GASTROENTEROLOGY 2001;121:1088 –1094
`
`Etanercept for Active Crohn’s Disease: A Randomized,
`Double-Blind, Placebo-Controlled Trial
`
`WILLIAM J. SANDBORN,* STEPHEN B. HANAUER,‡ SEYMOUR KATZ,§ MICHAEL SAFDI,㛳
`DOUGLAS G. WOLF,¶ RICHARD D. BAERG,# WILLIAM J. TREMAINE,* THERESE JOHNSON,*
`NANCY N. DIEHL,* and ALAN R. ZINSMEISTER*
`*The Mayo Clinic, Rochester, Minnesota; ‡University of Chicago, Chicago, Illinois; §Long Island Clinical Research Associates, Greatneck,
`New York; 㛳Consultants for Clinical Research, Cincinnati, Ohio; ¶Atlanta Gastroenterology Associates, Atlanta, Georgia;
`and #Tacoma Digestive Disease Center, Tacoma, Washington
`
`See editorial on page 1242.
`
`Background & Aims: We evaluated etanercept, a human
`soluble tumor necrosis factor receptor: Fc fusion protein,
`for the treatment of active Crohn’s disease. Methods:
`Forty-three patients with moderate to severe Crohn’s
`disease were enrolled in an 8-week placebo-controlled
`trial. Patients were randomized to subcutaneous etan-
`ercept 25 mg or placebo twice weekly. The primary
`outcome measure was clinical response at week 4,
`defined as a decrease in the baseline Crohn’s Disease
`Activity Index score >70 points or a Crohn’s Disease
`Activity Index score <150 points. Results: At week 4,
`39% of etanercept-treated patients had clinical
`re-
`sponse as compared with 45% of placebo-treated pa-
`tients (P ⴝ 0.763). The frequency of common adverse
`events including headache, new injection site reaction,
`asthenia, abdominal pain, Crohn’s disease–related ane-
`mia, and skin disorders was similar in both groups.
`Likewise, the frequency of severe or serious adverse
`events was similar in both groups. Conclusions: Subcu-
`taneous etanercept at a dose of 25 mg twice weekly is
`safe, but not effective, for the treatment of patients with
`moderate to severe Crohn’s disease. The dose of etan-
`ercept administered in this study is that approved for
`rheumatoid arthritis. Higher doses or more frequent
`dosing may be required to attain a response in patients
`with active Crohn’s disease.
`
`Tumor necrosis factor (TNF) ␣ is increased in the
`
`serum, intestinal tissue, and stool of patients with
`Crohn’s disease1–3 and plays an important role in the
`pathogenesis of the disease.4,5 There are 2 distinct cell-
`surface TNF receptors (TNFRs), designated p55 and
`p75.6,7 Soluble, truncated versions of membrane TNFRs,
`consisting of only the extracellular, ligand-binding do-
`main, are present in body fluids and are thought to be
`involved in regulating TNF activity in other chronic
`
`inflammatory diseases such as rheumatoid arthritis.8,9
`The significance of these soluble TNFRs in Crohn’s
`disease is unknown. Infliximab is a murine-human chi-
`meric monoclonal antibody to TNF-␣ that contains ap-
`proximately 25% murine protein. Infliximab is effective
`for induction of remission in patients with moderately to
`severely active Crohn’s disease10 and for closure of drain-
`ing enterocutaneous fistulas,11 and a pilot study sug-
`gested efficacy for maintenance of remission.12 Infliximab
`is also effective for rheumatoid arthritis.13–16 Infliximab
`therapy has been associated with adverse events that may
`result from immunologic responses to the murine pro-
`tein, including formation of human anti-chimeric anti-
`bodies, infusion reactions, and delayed hypersensitivity
`reactions.5,17
`Protein engineering techniques have been used to
`reduce or eliminate the amount of murine protein in
`monoclonal antibodies and other therapeutic proteins. In
`one process, 1 or more human soluble receptors are
`linked to the constant domain of a human antibody.18
`The resulting fully human fusion protein is potentially
`less immunogenic than chimeric monoclonal antibodies.
`Etanercept, a genetically engineered fusion protein con-
`sisting of 2 identical chains of the recombinant human
`TNFR p75 monomer fused with the Fc domain of hu-
`man immunoglobulin (Ig) G1, binds and inactivates
`TNF.19 Etanercept is effective for rheumatoid arthri-
`tis.20 –24 A small uncontrolled pilot study of 25 mg
`etanercept administered subcutaneously twice weekly for
`12 weeks in 10 patients with active Crohn’s disease
`reported a clinical response rate of 60% at week 2.25
`Based on these preliminary results, we conducted an
`
`IBDQ,
`Abbreviations used in this paper: CI, confidence interval;
`Inflammatory Bowel Disease Questionnaire; TNF, tumor necrosis fac-
`tor; TNFR, TNF receptor.
`© 2001 by the American Gastroenterological Association
`0016-5085/01/$35.00
`doi:10.1053/gast.2001.28674
`
`

`

`November 2001
`
`ETANERCEPT FOR CROHN’S DISEASE 1089
`
`8-week trial in which patients with active Crohn’s dis-
`ease received 25 mg subcutaneous etanercept (the dose
`approved for rheumatoid arthritis) or placebo twice
`weekly.
`
`Methods
`Selection of Patients
`
`The study was performed between September 1999
`and May 2000. Eligible patients were at least 12 years of age
`and had moderately to severely active Crohn’s disease, as
`defined by a score of 220 to 450 on the Crohn’s Disease
`Activity Index (CDAI).26
`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
`immediately in need of surgery for active gastrointestinal
`bleeding, peritonitis, intestinal obstruction, or intra-abdomi-
`nal or pancreatic abscess requiring surgical drainage; those
`with local or systemic infection (including septic lesions in the
`perianal region); those with symptoms of bowel obstruction
`within the preceding 6 months confirmed with objective ra-
`diographic or endoscopic evidence of a stricture with resulting
`obstruction (dilation of the bowel proximal to the stricture on
`barium or an inability to traverse the stricture at endoscopy),
`which had not been surgically corrected; those with a planned
`inpatient hospitalization during the study; those with other
`clinically important active diseases (such as renal or hepatic
`disease); and those with an active fistula to the vagina or
`bladder. Patients with a history of cancer within 5 years,
`dysplasia of the colon within 5 years, or clinically significant
`hematological or biochemical values were also ineligible, as
`were pregnant or breast-feeding women, and those with a
`history of drug or alcohol abuse within 6 months. The insti-
`tutional review board at each center approved the study, and
`all participants gave written informed consent.
`
`Concomitant Medications
`
`Patients who had received anti-TNF therapy with
`infliximab within 12 weeks were ineligible. No patient re-
`ceived other investigational therapies within 28 days preced-
`ing randomization. Patients receiving prednisone (no upper
`limit on prednisone dose) or budesonide for a least 4 weeks
`with a stable dose for at least 2 weeks were eligible, whereas
`patients in whom corticosteroid treatment was discontinued
`within 2 weeks were not eligible. Patients receiving stable
`doses of azathioprine or 6-mercaptopurine for at least 12
`weeks, or methotrexate or mycophenolate mofetil for at least 8
`weeks were eligible. Patients who had received tacrolimus,
`cyclosporine, thalidomide, interleukin 10, or interleukin 11
`within 4 weeks were not eligible. Continued treatment with
`oral or rectal 5-aminosalicylates, rectal corticosteroids, and oral
`antibiotics was allowed, provided the dose had been stable for
`at least 2 weeks. Nutritional therapy (parenteral nutrition or
`enteral nutrition with elemental or semi-elemental diets) was
`
`discontinued at the screening visit and was not permitted
`during the trial, with the exception of nocturnal tube feedings
`for adolescent patients with growth failure and enteral nutri-
`tion supplements for adult patients with malnutrition who
`were receiving a stable regimen for at least 2 weeks and
`continued that same regimen throughout the 8-week study.
`
`Study Medication
`
`Dose finding studies in patients with rheumatoid ar-
`thritis showed that etanercept 25 mg subcutaneously twice
`weekly (equivalent to 16 mg/m2 subcutaneously twice weekly)
`was the optimal dose.20 –22 A previous placebo-controlled dose
`finding trial of subcutaneous etanercept in 49 patients with
`active Crohn’s disease had a negative outcome and a relatively
`high placebo rate (50%) (Immunex Corporation, Seattle, WA;
`data on file). However, only 6 patients received the highest
`etanercept dose (32 mg/m2 intravenous load followed by 16
`mg/m2 subcutaneously twice weekly). To determine if the dose
`of etanercept that is approved to the treatment of rheumatoid
`arthritis is effective for active Crohn’s disease, an etanercept
`dose of 25 mg subcutaneously twice weekly was selected for
`this trial. Etanercept was supplied in single dose vials contain-
`ing a lyophilized powder consisting of 25 mg etanercept, 40
`mg of mannitol, 10 mg of
`sucrose, and 1.2 mg of
`tromethamine. The placebo had the same ingredients except
`for the omission of etanercept. The study drug was reconsti-
`tuted with 1.0 mL of bacteriostatic water and dispensed in
`prefilled syringes by an unblinded study pharmacist at each
`center. Patients injected the blinded study medication subcu-
`taneously twice weekly for 8 weeks. Both etanercept and
`placebo had a similar clear and colorless appearance.
`
`Design of the Study
`
`The 8-week study was a randomized, double-blind,
`placebo-controlled trial performed at 6 centers in the United
`States. The study was designed to assess the efficacy of the dose
`of etanercept shown to be effective for rheumatoid arthritis (25
`mg twice weekly) for the treatment of active Crohn’s disease.
`After a 1-week screening period, eligible patients were ran-
`domized to 1 of 2 treatment groups (etanercept or placebo) in
`a 1:1 ratio. The randomization schedule was generated by a
`statistician at Immunex Corporation, and patients were as-
`signed to treatment group according to the schedule main-
`tained at Immunex Corporation.
`At entry, each patient’s demographic characteristics, medi-
`cal history, and current medications were recorded. Disease
`activity was assessed at the baseline (randomization) visit, and
`after 2, 4, and 8 weeks. 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, laboratory tests, and patient’s global assess-
`ment of fistula disease activity were conducted, and patients
`were asked whether any adverse events had occurred. No
`medications for Crohn’s disease other than the study drug,
`anti-diarrheals (loperamide, diphenoxylate, opiates), and stable
`
`

`

`1090 SANDBORN ET AL.
`
`GASTROENTEROLOGY Vol. 121, No. 5
`
`doses of prednisone, budesonide, azathioprine, 6-mercaptopu-
`rine, methotrexate, mycophenolate mofetil, antibiotics, 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).11 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).27 Blood samples were taken for hemato-
`logic and biochemical assessments. Measurements of antinu-
`clear antibody, anti-DNA antibody, and anti-etanercept con-
`centrations (immunogenicity assay) were not performed.
`All adverse events were recorded and graded according to
`COSTART dictionary criteria.28 Injection site reactions were
`defined as new findings of erythema, itching, pain, or swelling
`at the sites of the study medication injection after receiving at
`least 1 dose of study medication. The decision to treat injection
`reactions was made on a case-by-case basis. No treatment was
`required for the majority of injection site reactions. In those
`rare cases in which treatment was deemed necessary, patients
`who were given treatment received topical preparations such as
`corticosteroids or oral antihistamines. Similarly, the decision
`to continue the study and administer additional injections 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 1 injection of study medication and
`had at least 1 efficacy evaluation after the first injection. All
`primary and secondary outcome measures detailed below were
`predefined. The primary outcome measure of clinical response
`was defined as a decrease in baseline CDAI score ⱖ70 points or
`a CDAI score ⬍150 points at week 4.10 Secondary outcome
`measures were: (1) the rates of clinical response (decrease in
`baseline CDAI score ⱖ70 points or a CDAI score ⬍150
`points) at week 2 and week 8; (2) the rates of clinical remission
`(CDAI score ⬍150 points) at each visit; (3) the rate of fistula
`improvement (defined as closure of ⱖ50% of open fistulas in
`patients with open fistulas at baseline maintained for at least 2
`visits, i.e., 4 weeks11); (4) the rate of fistula remission (defined
`as closure of all open fistulas in patients with open fistulas at
`baseline maintained for at least 2 visits, i.e., 4 weeks11); (5) the
`CDAI scores at each visit; (6) the IBDQ scores at each visit;
`and (7) adverse events at each visit.
`The rates of clinical response and clinical remission were
`compared using the Fisher exact test. All patients in the
`intention-to-treat population were used to calculate response
`and remission rates. The rates of fistula improvement and
`fistula remission were also compared using the Fisher exact
`test. The rates of adverse events were compared using 95%
`confidence intervals (CIs). A nonparametric analysis (Wilcoxon
`rank sum test) was used to compare the CDAI scores and
`
`IBDQ scores. For the analyses of CDAI scores and IBDQ
`scores, missing data on patients who were lost to follow-up or
`withdrawn from the study because of deterioration in their
`condition or adverse events were imputed using a last value
`carried forward approach. All tests were 2-sided. P values
`⬍0.05 were considered to indicate statistical significance.
`
`Sample Size
`
`This preliminary study was designed to look for a large
`therapeutic effect. We estimated that 14 patients were needed
`in each of the 2 groups (placebo, etanercept) to have 80%
`power to detect a true difference in the primary outcome
`measure between placebo and etanercept, assuming clinical
`response rates of 65% with etanercept compared with 15%
`with placebo. This estimate of a difference in clinical response
`rates of 50% was based on the results from a controlled trial of
`infliximab in a similar patient group.10 We planned to recruit
`a total of 40 patients. There would have been better than 90%
`power to detect a difference of 15% vs. 65% with the number
`of patients in this study. More specifically, with 20 patients on
`placebo and 23 on etanercept, there was 80% power to detect
`a difference of 15% vs. 55%, or 20% vs. 61%, or 30% vs.
`72%, between placebo and etanercept, respectively.
`
`Results
`A total of 49 patients were screened, of whom 43
`were randomized. Of the 43 randomized patients, 20
`received placebo and 23 received etanercept. All 43
`patients had at least 1 efficacy evaluation and are thus
`included in the intention-to-treat population. The base-
`line characteristics of the 2 groups of patients were
`similar (Table 1). The disposition of all patients who
`were randomized is shown in Table 2. Nine of 23 pa-
`tients (39%) in the etanercept group and 11 of 20
`patients (55%)
`in the placebo group completed the
`scheduled 8 weeks of treatment; P value was not signif-
`icant (this comparison should be interpreted with cau-
`tion because it was not prespecified).
`
`Clinical Efficacy
`
`The rates of clinical response at week 4 (primary
`study endpoint) were similar in patients treated with
`etanercept (9 of 23, 39%) compared with placebo (9 of
`20, 45%), P ⫽ 0.763 (Figure 1). Likewise, there were no
`significant differences detected in the rates of clinical re-
`sponse for etanercept and placebo at week 2 (11 of 23 [48%]
`vs. 5 of 20 [25%], P ⫽ 0.206) or week 8 (7 of 23 [30%] vs.
`6 of 20 [30%], P ⫽ 1.000) (Figure 1). The rates of clinical
`remission for the etanercept- and placebo-treated patients
`were also similar at week 2 (2 of 23 [9%] vs. 3 of 20 [15%],
`P ⫽ 0.650), week 4 (2 of 23 [9%] vs. 4 of 20 [20%], P ⫽
`0.393), and week 8 (3 of 23 [13%] vs. 5 of 20 [25%], P ⫽
`0.440) (Figure 1).
`
`

`

`November 2001
`
`ETANERCEPT FOR CROHN’S DISEASE 1091
`
`Table 1. Baseline Characteristics of the Patients
`
`Table 2. Disposition of Patients Enrolled in the Trial
`
`Variable
`
`Sex (M/F)
`Age at entry
`Median
`Range
`Weight (kg)
`Median
`Range
`Disease site (no. of patients)
`Ileum
`Ileocolon
`Colon
`No. of open perianal or
`enterocutaneous fistulas
`Previous intestinal resection
`(no. of patients)
`CDAI score
`Median
`Range
`IBDQ
`Median
`Range
`Concomitant medications
`Corticosteroids
`Azathioprine or 6-
`mercaptopurine
`Methotrexate
`Antibiotics
`5-Aminosalicylatesa
`Prior treatment with
`infliximab within the
`last year
`Prior treatment with
`infliximab at any time
`
`Placebo
`(n ⫽ 20)
`
`10/10
`
`39.3
`22–60
`
`75.3
`46–139
`
`5
`10
`5
`
`1
`
`9
`
`Etanercept
`(n ⫽ 23)
`
`16/7
`
`37.4
`20–69
`
`74.3
`43–104
`
`3
`18
`2
`
`4
`
`13
`
`265
`115–453
`
`123
`45–169
`
`303
`226–499
`
`125
`72–173
`
`7
`
`7
`1
`5
`9
`
`7
`
`8
`
`10
`
`10
`1
`4
`11
`
`9
`
`12
`
`a5-Aminosalicylates indicates: mesalamine, sulfasalazine, and olsala-
`zine.
`
`A total of 5 patients had actively draining fistulas at
`baseline. Among the 4 patients treated with etanercept,
`1 had fistula improvement during the study, whereas the
`1 patient on placebo did not have improvement (P value
`not significant). None of these 5 patients experienced a
`fistula remission over the course of the study. The me-
`dian CDAI scores and IBDQ scores are shown in Figure
`2. Twenty patients had previously been treated with
`infliximab (12 etanercept patients and 8 placebo pa-
`tients), including 16 patients treated within the last year.
`The rates of clinical response (defined as a decrease in
`baseline CDAI score ⱖ70 points or a CDAI score ⬍150
`points) at week 4 in those patients previously treated
`with infliximab (4 of 12 [33%] in the etanercept group
`and 4 of 8 [50%] in the placebo group) were similar to
`the rates of clinical response in infliximab naive patients
`(5 of 11 [45%] in the etanercept group and 5 of 12
`[42%] in the placebo group), P ⫽ 0.68 (Fisher exact
`test). At study entry, investigators asked 14 of the 16
`
`Disposition
`
`Completed the study
`Withdrawal for adverse eventa
`Withdrawal due to progression
`of Crohn’s disease
`Withdrawal due to patient
`request
`
`Placebo
`(n ⫽ 20)
`
`11 (55%)
`0 (0%)
`
`6 (30%)
`
`3 (15%)
`
`Etanercept
`(n ⫽ 23)
`
`9 (39%)
`2 (9%)
`
`11 (48%)
`
`1 (4%)
`
`NOTE. For patients who did not complete the study for more than 1
`reason, only 1 reason is included in the table, according to the
`following hierarchy: lost to follow-up ⬎ non–Crohn’s disease–associ-
`ated adverse event ⬎ progression of Crohn’s disease ⬎ withdrawal
`due to patient request ⬎ withdrawal due to decision of investigator.
`aOne patient who reported worsening arthritis and increased fatigue
`decided to withdraw from the study and pursue alternative therapy.
`One patient who reported fever and a 2-cm lesion on the left leg as
`well as exacerbation of Crohn’s disease decided to withdraw from the
`study.
`
`patients treated with infliximab within the last year to
`subjectively rate their response to infliximab as none,
`poor, fair, or good. Of these 14 patients, the rates of
`clinical response at week 4 in those patients previously
`treated with infliximab (3 of 9 [33%] in the etanercept
`group and 2 of 3 [67%] in the placebo group) were
`similar to the rates of clinical response in infliximab
`naive patients (0 of 0 [0%] in the etanercept group and
`1 of 2 [50%] in the placebo group).
`
`Adverse Events
`
`The proportions of patients with any adverse
`event, severe adverse events, or serious adverse events
`were similar in the 2 treatment groups (Table 3). Simi-
`larly, there were no significant differences between the 2
`
`Figure 1. Percentages of patients with Crohn’s disease with clinical
`response or clinical remission, according to treatment group. None of
`the differences were statistically significant. (A) Clinical response
`(decrease in CDAI score from baseline ⱖ70 points). (B) Clinical
`remission (CDAI score ⬍150 points).
`
`

`

`1092 SANDBORN ET AL.
`
`GASTROENTEROLOGY Vol. 121, No. 5
`
`those patients previously treated with infliximab and
`patients naive to infliximab. For 14 of the 16 patients
`treated with infliximab within the previous year, a sub-
`jective classification of each patient’s prior response to
`infliximab was available. Because the randomization
`schedule did not stratify on prior use of infliximab,
`neither of the 2 patients with documented nonresponse
`to infliximab within the prior year ended up being
`randomized to etanercept. Of the 9 patients with a
`response to infliximab in the last year who were treated
`with etanercept, 3 (33%) responded, a response rate very
`similar to the overall response rate for etanercept (39%)
`and similar to the response rate in those patients without
`any prior use of infliximab (45%). Among the 3 patients
`randomized to etanercept with an unkown response to
`prior infliximab treatment, 1 (33%) responded to etan-
`ercept. Thus, the lack of efficacy for etanercept in our
`study cannot be explained by selection of patients who
`were previously unresponsive to anti–TNF-␣ therapy
`with an alternative agent.
`Two different anti–TNF-␣ therapies have shown effi-
`cacy for rheumatoid arthritis: etanercept (a genetically
`engineered fusion protein consisting of 2 identical chains
`of the recombinant human TNF-receptor p75 monomer
`fused with the Fc domain of human IgG1),20 –24 and
`infliximab (a genetically engineered IgG1 murine-hu-
`man chimeric monoclonal antibody).13–16,29 Similarly, 1
`anti–TNF-␣ therapy, infliximab, has shown efficacy for
`Crohn’s disease10 –12; and another anti–TNF-␣ therapy,
`CDP571 (a genetically engineered IgG4 humanized
`monoclonal antibody constructed by linking the compli-
`mentarity-determining region of a mouse anti-human
`TNF-␣ monoclonal antibody to a human IgG4 anti-
`body), has shown preliminary evidence of efficacy for
`Crohn’s disease.30 –32 Given that etanercept and inflix-
`imab are both effective in rheumatoid arthritis, and that
`infliximab and CDP571 are both definitely or probably
`
`Figure 2. Median scores at each study visit, according to treatment
`group. None of the differences were statistically significant. (A) CDAI;
`(B) IBDQ quality of life index.
`
`treatment groups in the proportions of patients with the
`most frequent adverse events (frequency ⬎5%; Table 3).
`There were no clinically important differences between
`the treatment groups with respect to changes in labora-
`tory assessments.
`
`Discussion
`We found etanercept, when prescribed at 25 mg
`subcutaneously twice weekly, was not effective for in-
`ducing a clinical response at 4 weeks in patients with
`moderately to severely active Crohn’s disease, using a
`decrease in baseline CDAI score of ⱖ70 points or a CDAI
`score ⬍150 points as the definition of response. This lack
`of efficacy was supported by the lack of efficacy for any of
`the secondary endpoints including clinical response at 2
`or 8 weeks, clinical remission at 2, 4, or 8 weeks, fistula
`improvement, fistula closure, CDAI scores, or IBDQ
`scores. Twenty of the 43 patients had previously received
`infliximab; there were no significant differences in the
`rates of clinical response to etanercept or placebo for
`
`Table 3. Adverse Events in the 2 Treatment Groups
`
`Variable
`
`No. of adverse events
`No. of patients with adverse events
`No. of patients with serious adverse events
`No. of patients with severe adverse events
`Most frequent adverse events (no. of events)
`Headache
`New injection site reactions
`Asthenia
`Abdominal pain
`Mild anemia
`Skin disorders
`
`Placebo
`group
`(n ⫽ 20)
`
`19
`10 (50%)
`2 (10%)
`3 (15%)
`
`1 (5%)
`1 (5%)
`0 (0%)
`2 (10%)
`0 (0%)
`0 (0%)
`
`Etanercept
`group
`(n ⫽ 23)
`
`34
`17 (74%)
`1 (4%)
`1 (4%)
`
`3 (13%)
`3 (13%)
`2 (9%)
`0 (0%)
`2 (9%)
`2 (9%)
`
`Difference (%)
`
`95% Confidence
`intervals
`
`24
`⫺6
`⫺11
`
`8
`8
`9
`⫺10
`9
`9
`
`⫺5% to 48%
`⫺26% to 13%
`⫺32% to 9%
`
`⫺12% to 28%
`⫺12% to 28%
`⫺9% to 27%
`⫺30% to 6%
`⫺9% to 27%
`⫺9% to 27%
`
`

`

`November 2001
`
`ETANERCEPT FOR CROHN’S DISEASE 1093
`
`effective in Crohn’s disease, it is reasonable to expect that
`there would be an anti–TNF-␣ class effect in these
`diseases. Thus, our finding that etanercept was not effec-
`tive for Crohn’s disease is surprising. There are 4 poten-
`tial explanations for this observed lack of efficacy (study
`design, sample size, etanercept dose, and differences in
`mechanism of action or bioavailability in gut tissue for
`different anti-TNF biologic therapies).
`The entry criteria as well as the primary and secondary
`endpoints for our study were nearly identical to those
`performed with infliximab and CDP571.10,30,31 Al-
`though nearly half of the patients in our study had
`previously been treated with infliximab, prior treatment
`with infliximab did not influence response to etanercept
`(see above). Thus, it seems unlikely that differences in
`study design or patient populations from other studies of
`anti-TNF therapies for Crohn’s disease account for the
`lack of efficacy observed in our study. Similarly, it is
`unlikely that small sample size explains the negative
`result of our study for several reasons. First, the observed
`placebo response rate was actually higher than for etan-
`ercept (9 of 20, 45%, vs. 9 of 23, 39%, respectively). The
`observed response rate in placebo patients is statistically
`inconsistent with the a priori assumption of a 15%
`response rate (i.e., 95% CI for 45% is 23%– 68%). In
`addition, the observed response rate for etanercept pa-
`tients has a 95% CI of 20%– 61%. Again, this is incon-
`sistent with the a priori assumption of 65%. The chance
`of a type II error (i.e., missing a clinically important
`difference, in this case, approximately 40%), was less
`than 20%. Second, another placebo-controlled dose find-
`ing study of etanercept in a similar Crohn’s disease
`population of 49 patients had a similar negative outcome
`and a similar high placebo response rate (50%; Immunex
`Corporation, Seattle, WA, data on file). Although there
`are differences between etanercept,
`infliximab, and
`CDP571 that could potentially lead to differences in
`response, there is no clear pattern in these differences
`that would explain the lack of efficacy for etanercept.
`Infliximab is an IgG1 isotype, whereas CDP571 is an
`IgG4 isotype. Etanercept has an Fc domain of IgG1
`attached to the active receptor. Only infliximab fixes
`complement and causes antibody-dependent cytotoxicity–
`mediated destruction of TNF-␣–producing cells such as
`T lymphocytes, whereas etanercept, infliximab, and CDP571
`all bind soluble and membrane-bound TNF-␣.4,5 There
`may be differences in binding affinities that could ac-
`count for a potential difference in response rates, but
`such differences have not been clinically relevant in
`patients with rheumatoid arthritis. It is also possible that
`for some as yet unexplained reason, etanercept is not
`
`bioavailable to the gut mucosa. Finally, the dose of
`etanercept used in our study, 25 mg administered sub-
`cutaneously twice weekly, is the dose used in patients
`with rheumatoid arthritis. This dose is based on dose
`finding and pharmacokinetic studies of etanercept in
`healthy volunteers and patients with rheumatoid arthri-
`tis that showed a dose response for intravenous and
`subcutaneous etanercept at doses up to 25 mg twice
`weekly.20 –22,33 It is possible that greater doses of etaner-
`cept are required for efficacy in Crohn’s disease. A dose
`finding study of etanercept at doses greater than 25 mg
`twice weekly in patients with Crohn’s disease could be
`conducted to explore this hypothesis.
`Etanercept was well tolerated. The frequency of severe
`and serious adverse events (according to COSTART def-
`initions) was similar in the etanercept and placebo
`groups. The frequency of new injection reactions in
`etanercept-treated
`patients was
`13% (95% CI,
`3%–34%). The favorable adverse event profile of etaner-
`cept in patients with Crohn’s disease is similar to that
`observed in patients with rheumatoid arthritis.20 –24
`In conclusion, subcutaneous etanercept at a dose of 25
`mg twice weekly is safe but not effective for the treat-
`ment of patients with moderate to severe Crohn’s disease.
`The dose of etanercept administered in this study is that
`approved for rheumatoid arthritis. Higher doses or more
`frequent dosing may be required to attain a response in
`patients with active Crohn’s disease.
`
`References
`1. Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald
`TT. Serum concentrations of tumour necrosis factor alpha in
`childhood chronic inflammatory bowel disease. Gut 1991;32:
`913–917.
`2. Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT. Loca-
`tion of tumour necrosis factor alpha by immunohistochemistry in
`chronic inflammatory bowel disease. Gut 1993;34:1705–1709.
`3. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT.
`Tumour necrosis factor alpha in stool as a marker of intestinal
`inflammation. Lancet 1992;339:89 –91.
`4. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease.
`Gut 1997;40:443– 448.
`5. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for
`inflammatory bowel disease: a review of agents, pharmacology,
`clinical results, and safety. Inflamm Bowel Dis 1999;5:119 –133.
`6. Smith CA, Davis T, Anderson D, Solam L, Beckmann MP, Jerzy R,
`Dower SK, Cosman D, Goodwin RG. A receptor for tumor necrosis
`factor defines an unusual family of cellular and viral proteins.
`Science 1990;248:1019 –1023.
`7. Loetscher H, Pan YC, Lahm HW, Gentz R, Brockhaus M, Tabuchi
`H, Lesslauer W. Molecular cloning and expression of the human
`55 kd tumor necrosis factor receptor. Cell 1990;61:351–359.
`8. Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D. A
`tumor necrosis factor-binding protein purified to homogeneity
`from human urine protects cells from tumor necrosis factor tox-
`icity. J Biol Chem 1989;264:11974 –11980.
`9. Olsson I, Lantz M, Nilsson E, Peetre C, Thysell H, Grubb A, Adolf
`
`

`

`1094 SANDBORN ET AL.
`
`GASTROENTEROLOGY Vol. 121, No. 5
`
`G. Isolation and characterization of a tumor necrosis factor bind-
`ing protein from urine. Eur J Haematol 1989;42:270 –275.
`10. Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH,
`Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ. A short-
`term study of chimeric monoclonal antibody cA2 to tumor necro-
`sis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study
`Group. N Engl J Med 1997;337:1029 –1035.
`11. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Van
`Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody
`KL, Schaible TF, Van Deventer SJ. Infliximab for the treatment of
`fistulas in patients with Crohn’s disease. N Engl J Med 1999;
`340:1398 –1405.
`12. Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB,
`Present DH, Mayer L, Van Hogezand RA, Braakman T, DeWoody
`KL, Schaible TF, Van Deventer SJ. Efficacy and safety of retreat-
`ment with anti-tumor necrosis factor antibody (infliximab) to main-
`tain remission in Crohn’s disease. Gastroenterology 1999;117:
`761–769.
`13. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen
`JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H. Randomised
`double-blind comparison of chimeric monoclonal antibody to tu-
`mour necrosis factor alpha (cA2) versus placebo in rheumatoid
`arthritis. Lancet 1994;344:1105–1110.
`14. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfar-
`lane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF,
`Feldmann M. Therapeutic efficacy of multiple intravenous infu-
`sions of anti-tumor necrosis factor alpha monoclonal antibody
`combined with low-dose weekly methotrexate in rheumatoid ar-
`thritis. Arthritis Rheum 1998;41:1552–1563.
`15. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M,
`Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab
`(chimeric anti-tumour necrosis factor alpha monoclonal antibody)
`versus placebo in rheumatoid arthritis patients receiving concom-
`itant methotrexate: a randomised phase III trial. ATTRACT Study
`Group. Lancet 1999;354:1932–1939.
`16. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld
`FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M,
`Harriman GR, Maini RN. Infliximab and methotrexate in the treat-
`ment of rheumatoid arthritis. N Engl J Med 2000;343:1594–1602.
`17. Schaible TF. Long term safety of infliximab. Can J Gastroenterol
`2000;14(suppl C):29C–32C.
`18. Winter G, Harris WJ. Humanized antibodies. Immunol Today
`1993;14:243–246.
`19. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE,
`Fung VP, Madani H, Wid