The LW PHARMACY Liii17,242.Y
`New England
`Journal of Medicine
`
`Abstracts in the
`advertising
`sections
`'0,4
`
`Established in 1812 as The NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 330
`
`JUNE 30, 1994 (cid:9)
`
`NUMBER 26
`
`Original Articles
`Cyclosporine in Severe Ulcerative Colitis
`Refractory to Steroid Therapy (cid:9)
`S. LICIITIGER AND OTHERS
`
` 1841
`
`Low-Dose Cyclosporine for the Treatment of
` 1846
`Crohn's Disease (cid:9)
`B.G. FEAGAN AND OTHERS
`
`Diuretic Therapy for Hypertension and the
`Risk of Primary Cardiac Arrest (cid:9)
`D.S. SISCOVICK AND OTHERS
`
` 1852
`
`Neonatal Serologic Screening and Early Treat-
`ment for Congenital Toxoplasma gondii
`Infection (cid:9)
`N.G. GUERINA AND OTHERS
`
` 1858
`
`A Decision Analysis of Streptokinase plus
`Heparin as Compared with Heparin
`Alone for Deep-Vein Thrombosis ..... 1864
`J.J. O'MEARA III, R.A. MCNUTT, A.T. EVANS,
`S.W. MOORE, AND S.M. DOWNS
`
`Images in Clinical Medicine
` 1870
`Manifestations of Crohn's Disease (cid:9)
`C.D. FLOMBAUM, J.M. CARETHERS,
`AND W.M. MCDONNELL
`
`Case Records of the
`Massachusetts General Hospital
`A 20-Year-Old Philippine Woman with a Soft-
`Tissue Mass in the Forearm (cid:9)
` 1887
`P.H. KAZANJIAN AND A.R. MATTIA
`
`Editorials
`Incorporating Patients' Preferences into
`Medical Decisions (cid:9)
`J.P. KASSIRER
`
`Cyclosporine Therapy for Inflammatory
`Bowel Disease (cid:9)
`R.B. SARTOR
`
` 1895
`
` 1897
`
`Diuretic Therapy, Hypertension, and Cardiac
`Arrest (cid:9)
` 1899
`J.T. BIGGER, JR.
`
`Correspondence
`Sugar and Children's Behavior
` 1901
`More on Lorenzo's Oil (cid:9)
` 1904
`HIV-1 in Newborns (cid:9)
` 1905
`Images in Clinical Medicine: Porcelain Gallbladder 1906
`Thrombolytic Therapy for Thrombosis of an Aortic
`Bioprosthetic Valve (cid:9)
` 1906
` 1907
`Acetaminophen Treatment Nomogram (cid:9)
`Health-Related Claims at Fast-Food Chains (cid:9)
` 1908
`
`Review Articles
`Medical Progress: Systemic Lupus
`Erythematosus (cid:9)
`J.A. MILLS
`
`Seminars in Medicine of the Beth Israel
`Hospital, Boston: The Neurologic
`Basis of Fever (cid:9)
`C.B. SAPER AND C.D. BREDER
`
`Book Reviews (cid:9)
`
`Books Received (cid:9)
`
`Notices (cid:9)
`
` 1871
`
` 1880
`
`Information for Authors (cid:9)
`
` 1909
`
` 1912
`
` 1915
`
` 1916
`
`;) is pub-
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`Sandoz Ex. 1076
`
`Ex. 1076 - Page 1
`
`(cid:9)
`(cid:9)
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`The New England
`Journal of Medicine
`
`©Copyright, 1994, by the Massachusetts Medical Society
`
`Volume 330
`
`JUNE 30, 1994 (cid:9)
`
`Number 26
`
`CYCLOSPORINE IN SEVERE ULCERATIVE COLITIS REFRACTORY TO STEROID THERAPY
`
`SIMON LICHTIGER, (cid:9)
`DANIEL H. PRESENT, M.D., ASHER KORNBLUTH, M.D., IRWIN GELERNT, M.D.,
`JOEL BAUER, M.D., GREG GALLER, M.D., FABRIZIO MICHELASSI, M.D., AND STEPHEN HANAUER, M.D.
`
`Abstract Background. There has been no new effec-
`tive drug therapy for patients with severe ulcerative co-
`litis since corticosteroids were introduced almost 40
`years ago. In an uncontrolled study, 80 percent of
`32 patients with active ulcerative colitis refractory to
`corticosteroid therapy had a response to cyclosporine
`therapy.
`Methods. We conducted a randomized, double-blind,
`controlled trial in which cyclosporine (4 mg per kilogram
`of body weight per day) or placebo was administered by
`continuous intravenous infusion to 20 patients with severe
`ulcerative colitis whose condition had not improved after
`at least seven days of intravenous corticosteroid therapy.
`A response to therapy was defined as an improvement in
`a numerical symptom score (0 indicated no symptoms,
`and 21 severe symptoms) leading to discharge from the
`
`hospital and treatment with oral medications. Failure to
`respond to therapy resulted in colectomy, but some pa-
`tients in the placebo group who had no response and no
`urgent need for surgery were subsequently treated with
`cyclosporine.
`Results. Nine of 11 patients (82 percent) treated with
`cyclosporine had a response within a mean of seven days,
`as compared with 0 of 9 patients who received placebo
`(P<0.001). The mean clinical-activity score fell from 13 to
`6 in the cyclosporine group, as compared with a decrease
`from 14 to 13 in the placebo group. All five patients in the
`placebo group who later received cyclosporine therapy
`had a response.
`Conclusions.
`Intravenous cyclosporine therapy is rap-
`idly effective for patients with severe corticosteroid-resist-
`ant ulcerative colitis. (N Engl J Med 1994;330:1841-5.)
`
`ULCERATIVE COLITIS is a chronic inflamma-
`
`tory bowel disease with evidence of immune acti-
`vation.' Approximately 15 percent of patients with
`ulcerative colitis have,a severe attack requiring hospi-
`talization for intravenous corticosteroid therapy at
`some time during their illness.2 This treatment leads
`to remission in only 60 percent of patients, and pa-
`tients who do not have a response usually require total
`colectomy.'"
`Cyclosporine selectively inhibits immune respons-
`es mediated by T lymphocytes and has proved effec-
`tive in patients with chronic corticosteroid-resistant
`Crohn's disease.' In an uncontrolled study approxi-
`mately 80 percent of patients with severe ulcerative
`colitis refractory to treatment with corticosteroids re-
`sponded to cyclosporine therapy.`''' We undertook this
`study to evaluate further the efficacy and safety of
`intravenous cyclosporine therapy in patients with se-
`vere ulcerative colitis.
`
`METHODS
`Patient Selection and. Eligibility
`From April 1991 to April 1992, we studied 20 patients ranging
`from 18 to 65 years of age who had severe active ulcerative colitis
`
`From the Department of Medicine, Division of Gastroenterology (S.L.,
`D.H.P., Alt.), and the Department of Surgery (1.0., LB.), Mt. Sinai School of
`Medicine, New York; and the Department of Medicine, Division of Gastroenter-
`ology (G.G., S.H.), and the Department of Surgery (F.M.), University of Chica-
`go Medical Center, Chicago. Address reprint requests to Dr. Lichtiger at 1185
`Park Ave., New York, NY 10128.
`
`and were admitted to Mt. Sinai Hospital in New York or the Uni-
`versity of Chicago Hospital. Patients were eligible to enter the study
`if they had had no response to intravenous corticosteroid therapy
`(equivalent to a daily dose of 300 mg of hydrocortisone) after seven
`or more days. Patients who were transferred to either institution
`after having no response to this therapy elsewhere were also eligible
`for the study. Patients with a relapse of active disease after a recent
`hospitalization, during which they had responded to intravenous
`and then oral corticosteroid therapy, were also eligible if they had
`no response to an additional 60 hours of intravenous corticosteroid
`therapy. All the patients had a score of 10 or higher on a clinical-
`activity index used in an earlier open trial of cyclosporine,6'7 in
`which we found that patients with scores below 10 after treatment
`could leave the hospital without surgery (Table 1).
`The criteria of Lockhart-Mummery and Morson8 were used to
`establish the diagnosis of ulcerative colitis and to distinguish this
`form of colitis from Crohn's colitis. At some time before they en-
`tered the trial, all patients had a colonoscopy or barium enema
`showing the characteristic changes of ulcerative colitis extending at
`least to the splenic flexure. If a patient's disease had been inactive
`for more than one year, flexible sigmoidoscopy of the first 30 cm (or
`less) of the colon was performed to confirm that the disease was
`once again active. Abdominal x-ray films were obtained to establish
`the approximate extent of colitis and to exclude perforation or meg-
`acolon. Patients were excluded from the study if they had bacterial
`or parasitic pathogens in their stools, a positive test for Clostridium
`difficile toxin, septicemia, perforation of the bowel, megacolon, ac-
`tive fungal or viral infection, or uncontrolled hypertension, or if they
`had taken mercaptopurine, azathioprine, or any investigational
`drug within the preceding two weeks. Patients were also excluded if
`they had elevated serum concentrations of hepatic enzymes (more
`than three times normal), hyperbilirubinemia (levels more than two
`times normal), renal dysfunction (serum creatinine concentrations
`more than 33 percent above the upper limit of normal), or a serum
`cholesterol concentration of less than 120 mg per deciliter (3.1
`mmol per liter). The protocol was approved by the institutional
`
`Ex. 1076 - Page 2
`
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`

`1842 (cid:9)
`
`THE NEW ENGLAND JOURNAL OF MEDICINE (cid:9)
`
`June 30, 1994
`
`Table 1. Clinical-Activity Index for the Evalu-
`ation of Patients with Ulcerative Colitis.*
`
`SYMPTOM (cid:9)
`
`SCORE
`
`2
`3
`4
`
`0
`
`2
`3
`
`0
`1
`2
`
`Diarrhea (no. of daily stools)
`0-2
`3 or 4
`5 or 6
`7-9
`10
`Nocturnal diarrhea
`No
`Yes
`Visible blood in stool (% of
`movements)
`
`0
`<50
`
`100
`Fecal incontinence
`No
`Yes
`Abdominal pain or cramping
`None
`Mild
`Moderate
`Severe
`General well-being
`Perfect
`Very good
`Good
`Average
`Poor
`Terrible
`Abdominal tenderness
`None
`Mild and localized
`Mild to moderate and diffuse
`Severe or rebound
`Need for antidiarrheal drugs
`No
`Yes
`
`*The maximal score is 21. A score of less than 10 on two
`consecutive days was considered to indicate a clinical response
`
`review boards of both hospitals, and all patients gave written in-
`formed consent for the study.
`
`Drug Administration and Monitoring
`"The patients assigned to receive cyclosporine were given a dose of
`4 mg per kilogram of body weight per day by continuous infusion
`for up to 14 days. The patients assigned to the placebo group re-
`ceived an identical-appearing intravenous solution of cremaphor
`and alcohol.
`At each institution one physician who was aware of the patients'
`treatment assignments monitored blood cyclosporine concentra-
`tions and adverse effects. The dose of cyclosporine never exceeded
`4 mg per kilogram per day, but it was reduced if the serum creati-
`nine concentration increased by 30 percent above base line, serum
`liver-enzyme values increased by 50 percent, or diastolic blood pres-
`sure consistently exceeded 90 mm Hg despite antihypertensive ther-
`apy. Blood cyclosporine concentrations were measured every other
`day. In Chicago, concentrations of 100 to 400 ng per milliliter, as
`determined by radioimmunoassay with a monoclonal antibody
`(Sandoz, Hanover, NJ.), were considered therapeutic; in New York,
`concentrations of 400 to 800 ng per milliliter, as determined by
`radioimmunoassay with a polyclonal antibody (Sandoz), were con-
`sidered therapeutic. Although values obtained with the latter assay
`were used for dose adjustments in New York, the concentrations in
`those samples were also measured with the monoclonal-antibody
`assay to confirm the correlation and are reported here. More fre-
`quent measurements were made if the cyclosporine concentrations
`exceeded these ranges or if the monitoring physician, who also
`randomly adjusted the dosages of placebo, deemed them necessary.
`
`Concurrent Therapy
`All patients received 100 mg of hydrocortisone intravenously ev-
`ery eight hours and hydrocortisone enemas (100 mg in a total vol-
`
`ume of 60 ml) nightly if the drug could be retained. Patients receiv-
`ing mesalamine enemas before entry continued to receive them if
`the drug could be retained. Likewise, oral sulfasalazine, olsalazine,
`or mesalamine was continued in the same doses in patients already
`taking these medications. Therapy with topical or oral mesalamine
`or related drugs was not initiated during the study.
`Patients who were already taking antibiotics continued to receive
`them if clinically indicated. Antibiotic therapy was not initiated
`during the study unless indicated — for example, for pulmonary or
`urinary tract infection.
`The patients were treated with loperamide or codeine in an at-
`tempt to control diarrhea; the use of these drugs was: accounted for
`in the clinical-activity score. The dosage of these drugs was not
`increased once the patient entered the trial. Antihypertensive drugs
`were continued or initiated, as indicated, if the diastolic blood pres-
`sure consistently exceeded 90 mm Hg. Acetaminophen, H2-receptor
`antagonists, or aluminum-based antacids were given as needed.
`Three patients were receiving total parenteral nutrition when they
`entered the study, but it was not initiated in any patient during the
`study. Oral intake of food was allowed at the discretion of the
`gastroenterologist, who was unaware of the patients' treatment as
`signments.
`
`Patient Monitoring and Study End Points
`
`The patients were evaluated daily by a gastroenterologist who
`was aware of their treatment assignments and by at least one gas-
`troenterologist who was not aware of their treatment assignments or
`the results of any laboratory studies. The latter gastroenterologist
`determined the need for concomitant medications but did not ask
`the patients about adverse drug effects or review blood-pressure
`readings.
`Clinical-activity scores (Table I) were determined daily by the
`physicians after they had reviewed with the patient his or her daily
`log of the number of bowel movements (trips to the bathroom), the
`number of nocturnal bowel movements (ones that awakened the
`patient from sleep), and the incidence of blood in the stool, inconti-
`nence, and abdominal pain or cramping. The physicians also deter-
`mined whether abdominal tenderness was present, decided whether
`antidiarrheal drugs were needed, and asked about the, patient's
`well-being. The maximal clinical-activity score was 21. If there was
`disagreement in scoring between physicians, the admitting gastro-
`enterologist's score was used. All the patients were also evaluated
`daily by a surgeon who was unaware of their treatment assign-
`ments. The surgeon could recommend at any time that a patient
`discontinue the treatment and undergo eolectomy, on the basis of
`clinical findings.
`Vital, signs were assessed four times daily. All patients had fre-
`quent abdominal x-ray films obtained to exclude perforation or
`megacolon. A complete blood count and biochemical studies, in-
`cluding tests of renal and hepatic function, were done every other
`day. Sigrnoidoscopy or colonoscopy was not performed during the
`study.
`The primary end point was the clinical-activity score. A score of
`less than 10 on two consecutive days was considered to indicate a
`positive response to therapy. The score on the second of these two
`days was considered the final score. In patients who had a response,
`therapy was changed to 60 mg of oral prednisone daily and either
`oral cyclosporine (6 to 8 mg per kilogram per day) or oral placebo.
`If the response was maintained for an additional two days, the
`patient was allowed to go home while continuing to take these medi-
`cations.
`Patients whose clinical-activity scores did not fall below 10 for
`2 consecutive days after 14 days of treatment or whose condition
`worsened were considered to have no response to treatment. De-
`pending on the severity of their colitis as determined by the gastro-
`enterologist and surgeon, they either underwent colectomy or were
`offered open-label cyclosporine therapy, administered by continu-
`ous intravenous infusion in a dose of 4 mg per kilogram per day for a
`maximum of 14 days (after they had withdrawn from the trial; the
`treatment code was not broken).
`
`Statistical Analysis
`
`Quantitative variables were compared with two-tailed Student's
`t-tests. Qualitative variables and differences between centers were
`
`Ex. 1076 - Page 3
`
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`

`

`Vol. 330 No. 26 (cid:9)
`
`CYCLOSPORINE FOR REFRACTORY ULCERATIVE COLITIS (cid:9)
`
`1843
`
`compared with chi-square analysis with Yates' correction. All pa-
`tients were assessed on an intention-to-treat basis.
`The trial was terminated after 20 patients had been studied, when
`the physician who was aware of their treatment assignments noted a
`significant difference between the two groups. This was confirmed
`by the study monitor and two independent reviewers.
`
`RESULTS
`Characteristics of the Patients
`Among the 20 patients, 11 received cyclosporine
`and 9 placebo. The mean age, duration and extent of
`disease, initial clinical-activity score, duration of cor-
`ticosteroid therapy before the study, number of pa-
`tients requiring parenteral nutrition, and number re-
`quiring concomitant medications before and during
`the trial were similar in the two groups (Table 2).
`Fourteen patients were studied in New York, and six
`in Chicago.
`Nine of the 11 patients (82 percent) in the intra-
`venous cyclosporine group had a response to therapy,
`as defined by an improvement in the clinical-activity
`score, as compared with none of the 9 patients in
`the placebo group (P<0.001) (Fig. 1) . The mean
`length of time to a response (second consecutive day
`on which the clinical-activity score was less than
`10) was 7 days (range, 3 to 14). The mean clinical-
`activity score in the cyclosporine group fell from
`13 (range, 10 to 16) to 6 (range, 2 to 8), and the mean
`score in the placebo group fell from 14 (range, 12 to
`17) to 13 (range, 11 to 18). At the end of the study
`the mean decline in the clinical-activity score in
`the cyclosporine group was significantly greater than
`that in the placebo group (P<0.001). Among the
`
`Table 2. Base-Line Characteristics of 20 Patients with Severe
`Ulcerative Colitis.*
`
`CHARACTERISTIC
`
`Mean age — yr (range)
`Sex — MR
`Mean duration of disease— yr (range)
`Mean duration of parenteral corticosteroid
`therapy before the study—days (range)
`Mean clinical-activity index (range)
`Extent of disease — no. of patients (%)
`Universal
`Left-sided
`Concomitant medications before and during
`the trial — no. of patients (%)
`Sulfasalazine or analogue
`Glucocorticoid or mesalamine. enemas
`Antibiotics
`Transfusions — no. of patients (%)
`Parenteral nutrition — no. of patients (%)
`
`CYCLOSPORINE
`GROUP
`(N = 11)
`
`34 (18-60)
`4/7
`6 (<1-22)
`16 (3-30)
`
`PLACEBO
`GROUP
`= 9)
`(N
`
`43 (20-65)
`5/4
`2 (<1-8)
`17 (3-36)
`
`13 (10-16)
`
`14 (12-17)
`
`8 (73)
`3 (27)
`
`5 (45)
`4 (36)
`8 (73)
`7 (64)
`1 (9)
`
`8 (89)
`1 (11)
`
`4 (44)
`5 (56)
`6 (67)
`5 (56)
`2 (22)
`
`'There were no significant differences between the two groups.
`
`patients who had a response, seven were studied
`in New York and two in Chicago.
`One patient in the cyclosporine group who- had a
`response to therapy elected to undergo colectomy and
`therefore did not begin oral therapy. Of the two
`patients in the cyclosporine group who did not have
`a response, one had a grand mal seizure 12 hours
`after beginning therapy. The drug was stopped, and
`the patient underwent a colectomy. This patient
`had hypocholesterolemia and should have been ex-
`cluded from the study, but- she was counted as hav-
`
`20
`Patients
`
`9
`
`2
`
`4
`
`5
`
`11
`
`/CyclosporinN
`
`9
`
`Response
`
`No response:
`surgery
`
`No response:
`surgery
`
`Elective (cid:9) Oral cyclosporine
`colectomy
`
`No response:
`open-label intravenous
`cyclosporine
`(crossover)
`
`5
`
`Response
`
`5
`
`Oral cyclosporine
`
`Figure 1. Results of Cyclosporine or Placebo Administration in 20 Patients with Severe Ulcerative Colitis.
`
`Ex. 1076 - Page 4
`
`

`

`1844 (cid:9)
`
`THE NEW ENGLAND JOURNAL OF MEDICINE (cid:9)
`
`,June 30, 1994
`
`ing no response to cyclosporine therapy according
`to the intention-to-treat criterion. The condition of
`the second patient rapidly deteriorated after eight
`days of cyclosporine therapy, and a colectomy was
`performed.
`No patient in the placebo group had a decline in the
`clinical-activity score to below 10 on two consecutive
`days. Four of the nine patients (44 percent) under-
`went colectomy. One underwent colectomy on day 3
`because of toxic megacolon. Another underwent co-
`lectomy after clinical deterioration in her condition
`was noted; this patient later died of gram-negative
`sepsis with superimposed cytomegalovirus infection.
`Two patients had surgery for refractory symptoms.
`The condition of the other five patients (56 percent)
`was stable, and they were therefore given open-label
`intravenous cyclosporine after the study period.
`During this period of open-label cyclosporine thera-
`py, the evaluating physicians remained unaware of
`the patients' initial treatment assignments and no oth-
`er treatment was introduced. The condition of all five
`patients who had received placebo earlier improved,
`with a decrease in their mean clinical-activity score
`from 11 (range, I1 to 13) to 7 (range, 2 to 9). The
`mean time to a response in this subgroup was seven
`days (range, four to eight).
`No characteristics were identified that predicted a
`response to therapy in either the initial or the cross-
`over phase of the study. All 14 patients with a re-
`sponse, except the 1 who chose to undergo colectomy,
`were treated with oral cyclosporine and discharged
`from the hospital 48 hours later.
`
`Blood Cyclosporine Concentrations
`Among the 11 patients who initially received cyclo-
`sporine, the mean blood concentration was 482 ng per
`milliliter (range, 339 to 653) in the 9 who had a re-
`sponse to therapy and 484 ng per milliliter in 1 who
`had no response (the other patient who had no re-
`sponse received cyclosporine for only 12 hours). In the
`five patients who received cyclosporine after receiving
`placebo, the mean blood cyclosporine concentration
`was 524 ng per milliliter (range, 375 to 620). There
`was no correlation between blood concentrations and
`the rapidity of response. The dosage was decreased in
`five patients because of elevated blood cyclosporine
`concentrations.
`
`Adverse Effects
`Four of the 11 patients initially treated with cyclo-
`sporine had paresthesias (36 percent), as compared
`with none of the patients in the placebo group. Hyper-
`tension, defined as a systolic blood pressure of more
`than 140 mm Hg or a diastolic blood pressure of more
`than 90 mm Hg for two consecutive days, was noted in
`four patients in the cyclosporine group (36 percent),
`two of whom required treatment. Hypertension devel-
`oped in one patient in the placebo group (11 percent).
`One patient in each group reported nausea and vomit-
`ing. None of the patients had nephrotoxicity or hepa-
`totoxicity. As noted above, one patient treated with
`
`cyclosporine had a grand mal seizure after the initi-
`ation of therapy but had no more seizures after cyclo-
`sporine was discontinued. Headaches occurred as the
`only side effect in two of the patients who received
`cyclosporine after receiving placebo.
`
`DISCUSSION
`
`For many years the standard treatment for severe
`ulcerative colitis has been intravenous corticosteroids
`followed by colectomy if there is no response.' No sub-
`stantial improvement in response rates has been re-
`ported with any new treatment regimen in the past 20
`years.' The recognition that cyclosporine has immu-
`nosuppressive properties has led to its use in patients
`with severe ulcerative colitis, with variable results. A
`review of uncontrolled studies found that 80 per-
`cent of patients had a response to intravenous cyclo-
`sporine, whereas only 60 percent had a response to
`oral cyclosporine." In our study, 82 percent of the
`patients treated with cyclosporine initially and 100
`percent of those who had no response to placebo and
`who were then treated with cyclosporine had a re-
`sponse to the therapy. Our rationale for administer-
`ing cyclosporine intravenously was based on studies
`documenting poor absorption of orally administered
`cyclosporine in patients with diarrhea and various
`inflammatory diseases of the bowel." In addition,
`when cyclosporine is administered by continuous in-
`travenous infusion, blood concentrations of the drug
`are constant.6'7 Furthermore, colonic-tissue concentra-
`tions of cyclosporine are 10 times higher in normal
`subjects given cyclosporine parenterally than in those
`given the drug orally.' Although there is no proved
`correlation between blood and colonic-tissue concen-
`trations of cyclosporine, it is probably the colonic con-
`centration of cyclosporine that determines the clinical
`response.'
`We believe that the intravenous route in this thera-
`peutic dose range is more appropriate for short-term
`use in patients with severe ulcerative colitis than the
`lower therapeutic dose range and oral route used in
`patients with other more chronic autoimmune dis-
`eases." The starting dose used in this study — 4 mg
`per kilogram per day — was chosen because of its
`efficacy and low level of toxicity in our open-label
`trial.6'7 However, Actis et al.' recently reported suc-
`cess in treating three patients with severe, ulcerative
`colitis refractory to treatment with steroids with an
`intravenous dose of 1 to 2 mg of cyclosporine per
`kilogram per day.
`In our study the evaluation of the efficacy of
`the drug was based on a clinical-activity index that
`included both objective elements (number of stools,
`number of nocturnal bowel movements, frequency
`of visible blood in stool, frequency of incontinence,
`and the need for antidiarrheal drugs) and subjec-
`tive elements (degree of pain, degree of cramping,
`assessment of general well-being, and presence of ab-
`dominal tenderness). When two or more physicians
`calculated the index, there was never a difference of
`more than one point in their scores. The similar rates
`
`Ex. 1076 - Page 5
`
`

`

`Vol. 330 No. 26 (cid:9)
`
`CYCLOSPORINE FOR REFRACTORY ULCERATIVE COLITIS (cid:9)
`
`1845
`
`of improvement in both the open-label and the dou-
`ble-blind trial suggest the validity of this index.
`The decision to terminate a clinical trial requires
`consideration of three issues: ethics, clinical practice,
`and biostatistics.' After 20 patients had been en-
`rolled, the study monitor and two independent review-
`ers found a significant difference in the response rates
`between the cyclosporine and placebo groups. All
`three agreed it was unethical to continue to enter pa-
`dents into the placebo arm. From a clinical stand-
`point, it was clear that the use of cyclosporine obviat-
`ed the need for colectomy and that the patients in the
`placebo arm fared poorly. Finally, from a biostatistical
`standpoint, although an interval analysis had not been
`planned, the finding of a P value of less than 0.001
`made it extremely unlikely that entering additional
`patients would change the results.18
`The response to cyclosporine was rapid; the mean
`time to a response was seven days in the cyclosporine
`group and in the crossover cyclosporine group. Al-
`though, no predictive factors were identified, a de-
`crease in bleeding was the first sign of clinical im-
`provement. The response time was shorter than in
`other studies, possibly reflecting the use of continuous
`intravenous infusions.
`The greatest concern associated with long-term cy-
`closporine treatment is nephrotoxicity." In this tri-
`al there was no renal toxicity because of the strict
`exclusion criteria, the relatively young age of the pa-
`tients, the short duration of treatment, and the fre-
`quent measurement of blood cyclosporine concentra-
`tions.
`Twenty percent of recipients of kidney and liver
`transplants who are treated with cyclosporine have
`neurologic side effects. These include paresthesias,
`which were noted in four study patients, and seizures,
`which occurred in one patient. The seizures may be
`triggered by hypomagnesemia or hypocholesterole-
`mia, both of which allow easier diffusion of cyclospor-
`ine across the blood-brain barrier.2' The patient who
`had a seizure also had hypocholesterolemia,
`Several patients became hypertensive and respond-
`ed to treatment with calcium-channel blockers. There
`were no infectious complications in the cyclosporine-
`treated patients.
`Almost 60 percent of the patients in our open trial
`maintained their clinical response six months after
`discharge, and many were subsequently able to dis-
`continue corticosteroid therapy and had endoscopic
`evidence of healing! Patients in this controlled trial
`continue to be monitored after discharge from the hos-
`pital to verify our initial long-term observations.
`Since patients with ulcerative colitis have a high
`incidence of colon cancer, there is concern that immu-
`nosuppression may increase the risk of this complica-
`
`tion.22 No colon cancers have been reported in patients
`with ulcerative colitis who were treated with cyclo-
`sporine for up to 8 months and in whom the mean
`follow-up was 4.5 years (unpublished data). We con-
`clude that intravenous cyclosporine therapy is effec-
`tive and safe in severely ill patients with ulcerative
`colitis that has not responded to intravenous cortico-
`steroid therapy.
`
`We are indebted to Mr. Lawrence Kupferschmidt, Dr. Thomas
`Twaddell, Dr. David Sachar, Dr. Thomas Chalmers, and Dr. John
`Singleton for their help and to Ms. Carol Chiofolo-Stamaty and Ms.
`Debbie K. James for their assistance in carrying out this study.
`
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