate-to-severe, treatment-resistant Crohn's
`disease.
`
`Clinical Response and Remission
`
`Week 2
`Figure 1A demonstrates that clinical response was
`achieved early: 61 percent of cA2-treated patients
`had a clinical response by week 2, as compared with
`17 percent of patients in the placebo group (P<
`0.001). At two weeks, 27 percent of cA2-treated pa-
`tients were in clinical remission (defined as a score
`of less than 150 on the Crohn's Disease Activity In-
`dex), as compared to 4 percent of the patients in the
`placebo group (P = 0.06) (Fig. 1B).
`
`Week 4
`Four weeks after the infusion, the primary end
`point of a reduction of 70 or more points in the
`score on the Crohn's Disease Activity Index was
`
`reached in 81 percent of those given 5 mg of cA2
`per kilogram (22 of 27 patients), 50 percent of
`those given 10 mg of cA2 per kilogram (14 of 28
`patients), and 64 percent of those given 20 mg of
`cA2 per kilogram (18 of 28 patients), as compared
`with 17 percent of those given placebo (4 of 24 pa-
`tients) (Fig. 1A). The overall response of the cA2
`groups was 65 percent (P<0.001 for the compari-
`son with placebo). No dose—response relation was
`seen during this period. At four weeks, 33 percent
`of the cA2-treated group were in remission, as
`compared with 4 percent of the placebo group
`(P = 0.005). Thus approximately half of the patients
`who had a clinical response at either two or four
`weeks also entered remission. Consistent treatment
`effects were observed when the analyses for both re-
`sponse and remission at week 4 were stratified ac-
`cording to the location of disease or concurrent drug
`regimens (data not shown).
`
`Changes in Clinical and Inflammatory Measures
`during the First Four Weeks
`The mean change in the scores on the Crohn's
`Disease Activity Index in the cA2-treated group as a
`whole was significant at weeks 2 and 4 of the trial,
`as compared with the changes in scores in the place-
`bo group (P<0.001) (Table 2). The mean decrease
`in the score on the Crohn's Disease Activity Index
`
`Volume 337 Number 15 • 1031
`
`'4.4.. '1, ...Apneitrk (cid:9)
`
`•• -•- .
`
`577
`
`Ex. 1052 - Page 7
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`

`

`The New England Journal of Medicine
`
`the mean decrease in C-reactive protein was 16.3,
`11.1, and 15.0 mg per liter in the groups treated
`with 5, 10, and 20 mg of cA2 per kilogram, respec-
`tively, yielding a mean decrease of 14.3 mg per liter
`in the group as a whole, as compared with a mean
`increase of 2.0 mg per liter in the placebo group
`(P<0.001). The maximal reduction in C-reactive
`protein occurred within the first two weeks. At two
`weeks, the mean decrease in C-reactive protein in
`the cA2 groups as a whole was 16.0 mg per liter, as
`compared with a mean increase of 3.9 mg per liter
`in the placebo group (P<0.001).
`
`Week 12
`The differences in the rates of clinical response be-
`tween the cA2-treated groups and the placebo
`group remained significant through the 12 weeks of
`follow-up: it was 48 percent in the group given
`5 mg of cA2 per kilogram (13 of 27 patients), 29
`percent in the group given 10 mg of cA2 per kilo-
`gram (8 of 28 patients), and 46 percent in the group
`given 20 mg of cA2 per kilogram (13 of 28 pa-
`tients), for an overall rate of response of 41 percent
`(34 of 83 patients), as compared with a rate of 12
`percent in the placebo group (3 of 25 patients)
`(P = 0.008). The difference in the percentage of pa-
`tients who were in remission was not significant at
`12 weeks: 30 percent of the group given 5 mg of cA2
`per kilogram (8 of 27 patients), 18 percent of the
`group given 10 mg of cA2 per kilogram (5 of 28 pa-
`tients), and 25 percent of the group given 20 mg of
`cA2 per kilogram (7 of 28 patients), for an overall
`rate of remission achieved of 24 percent (20 of 83
`patients), as compared with a rate of 8 percent in the
`placebo group (2 of 25 patients) (P = 0.31).
`
`Characterization of the Response to Treatment
`The magnitude and duration of response were
`characterized through the 12-week follow-up period
`in the 54 patients who responded to a single infu-
`sion of cA2. The improvement in the scores on the
`Crohn's Disease Activity Index (clinical remission
`was defined as a score below 150) and Inflammatory
`Bowel Disease Questionnaire (remission was defined
`as a score between 170 and 190) in patients with a
`response was maintained. The mean ( ±SD) score on
`the Crohn's Disease Activity Index was 318±52 at
`base line, 144±67 at week 4, 151±86 at week 8,
`and 182±91 at week 12, and the mean score on
`the Inflammatory Bowel Disease Questionnaire was
`121±26 at base line, 175±26 at week 4, 165±36
`at week 8, and 162±35 at week 12. Concentrations
`of C-reactive protein (normal, <8 mg per liter) be-
`gan to rise at 12 weeks, potentially indicating a re-
`lapse of disease (from 25.8 ±2.7 mg per liter at base
`line to 7.5±1.5 mg per liter at week 4, 11.0±2.1 mg
`per liter at week 8, and 14.1±2.2 mg per liter at
`week 12).
`
`O Placebo
`El 5 mg of cA2/kg
`• 10 mg of cA2/kg
`Q 20 mg of cA2/kg
`• All cA2 groups
`
`t
`
`100:
`
`75-
`
`50-
`
`25-
`
`0
`
`Base Line
`
`1
`
`3
`
`4
`
`Week
`
`75-
`
`50-
`
`25-
`
`0-
`
`P<0.001
`
`Base Line
`
`1
`
`2 (cid:9)
`
`3
`
`4
`
`a)
`
`a.
`U)
`a)
`cC
`
`A
`
`Remission (%)
`
`B
`
`No. OF PATIENTS EVALUATED
`25
`Placebo (cid:9)
`27
`5 mg of cA2/kg (cid:9)
`10 mg of cA2/kg 28
`20 mg of cA2/kg 28
`All cA2 groups (cid:9)
`83
`
`Week
`
`24
`26
`23
`28
`77
`
`24
`27
`28
`28
`83
`
`Figure 1. Rates of Clinical Response and Remission after a Sin-
`gle Infusion of cA2 or Placebo.
`Clinical remission was defined as a score of less than 150 on
`the Crohn's Disease Activity Index and a score of 170 to 190 on
`the Inflammatory Bowel Disease Questionnaire. The asterisks
`(P<0.001 I, daggers IP<0.01), and double dagger (P<0.05) indi-
`cate a significant difference from placebo.
`
`in the cA2 group as a whole was 110 at four weeks,
`as compared with 13 in the placebo group. Most of
`this decrease had occurred by week 2, with a mean
`decrease of 103 in the cA2 group and 16 in the pla-
`cebo group.
`The Inflammatory Bowel Disease Questionnaire
`was given at base line and four weeks. There was a
`mean increase of 46, 30, and 32 in the groups treated
`with cA2 at 5, 10, and 20 mg of cA2 per kilogram,
`respectively, yielding a mean increase of 36 in the cA2
`group as a whole, as compared with a mean increase
`of 5 in the placebo group (P = 0.001) (Table 2).
`Concentrations of C-reactive protein were meas-
`ured at base line and weeks 2 and 4. At four weeks,
`
`1032 • October 9, 1997
`
`Ex. 1052 - Page 8
`
`

`

`CHIMERIC MONOCLONAL ANTIBODY cA2 TO TUMOR NECROSIS FACTOR a FOR CROHN'S DISEASE
`
`TABLE 2. MEASURES OF CLINICAL RESPONSE AND INFLAMMATION AT BASE LINE
`AND WEEKS 2 AND 4.*
`
`VARIABLE
`
`Score on Crohn's Disease
`Activity Index
`Base line
`2 weeks
`4 weeks
`Score on