The
`New England
`Journal of Medicine
`
`Abstracts in the
`advertising
`sections
`
`Elltabllsbed in 181.2 as The NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 313
`
`AUGUST 8, 1985
`
`UM BER 6
`
`Original Articles
`A Randomized Clinical Trial of OKT3 Mon(cid:173)
`oclonal Antibody for Acute Rejection
`of Cadaveric Renal Transplants ...... .
`0RTHO MULTICENTER TRANSPLANT STUDY GROUP
`
`Emergency Coronary Angioplasty in Re-
`fractory Unstable Angina ........ . ... .
`PrM j
`. DE FEYTER, P ATR ICK W. SERRUYS,
`MARCEL VAN DEN BRAND,
`K uLASEKARA M B ALA KUMARAN,
`B A HAMS Ht R Moc HTAR, ALAN L. SowARD,
`ALF E. R . ARNOLD, AND P AUL G. H UGENHO LTZ
`
`Congenital Heart Disease in Relation to Ma(cid:173)
`ternal Use of Bendectin and Other
`Drugs in Early Pregnancy ...... . .... .
`SALLY ZIERLER AND K ENNETH j. R OTH MAN
`
`In Situ Characterization of Autoimmune
`Phenomena and Expression of HLA
`Molecules in the Pancreas in
`Diabetic Insulitis .................... .
`GtAN F RANCO B oTTAzzo, B ETTY M . D EAN,
`j ESSICA M. McNALLY, E. H uGH MAc K AY,
`P ETER G.F. SwiFT, AND D. R oBERT GAMBLE
`
`Special Article
`Racial and Socioeconomic Disparities in
`Childhood Mortality in Boston ....... .
`P AuL H. W tsE, M ILTON K oTELCHUCK,
`MARK L. W ILSON, AND MA R K M ILLS
`
`Medical Intelligence
`Current Concepts: Acute Fatty Liver of
`Pregnancy .......................... .
`MA RSHALL M. K APLAN
`
`Prenatal Diagnosis of Congenital Heart De(cid:173)
`fects in Thoracoabdominally
`Conjoined Twins .................... .
`STEPH EN P . SANDERS, ALV IN j
`. CH IN,
`I RA A . P ARNESS, BERYL B ENACE RR AF,
`M ICHAEL F. GREENE, M ICHAEL F . EPSTEIN,
`STEVEN D . COLAN, AND F REDRICK D. FR!GOLETTO
`
`337
`
`342
`
`347
`
`353
`
`360
`
`367
`
`370
`
`Case Records of the
`Massachusetts General Hospital
`Recurrent Pneumothorax, Hemoptysis, and
`Hemothorax in Association with
`Multiple Lung Cysts ................. ,
`L YNNE R EID AND EuGENE ]. M ARK
`
`374
`
`Editorial
`The Limits of Medical Care .............. .
`R oBERT j
`. H AGGERTY
`
`Correspondence
`Prevalence of HTLV-III Antibody in American
`Blood Donors ..••••........•••••••••..
`Dissolution of Gallstones by Methyl Tert-Butyl
`Ether .........•••••...•.....•••••••..
`Treatment of Obstructive Sleep Apnea with a
`Nocturnal Airway-Patency Appliance ....••
`Radio-Frequency Interference in Cochlear
`Implants ..........••••••......•••••••
`Hyponatremia and Hypovolemia ......•••••••
`Focal Signs and Brain CT Scans in Psychiatric
`Patients ••••.••........•••••......••••
`Alzheimer's Disease: Does Neuron Plasticity Pre(cid:173)
`dispose to Axonal Neurofibrillary
`Degeneration? ... • •........••••••.•...•
`Shared Antigens on Acetylcholine Receptor and
`Bacterial Proteins •.••.••...•.•.••••.•..
`The Ethics of Professional Regulation by the State
`Boards •.••.........•..•••••.......•••
`
`Book Reviews ......................... .
`
`Notices ................................ .
`
`Health Policy Report
`The Use of Animals in Research
`j O H N K . I GLEHART
`
`Correction
`The Ethics of Professional Regulation by the State
`Boards (Oregon and Alabama) ••..........
`
`383
`
`384
`
`385
`
`386
`
`387
`387
`
`388
`
`388
`
`389
`
`390
`
`392
`
`395
`
`395
`
`391
`
`Owned, Published, and ©Copyrighted, 1985, by the Massachusetts Medical Society
`
`THE NEw ENGLAND jOURNAL OF MEDICINE (ISSN 0028-4793) is published weekly from ed itorial offices at 10 Sha ttuck Street, Boston , MA 021 15~
`Subscription price: $55.00 per year. Second-class postage paid at Boston and a t additional mailing offices.
`POSTMASTER: Send address changes to 1440 Main Street, Wa ltham , MA 02254.
`
`BIOEPIS EX. 1026
`Page 1
`
`

`

`The New England
`Journal of Medicine
`
`©Copyright , 1985, by the Massachusetts Medical Society
`
`me 31 3
`
`AUGUST 8, 1985
`
`Number 6
`
`A RANDOMIZED CLINICAL TRIAL OF OKT3 MONOCLONAL ANTIBODY FOR ACUTE
`REJECTION OF CADAVERIC RENAL TRANSPLANTS
`
`OR THO M u LTI CENTER TRANSPLANT STUDY GROU P*
`
`Since the murine monoclonal antibody OKT3
`human T cells and blocks their function, we
`effectiveness in treating T-cell-mediated re(cid:173)
`renal allografts. In a prospective randomized
`r trial, 123 patients undergoing acute rejection
`r.::~l11;:~v,"rir. renal' transplants were treated either with
`daily for a mean of 14 days, with concomitant lower(cid:173)
`the dosage of other immunosuppressive drugs (63
`or with conventional high-dose steroids (60 pa(cid:173)
`. OKT3 reversed 94 per cent of the rejections - a
`that was significantly better (P = 0.009) than the 75
`
`per cent reversal rate obtained with conventional steroid
`treatment. This superior reversal rate with OKT3 was
`reflected in an improved one-year graft survival of 62
`per cent for the OKT3-treated group, as compared with 45
`per cent for the steroid-treated group (P = 0.029}, in
`patients who were all selected by v!rtue· -pf having had
`acute rejection. We conclude that treatment with OKT3
`(with concomitant lowering of the dosage of other im(cid:173)
`munosuppressive drugs) is ari effective iiPproaGh fqr
`acute renal-allograft rejection. (N Engl J Med 1985; 313:
`337-42.)
`.
`
`improvements in tissue ma tching and
`introduction of newer immunosuppressive
`acute rej ection of the allograft remains a major
`iment to the success of clinical renal transplan(cid:173)
`Conventional therapies include the use of high-
`steroid pulses and of anti thymocyte globulins. 1-4
`use of high-qose steroids results in a high inci-
`of infection and otl)er side effects. Antithymo(cid:173)
`globulins are more effective than steroids in re(cid:173)
`ng acute renal rej ection, but diffi culties in lot
`· ation, giving variations in efficacy and in
`incidence of adverse reactions among lots, con tin(cid:173)
`be a major problem. OJ<_T3 is a murine mono(cid:173)
`antibody that is reactive with a 20,000-dalton
`found only on the surface of thymocytes or
`human T cells.5 The structure recognized by
`is linked to the T -cell antigen receptor6
`7 and
`•
`vital for the functioning of huma n T cells .8
`, OKT3 in vitro blocks both killing by cytotoxic
`
`Onho Multicenter Transplant Study Group comprised Gideon Goldstein ,
`D., John Schindler, Ph.D., and Huei Tsai , Ph.D. (Ortho Phannaceuti(cid:173)
`' Raritan, N.J.); A. Benedict Cosimi , M.D., and PaulS . Russell, M.D.
`Hospital, Boston); Douglas Norman, M.D. , and John Barry ,
`of Oregon Health Sciences Center, Portland); Charles F.
`(St. Francis Hospital, Wichita, Kans.); Sang I. Cho, M.D. , and
`Levey. M .D. (New England Medi cal Center Hospital. Boston);
`. Burdick, M.D., and G . Melvin Williams, M.D. (Johns Hopkins Hospi-
`Frank P. Stuart, M.D. (The University of Chicago, Chicago);
`Alexander, M.D., and Roy Fir t, M .D. (University of Cincinnati ,
`Ohio); Peter Gailiunas, M.D., and J. Harold Helderman, M.D.
`Medical School, Dallas); Ronald L. Wathen, M.D. , and Robert E.
`M.D. (The Jewish Hospital, University of Louisville, Louisville , Ky.);
`Sampson, M.D. (deceased) , and Barry S. Levin , M.D. (Presbyterian
`of Pacific Medical Center, San Francisco); and Anthony Monaco, M.D.
`Deaconess Hospital, Boston).
`reprint requests to .Or. Goldstein at the lmmunobiology Division,
`Pharmaceutical Corporation , Raritan , NJ 08869.
`
`human T cells and the generation of other T-cell func(cid:173)
`tions9- 11; furth ermore, T-cell function is lost ifOKT3
`interacts with and causes the removaf of the antigen
`13
`T3 on the T-cell surface. 12
`•
`We have previously reported an open pilot study
`showing that OKT3 reversed acute renal-allograft re(cid:173)
`jection in all of 10 patients. 14
`16 We now present the
`-
`results of a randQmized prospective protocol compar(cid:173)
`ing the safety and efficacy ofOKT3 (with reduction in
`the dosage of concomitant immunosuppressive medi(cid:173)
`cation) with those of conventional steroid treatment in
`reversing aCI.!te renal-allograft rejection.
`
`METHODS
`
`Production of OKT3
`
`OKT3 was produced from seed lots of th e pa rent hybridoma. The
`immunoglobulin was purified from ascites and formulated , and am(cid:173)
`pules were fill ed unqer sterile conditions. Each ba tch was tested for
`purity a nd safety and conform ed to the sta ndards of the Food and
`Drug Administra tion.
`
`Organization
`
`This clinical trial was orga nized by th e lmmunobiology Division
`of the Orthq Pha rm aceutical Corporation after a prelimina ry inves(cid:173)
`tigators' meeting at which a consensus was reached on protocol
`d esign. At each parti cipa ting center a n institutiona l review board
`approved the protocol and the informed-consent form and foll owed
`the progress of th e study. All the patients were full y informed of th e
`na ture of the stud y and signed consent forms.
`
`Eligibility Criteria
`
`Pa tients had to be diagnosed as having th eir first rej ection episode
`after cadaveric rena l transpla ntation . Rej ection criteria were docu(cid:173)
`mented and were those used by Shield et at.' T o avoid cases of renal
`fa ilure attributa ble to ca uses other tha n acute cellular rej ection,
`
`BIOEPIS EX. 1026
`Page 2
`
`

`

`338
`
`THE NEW ENGLAND JO U RNAL OF MEDICINE
`
`Aug. 8,
`
`entry was restricted to patients wi th rejections occurring from 6 to
`93 days after transplantation.
`Patients received a standard regi men of immunosuppression after
`transplantation. This comprised prednisone, starting at 2 mg per
`kilogram of body weight per day a nd tapering to 0.5 mg per kilo(cid:173)
`gra m per day by Week 9, and the maximal tolerated dose of azathio(cid:173)
`prine -
`approximately 100 to !50 mg per day.
`
`Randomization
`
`Patients meeting the eligibility criteria were randomly assigned at
`entry to receive either OKT3 or steroid treatment, the randomiza(cid:173)
`tion schedule being generated by com puter for each center.
`
`OKT3 Group
`
`After a negative skin test (0. 1 ml of a 1 -~-tg-per-milliliter solution
`intradermally) , OKT3 was ad ministered by intravenous push a t a
`dose of 5 mg per day for 14 consecutive days (Fig: I). Investigators
`had the option of continuing therapy, and 14 patients were treated
`for additional periods of I to 14 days. During OKT3 administration
`the dosages of concomi tant immunosuppressive agents were re(cid:173)
`duced -azathioprine to 25 mg per day and ·prednisone to 0.5 mg
`per kilogram P-er day. These were raised to the continuing dosages
`on the day after OKT3 therapy was stopped, as if rejection had not
`
`OKT3 TREATMENT
`Re jection
`Tran splant
`
`t
`
`1 mg /kg METHYLPREDNISOLONE , I. V.
`
`2.0 t
`1.0[
`1::t1· ··m· m,1,,,,~,~.~.;.~~2.~~,~~,~,,,,g
`
`DOSE
`I
`.
`
`mg/kg
`
`mg/day
`
`mg/day g [
`
`I
`
`lllllllilllloKT31111111111111
`
`500 mg METHYLPR EDNISOLONE , I.V.
`
`CONVENTIONAL STEROID TREATMENT
`Re jection
`t
`+H
`
`Tr a nsp lant
`
`:::1~
`
`1. 0
`
`mg/kg
`
`DA YS
`
`Figure 1. Plan of Daily Immunosuppressive Drug Regimens for
`Patients Randomly A$signed to OKT3 or Steroid Treatment for
`·
`Acute Renal-Allograft Rejection.
`During OKT3 treatment, dosages of steroids and azathioprine
`were reduced, with resumption of the prerejection tapered dos(cid:173)
`age of steroids and the azathioprine dosage when OKT3 was
`discontinued . By contrast, steroid treatment involved a high ste(cid:173)
`roid dosage, with maintenance of the azathioprine dosage. I.V.
`denotes intravenous.
`
`occurred . A bolus injection of I mg of methylprednisolone per kiJo.
`gram a nd concomitant acetaminophen and antihistami nes w
`permitted with the ~rst dose ofOKT3 to reduce the fever and chl:;:
`that were known to accompany this first dose.
`
`Conventional-Steroids Group
`
`Azathioprine and. prednisone were continued at prerejection
`levels. Methylpredmsolone (500 mg per day) was given17,1B &If
`a maximum of three days, after which prednisone could be given
`at a dosage of 3 mg per kilogram per day, if necessary, and tapered
`over the next seven days so that a dose of I mg per kilogram per
`day was achieved on the seven th day. T he prednisone dosage waa
`then tapered to what it would have been if rejection had not oc(cid:173)
`.
`curred (Fig. ! ) .
`
`" Rescue" Tr~atmeht
`
`Any patient whose serum creatinine level did not decrease on the
`sixth day or la ter and whose transplant rej ection was judged not 10
`have been reversed could be treated with additional conventional
`treatment (for the OKT3 group) or eq uine anti thymocyte globulin
`(for the steroid group).
`
`Reversal of Rejection
`
`T he therapeutic goal was reversal of renal-allograft rejection u
`judged by a three-day progressive fall in serum creatinine levels.
`The investigators judged .tha t reversal had occurred in an additional
`three pa tients in the OKT3 group and eight patients in the steroid
`group, on the basis of d inical crite'ria alone, such as reduction in
`kid ney swelling and tenderness, decreased fever, and resumption o(
`diuresis.
`
`Procedures
`
`Before trea tment for rej ection, demographic· data and a medical
`history were recorded for each patient. In addition, the patient
`underwent a complete pretreatment physical examination, with fuD
`clinical laboratory evalua tion (blood-chemistry and hematologic
`studies and' urinalysis) and chest radiography. During treatment
`for rejection, there were daily recordings of the serum creatinine
`level, body temperature,. blood pressure, and white-cell count with
`differential cell couht, and periodic measurement of other clinical
`la boratory indexes. On the term ina tion of rejection therapy, aD
`clinical laboratory measurements were repeated. Routine follow-up
`examinations were performed at 3, 6, .12, and 24 months after trans(cid:173)
`plantation a nd included a determina tidn of graft status and .the
`same physical and labora tory examina tions performed before reJec(cid:173)
`tion therapy. Throughout the trial, all adverse experiences and in(cid:173)
`fections were recorded.
`
`Statistical Methods
`Fisher's exact test 19 Wilcoxon's rank-sum test 20 or the extended
`M antel-Haenszel chi-square test21 was used for ~retreatmen! com(cid:173)
`parisons based on demographic and disease-history vana~lc:l·
`Reversal of rejection was analyzed with stratification by invesU~
`tors using the Mantel-Haenszel chi-square test.22 When reve eel
`and graft-survival rates were being calculated, one OKT3-treat
`patient "rescued" with steroids was cquntt d as constituting a tree!"
`ment failure, as were 10 steroid-treated pa tients rescued with.~DD­
`. thymocyte globulin. Steroid-treated patients rescued with add•uon;
`al steroids were considered treatment successes. Fisher's exact tc:lt
`was also used to compare the ihcidence rates in the two treatm~
`groups for the following indexes: repeated rejection, adverse ex~
`ences, and infections. Life-table comparisons were performed WI
`use of Breslow's test. 23
`
`R ESULT S
`
`Patient Entry
`63 in the OKT3 group
`In all, 123 patients -
`60 in the steroids group - were treated with
`medica tions. Summary data on d emographic
`
`BIOEPIS EX. 1026
`Page 3
`
`

`

`TRIAL OF OKT3- ORTHO MULTICENTER TRANSPLANT STUDY GROUP
`
`339
`
`pertinent medical history for
`population are shown
`1. There were no sta(cid:173)
`significant differences be-
`the groups in any of these
`characteristics, and the
`overall appeared repre(cid:173)
`of the population expe(cid:173)
`a first episode of acute re-
`rejection . However,
`63 patients treated with
`diagnosed in retrospect
`undergone a deteriora(cid:173)
`function due to cyto(cid:173)
`infection rather than
`renal rej ection, and he was
`excluded from the efficacy
`
`Table 1. Clinical Characteristics of Patients Randomly Assigned to OKT3 or Steroid
`Treatment for Acute Renal-Allograft Rejection.
`
`CHARACTERISTIC
`
`Sex (MIF)
`
`Median age (yr)t
`Median weight (kg)t
`Race (white/nonwhite)
`
`No. with diabetes mellitus
`No . with prior transplants (011 /2)
`No. with pretransplant transfusions
`(0/ 1-4/>4)
`Acute tubular necrosis and dialysis at entry
`Renal disease (glomerulonephritis)
`
`Crossmatch ( - / +)
`Preformed antibodies
`((}-24%/26-100% positive)
`
`TREATMENT GROUP*
`
`OKT3
`
`STEROIDS
`
`43/20
`38 (17--{;5)
`
`67 (42- 103)
`
`39/21
`36 ( 16-64)
`66 (3(}-1 11 )
`
`50113
`20
`5517/1
`1112144
`
`12
`
`23
`6310
`44110
`
`49/ 11
`14
`
`52/6/2
`3110140
`
`18
`5911
`
`39118
`
`Median time from transplant to rejection (days)t
`
`10 (6-74)
`
`II (6-9 1)
`
`*There were no statistically significant differences between the two groups in any of these indexes.
`tNumbers in parentheses represent the range of values.
`
`was administered intrave(cid:173)
`at a dosage of 5 mg per day
`period of 14 days (range, 1 to 28). In-
`amounts of steroids were also administered as
`therapy in the control group for a mean
`days (range, 3 to 36). On the day before rejec(cid:173)
`the mean daily doses of prednisone and azathio-
`among patients entered into the OKT3 group
`1.07 mg per kilogram and 142 mg, respectively.
`the period ofOKT3 administration, the mean
`of prednisone and azathioprine were
`to 0.56 mg per kilogram and 30 mg, respec-
`2 shows the cumulative doses of the con(cid:173)
`immunosuppressives for each group for the
`beginning with the day of rejection and indi(cid:173)
`marked steroid-sparing effect of the OKT3
`
`reversed acute renal-allograft rejection in
`62 patients (94 per cent) -
`a significantly high(cid:173)
`rate (P = 0.009) than that for convention(cid:173)
`treatment, which reversed rejection in 45
`ts (75 per cent) (Table 3). If reversal was
`strictly according to the objective criterion of
`rrence of a progressive decrease in the serum
`level, the reversal rates became 55 of 62
`cent) for the OKT3 group and 37 of 60 (62
`t) for the steroids group (P<O.OO I). The distri(cid:173)
`of reversal results was generally consistent
`investigators, and there was no statistically
`t difference among the centers (P = 0.36).
`patients in whom rej ection was reversed,
`n time to reversal was shorter in the OKT3-
`group (3.3 days) than in the steroid-treated
`(4.9 days) .
`
`the reversal of acute rejection by OKT3 or
`steroid treatment, both groups were
`similarly with conventional therapy for both
`
`maintenance and repeated episodes of rejection. Be(cid:173)
`cause of the efficacy ofOKT3 in reversing acute rejec(cid:173)
`tion there were more patients (58) in whom rejection
`had been reversed by OKT3 than by conventional
`steroid treatment (45) . A second rejection was com(cid:173)
`mon in both groups, occurring in 38 of 58 patients (66
`per cent) initially treated with OKT3 and 33 of 45
`patients (73 per cent) initially treated with conven(cid:173)
`tional steroids (P = 0.52) . The incidence of kidney
`loss due to repeated rejection was also similar in
`both groups: 19 of 58 patients (33 per cent) initially
`treated with OKT3 and 17 of 45 (38 per cent) initial(cid:173)
`ly treated with conventional steroids lost a kidney
`(P = 0.68).
`
`Patient and Kidney Survival
`Two patients in the steroid-treated group were lost
`to follow-up. At one year, 53 of 62 patients (85 per
`cent) treated with OKT3 and 52 of 58 (90 per cent)
`of those treated with steroids were alive (P = 0.47)
`(Table 3). All 53 living patients treated with OKT3
`and the 52 living patients treated with steroids were
`followed for one year. According to life-table anal-
`
`Table 2. Mean Cumulative Dosage of Immunosuppressive Med(cid:173)
`ications over the First 28 Days of Treatment for Patients Ran(cid:173)
`domly Assigned to OKT3 or Steroids for Acute Renal-Allograft
`Rejection.
`
`MEDICATION
`
`OKT3
`
`STEROIDS
`
`NO. OF
`PATIENTS
`
`M.EA.N
`CUMULATIVE
`DOSAGE
`
`NO . OF
`PATIENTS
`
`CUMULATIVE
`OOSAGE
`
`Prednisone
`
`Methylprednisolone
`sodium succinate
`
`Azathioprine
`
`63
`
`62*
`
`63
`
`mg
`
`121 8
`
`965
`
`1765
`
`mg
`
`2042
`
`2019
`
`60
`
`60
`
`59*
`
`2711
`
`*One OKT3-group patient did not receive methylprednisolone , and one steroid-group patient
`received cyclophosphamide rather than azathioprine.
`
`BIOEPIS EX. 1026
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`

`340
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 8, 1985
`
`ness; in all four cases reversal had already been es.
`tablished.
`
`Infections
`Infections occurred at comparable rates in both
`groups. During the first 45 days after the start of treat.
`ment, infection developed in 43 of 63 patients (68 per
`cent) and 39 of60 patients (65 per cent) in the 0KT3
`and steroid groups, respectively. During this period
`II patients in each group ( 18 per cent) had sever;
`infections. In the follow-up period of one year, the
`incidence of infection continued to remain comparable
`for the two groups (54 and 50 per cent, respectively).
`
`Skin Tests and Development of Antibodies
`No patient had a positive skin test in response to
`OKT3 . Antibodies to OKT3 developed in 80 per cent
`of the patients either during or after the second week of
`treatment with the drug. These antibodies were pri(cid:173)
`marily of the IgG class, with titers from I : I 00 to
`I : 1000 in the enzyme-linked immunosorbent assay
`system used for their detection . They did not affect the
`success of treatment, and there was no evident devel·
`opment of allergy, anaphylaxis, or serum sickness, al(cid:173)
`though one patient acquired a rash and pruritus that
`were subsequently attributed to other medications.
`
`Table 3. Efficacy of Treatment with OKT3 or Steroids for Acute Renal-Allograft
`Rejection.
`
`ysis, kidney survival rates for the OKT3 group and the
`steroid group were 62 and 45 per cent, respectively
`(P = 0.029) (Fig. 2).
`
`Discontinuance of Initial Reversal Treatment
`OKT3 was discontinued prematurely in 13 patients
`because of failure of reversal (two patients) , a second
`rejection during treatment (one), adverse experiences
`(six, four of whom had already had reversal ), or ad(cid:173)
`ministrative error (four, all of whom had already had
`reversal).
`Steroid treatment was discontinued prematurely
`in 15 patients because of its fai lure to reverse re(cid:173)
`jection; rescue with equine antithymocyte globulin
`was attempted in 10 of these cases, with reversal
`achieved in 7.
`
`Adverse Experiences
`The first and, to a lesser extent, second injections of
`OKT3 were associated with a symptom complex that
`did not occur with subsequent injections. This typical(cid:173)
`ly commenced 45 to 60 minutes after the first injec(cid:173)
`tion ofOKT3 and lasted for several hours. It involved
`pyrexia (73 per cent), chills (57 per cent) , tremor (10
`per cent), dyspnea (21 per cent) , chest pain and tight(cid:173)
`ness (-14 per cent) , wheezing (II per cent) , nausea (II
`per cent) , and vomiting ( 13 per cent). This symptom
`complex was considered to be due to a physiolog(cid:173)
`ic response to mediators released from T cells after
`the initial OKT3 treatment, with resulting effects on
`temperature control, bronchial smooth-muscle tone,
`and the gastrointestinal tract. In one patient who was
`in a state of fluid overload before treatment, chills,
`bronchospasm, wheezing, shortness of breath, anxi(cid:173)
`ety, increased blood pressure, and pulmonary ede(cid:173)
`ma developed after the first dose of OKT3. The pa(cid:173)
`tient was treated promptly and successfully with
`fluid reduction and steroids. The trial in one patient
`in the OKT3 group was discontinued because of
`renal-artery thrombosis. OKT3 was discontinued
`in four other patients because of high fever, rash
`and pruritus, thrombocytopenia, or profound weak-
`
`Reversal of rejection (according to
`different criteria)
`Serum creatinine level plus clinical indexes
`Serum creatinine level alone
`One-year foll ow-up
`Patient survival
`Actual
`Life table
`Kidney survival
`Actual
`Life table
`
`*Two patienlS were losr to follow· up.
`t NS denotes not significant.
`
`OKT3
`
`STEROIDS
`
`incidence(%)
`
`58/62 (94)
`55162 (89)
`
`(75)
`45160
`37/60 (62)
`
`53/62 (85)
`- (85)
`
`52158* (90)
`(90)
`
`36/53 (68)
`- (62)
`
`25152
`
`(48)
`(45)
`
`D ISCUSSION
`The efficacy of reversal of rejection by OKT3 (94
`per cent) was significantly better (P = 0.009) than
`that with conventional steroid treatment (75 per cent),
`and the high reversal rate with OKT3 was obtained
`with a significant reduction in the concomitant dos(cid:173)
`ages of steroids and azathioprine. Once the reversal
`of rejection was achieved, patients in both groups
`were treated similarly with prednisone and azathio(cid:173)
`prine maintenance immunosuppression, and they were
`treated with high-dose steroids or anti thymocyte glob(cid:173)
`ulin for repeated episodes of rejection. Both groups
`had similar subsequent rates of repeated rejection
`and consequent kidney loss, so that the number of
`kidneys saved as a result of a superior reversal rate
`with OKT3 was reflected in the
`higher numbers of functioning kid·
`neys in this group at one rear.
`Thus, in patients selected by v1rtue
`of having had acute rej ection, one(cid:173)
`year kidney survival according to
`life-table analysis was 62 per cen~
`for the OKT3-treated group an
`45 per cent for the steroid-treated
`group (P = 0.029) . Since 15 to 20
`per cent of the recipients of cadaver
`kidneys never have rejection, t~~
`overall kidney survival rates wou
`. ci·
`be proportionately higher.
`Patient survival and the ID.
`dence of infections were similar ~n
`both treatment groups. T he matn
`
`p VA.LUE
`
`0.009
`< 0.001
`
`0.47 (NS)t
`
`0.029
`
`BIOEPIS EX. 1026
`Page 5
`
`

`

`TRIAL OF OKT3- ORTHO MULTICENTER TRANSPLANT STUDY GRO UP
`
`34 1
`
`MEAN END OF
`TREATMENT PERIOD
`
`/
`
`OKT3 TREATED GROUP
`
`/
`
`'
`
`•.
`
`-;········! ..... ~.1 ••• ~ ..... 1 ••••• ._ •••
`
`STEROID TREATED GROUP
`
`0
`
`100
`
`200
`
`300
`
`400
`
`TIME (Days)
`
`2. Life-Table Analysis of Kidney Survival in Patients Ran·
`Assigned to OKT3 or Steroid Treatment for Acute Renal·
`Allograft Rejection.
`living OKT3·treated patients were followed for one year. In
`18n:>id·tre1atEld group, two patients were lost to follow-up, and
`ng living patients were followed for one year. The
`of the treatment period is shown by the vertical bar.
`
`reaction attributable to OKT3 was a symp(cid:173)
`complex involving fever and pulmonary and
`·
`symptoms and occurring 45 to 60
`the initial dose. We a ttribute these
`to media tors released from T cells opso-
`by OKT3 and localized in the reticuloendothe-
`24 These first-dose symptoms were not due
`ypen;ertsi·1 tivity, since they occurred in almost all
`(with no previous exposure to mouse im(cid:173)
`~glot•uli'. n ), the skin tests before OKT3 adminis(cid:173)
`were uniformly negative, and symptoms were
`with later injections of OKT3 .
`case of pulmonary edema occurred in this
`after a first injection of OKT3 in a patient in a
`of fluid overload. Four additional cases ofpulmo(cid:173)
`edema have occurred after the initial injection of
`for acute renal-allograft rejection in other stud-
`two of those pa tients died of anoxic sequelae
`Pharmaceutical: unpublished data). It is note(cid:173)
`that in all cases there was evidence of fluid
`, as judged by weight gain and chest-film
`before OKT3 injection. No cases of pulmo(cid:173)
`have occurred in 136 pa ti ents treated for
`other than acute renal rejection, and no
`have occurred in 197 patients treated for acute
`llograft rejection who did not have fluid over-
`judged by ches t films"and a weight gain ofless
`cent in the week preceding treatment. We
`that the pharmacologic effects of the media(cid:173)
`cet ea~;ed after the first dose can impose a left ven-
`strain and cause pulmona ry edema, but only
`ts with impending left ventricular failure due
`
`to fluid overload; pa tients should be brought to appro(cid:173)
`priate fluid balance before treatmen t with OKT3 is
`initiated.
`Other monoclonal antibodies have been used thera(cid:173)
`peutically for acute renal-allograft rejection. 25
`27 Al(cid:173)
`•
`though these antibodies have resulted in the removal
`of circulating T cells, they have not produced the strik(cid:173)
`ing reversal rate obtained with OKT3; it may well be
`that the pharmacologic effect of OKT3 in blocking
`T-cell function is essential for its th erapeutic efficacy.
`Host antibodies
`to the murine immunoglobulin
`OKT3 frequently developed shortly after treatment
`with OKT3 was stopped .28
`29 These antibodies did
`•
`not result in hypersensitivity, anaphylaxis, or serum
`sickness. OKT3 administered in the presence of these
`antibodies may be consumed and rendered unavail(cid:173)
`able for binding to T3 antigen on T cells. 30 Thus, if
`OKT3 is to be used for the treatment of subsequent
`episodes of rej ection after successful reversal of initial
`rejection, it will be necessary to develop protocols for
`preventing antibody formation or to give sufficient
`amounts of OKT3 to consume the host antibody and
`esta blish adequate levels of free OKT3 in the circu(cid:173)
`lation.
`Our results were achieved in patients receiving con(cid:173)
`ventional azathioprine and prednisone therapy. Pre(cid:173)
`liminary studies in patients treated with cyclosporine
`and pred nisone show similar high reversal rates and
`give promise that even better overall rates of kidney
`survival may be attainable.
`
`REFERENCES
`
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`BIOEPIS EX. 1026
`Page 6
`
`

`

`342
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
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`Aug. 8, 1985
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