CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:888 – 893
`
`Onercept for Moderate-to-Severe Crohn’s Disease: A
`Randomized, Double-Blind, Placebo-Controlled Trial
`
`PAUL RUTGEERTS,* WILLIAM J. SANDBORN,‡ RICHARD N. FEDORAK,§ DANIEL RACHMILEWITZ,储
`DINO TARABAR,¶ PETER GIBSON,# OLE HAAGEN NIELSEN,** GARY WILD,‡‡
`STEFAN SCHREIBER,§§ CLAUDIA PENA ROSSI,¶¶ MONIA ZIGNANI,¶¶
`AND THE ONERCEPT STUDY GROUP储 储
`*University Hospital Gasthuisberg, Leuven, Belgium; ‡Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota; §University of
`Alberta Hospital, Edmonton, Canada; 储Shaare Zedek Medical Center, Jerusalem, Israel; ¶Military Medical Academy, Belgrade, Yugoslavia;
`#Box Hill Hospital, Box Hill, Australia; **Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; ‡‡Montreal General Hospital,
`Montreal, Canada; §§Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany; and the ¶¶Serono International
`SA, Geneva, Switzerland; 储 储Members of the Onercept Study Group are listed in the Acknowledgment section
`
`Background & Aims: Onercept is a recombinant, soluble
`to tumor necrosis factor-␣.
`human p55 receptor
`Methods: A randomized, double-blind, placebo-con-
`trolled, dose-ranging trial was performed to evaluate the
`efficacy of onercept induction therapy in patients with
`Crohn’s disease (CD). Patients (n ⴝ 207) with moderate-
`to-severe acute or chronic active CD were randomized to
`receive subcutaneous onercept (10, 25, 35, or 50 mg) or
`placebo 3 times weekly for 8 weeks. Primary analysis
`was induction of remission (defined as a CD activity
`index score < 150) at week 8. Results: A total of 104
`patients had acute active CD. Remission rates at week 8
`were 23.5% for placebo (n ⴝ 17), and 34.8%, 20.0%,
`26.1%, and 28.6% for onercept 10 mg (n ⴝ 23), 25 mg
`(n ⴝ 20), 35 mg (n ⴝ 23), and 50 mg (n ⴝ 21),
`respectively (P ⴝ .98). A total of 103 patients had
`chronic active CD. Remission rates at week 8 were
`23.8% for placebo (n ⴝ 21), and 23.8%, 9.1%, 35.3%,
`and 13.6% for onercept 10 mg (n ⴝ 21), 25 mg (n ⴝ
`22), 35 mg (n ⴝ 17), and 50 mg (n ⴝ 22), respectively
`(P ⴝ .66). There were no differences between treatment
`groups in the incidence of adverse events. However,
`mild-to-moderate injection-site reactions occurred in up
`to 12% of onercept-treated patients. Conclusions: Oner-
`cept was well tolerated but was not effective at the
`doses studied in patients with active CD.
`
`Tumor necrosis factor (TNF)-␣ is a proinflammatory
`
`cytokine that plays a pivotal part in the pathogenesis
`of Crohn’s disease (CD).1 A number of anti-TNF thera-
`pies have been developed for the treatment of CD. The
`chimeric anti-TNF monoclonal antibody, infliximab, has
`been shown to be effective for the control of active CD
`refractory to standard therapies2 and for the healing of
`fistulas.3 Infliximab is also an effective maintenance ther-
`apy for patients with CD who respond to the initial
`treatment.4 However, patients treated with chimeric an-
`
`tibodies are at risk for developing antichimeric antibod-
`ies.5 The presence of such antibodies can be associated
`with a decreased response to treatment and an increased
`risk for infusion reactions.5 Hence, there is considerable
`interest in developing alternative anti-TNF therapies for
`the treatment of CD.
`Onercept (Serono International SA, Geneva, Switzer-
`land) is a recombinant form of the soluble human p55
`TNF-␣ receptor (also known as TNF-binding protein 1)
`produced by recombinant DNA technology. Its putative
`mechanism of action involves neutralizing the effects of
`TNF-␣ by the formation of high-affinity complexes.
`Onercept has a favorable safety profile in healthy volun-
`teers.6 A randomized, open-label, pilot study (11.7 vs 50
`mg 3 times weekly for 2 weeks) in a small number of
`patients with active CD7 indicated that onercept was
`well tolerated and treatment was associated with a rapid
`decrease in Crohn’s disease activity index (CDAI).8 Im-
`provement was sustained for 2– 4 months after stopping
`treatment. The effects of onercept appeared to be dose
`dependent because patients treated with 50 mg 3 times
`weekly showed more improvement than those random-
`ized to 11.7 mg 3 times weekly.
`Based on these results, we designed a randomized,
`double-blind, placebo-controlled, dose-finding study of
`onercept in patients with active CD.
`
`Abbreviations used in this paper: AACD, acute active Crohn’s dis-
`ease; CACD, chronic active Crohn’s disease; CD, Crohn’s disease; CDAI,
`Crohn’s disease activity index; CRP, C-reactive protein; TBP-1, TNF-
`binding protein 1; TNF, tumor necrosis factor.
`© 2006 by the American Gastroenterological Association Institute
`1542-3565/06/$32.00
`doi:10.1016/j.cgh.2006.04.022
`
`

`

`July 2006
`
`ONERCEPT IN CROHN’S DISEASE 889
`
`Methods
`Participants
`
`The study was performed at 27 centers in 13 countries
`in North America, Europe, and Asia. Participants were pa-
`tients aged 18 years or older with a previously established
`diagnosis of CD of at least 6 months’ duration. Patients were
`required to have active CD with a CDAI between 250 and 400
`at baseline. The study population was stratified further into
`patients with acute active Crohn’s disease (AACD) and those
`with chronic active Crohn’s disease (CACD) according to the
`definitions provided by the European Agency for the Evalua-
`tion of Medicinal Products.9 Patients with AACD were re-
`quired to have received no glucocorticoid treatment for 4
`weeks and no immunosuppressants for 3 months before the
`start of the study. Patients with CACD were defined as those
`with active disease despite treatment with oral glucocorticoids
`and/or immunosuppressants in the 3 months before the start of
`the study. Patients were required to have a white cell count of
`3.5 ⫻ 109/L or more, a neutrophil count of 1.5 ⫻ 109/L or
`more, a platelet count of 100 ⫻ 109/L or more, and a hemo-
`globin level of 8.5 g/dL or more. Maintenance treatment with
`oral sulfasalazine or mesalamine derivatives in the 4 weeks
`before the study was allowed, but not required.
`Exclusion criteria included prior treatment with cytokines,
`anticytokines, intercellular adhesion molecule 1, antisense oli-
`gonucleotide (alicaforsen, Isis 2302 [Isis Pharmaceuticals Inc,
`Carlsbad, CA]), or anti-CD4; inadequate liver or renal func-
`tion; symptoms of stenosis regarded as mainly noninflamma-
`tory; presence of a stoma; history of small-bowel resection;
`active infection; history of cancer; need for emergency surgery;
`and elective surgery planned during the study.
`The study was approved by the independent ethics commit-
`tee or institutional review board at each center. All patients
`gave written informed consent before entry into the study.
`
`Treatments
`
`Patients were assigned randomly to receive placebo
`or 10 mg, 25 mg, 35 mg, or 50 mg of onercept 3 times
`weekly by subcutaneous
`injection. Treatment
`lasted 8
`weeks, with follow-up visits at 2, 4, and 12 weeks after
`treatment.
`
`Outcomes
`
`The primary efficacy end point was the proportion of
`patients in remission (defined as a CDAI score of ⱕ 150) after
`8 weeks. Secondary outcome measures evaluated the effect of
`treatment with onercept on disease-related symptoms as as-
`sessed by the CDAI, C-reactive protein (CRP) as a biological
`marker of inflammation, and requirement of additional ther-
`apy for CD (treatment failure). Safety outcomes included
`changes in physical examination, vital signs, and clinical lab-
`oratory test results, and incidence and severity of adverse
`events.
`
`Sample Size
`
`A sample size of 200 was chosen for the study with 40
`patients per treatment group; 100 of these patients were to
`have AACD and 100 were to have CACD. Randomization was
`stratified by disease category (AACD or CACD) and by center;
`therefore, 20 patients with each type of disease would be
`recruited per treatment group. A remission rate of 20% was
`expected for placebo-treated patients, with expected remission
`rates of 25%, 35%, 50%, and 65% in the 10 mg, 25 mg, 35
`mg, or 50 mg of onercept dose groups, respectively. With a
`sample size of 200, using the ␹2 test for trend (2-sided at the
`.05 significance level), the power to detect a significance would
`be 77%. By using logistic regression for linear trend (all else
`being constant), the power would be 93%. Because this was a
`dose-finding study, we made no precise assumptions about the
`type of trend (linear or nonlinear) that would be observed over
`the doses.
`Randomization and Blinding
`
`Patients were assigned to treatment by a centralized
`randomization procedure using an interactive voice-response
`system located at the International Drug Development Insti-
`tute in Brussels, Belgium. The treatment allocation was strat-
`ified by disease (AACD or CACD) and center. Treatment
`allocation was processed using a deterministic minimization
`technique balancing across the type of disease and center. The
`randomization algorithm included the availability of the drug
`at a center at the time of randomization—if medication for a
`certain dose group was not available, then randomization
`would exclude that dose group for the randomization of that
`patient. Solutions of onercept and placebo were identical in
`appearance, and labeling and packaging were prepared to
`preserve the blinded nature of the study.
`Statistical Methods
`
`The intent-to-treat population included all random-
`ized patients who received at least 1 injection of study medi-
`cation, analyzed as randomized. The safety population in-
`cluded all randomized patients who received at least 1
`injection of study medication, analyzed as treated.
`The primary efficacy end point (proportion of patients in
`remission after 8 weeks of treatment) was plotted with 95%
`confidence intervals by dose level for visual comparison. The
`Cochran–Armitage trend test was used to test for a dose-
`efficacy relationship at a significance level of .05 (2-sided). The
`primary efficacy end point also was modeled using logistic
`regression to investigate the effect of specific covariates. Ad-
`justments were made for covariates that significantly affected
`the likelihood of achieving remission at week 8.
`The primary end point and secondary end points based on
`categoric data were evaluated for each treatment dose vs pla-
`cebo and for total onercept-treated vs placebo using the Coch-
`ran–Mantel–Haenszel test or, if the numbers in each cell were
`not sufficient, using the Fisher exact test. Analysis of variance
`was used to analyze continuous secondary end points. If nor-
`mality assumptions were not met, transformations of the end
`
`

`

`890 RUTGEERTS ET AL
`
`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7
`
`Table 1. Baseline Demographic and Clinical Characteristics of the Intent-to-Treat Population
`
`Onercept
`
`Age, y
`Weight, kg
`Sex
`Male
`Female
`Duration of CD, mo
`Baseline CDAI
`AACD
`CACD
`Baseline CRP (mg/dL)
`AACD
`CACD
`Disease location
`Ileum
`Colon, left side
`Colon, right side
`Jejunum
`Duodenum
`Other
`Concomitant
`medications
`Glucocorticoids
`Azathioprine
`Antibiotics
`Maintenance
`therapy
`Other
`
`Placebo (n ⫽ 38)
`
`10 mg (n ⫽ 44)
`
`25 mg (n ⫽ 42)
`
`35 mg (n ⫽ 40)
`
`50 mg (n ⫽ 43)
`
`Total (n ⫽ 207)
`
`39.1 ⫾ 11.3
`70.0 ⫾ 13.4
`
`22 (57.9%)
`16 (42.1%)
`150.4 ⫾ 94.8
`
`34.0 ⫾ 11.0
`66.7 ⫾ 14.4
`
`15 (34.1%)
`29 (65.9%)
`93.5 ⫾ 69.3
`
`35.7 ⫾ 11.5
`70.3 ⫾ 19.8
`
`39.2 ⫾ 13.2
`67.1 ⫾ 15.6
`
`35.6 ⫾ 10.8
`67.8 ⫾ 14.7
`
`36.6 ⫾ 11.7
`68.3 ⫾ 15.7
`
`21 (50.0%)
`21 (50.0%)
`146.3 ⫾ 101.9
`
`17 (42.5%)
`23 (57.5%)
`125.2 ⫾ 87.1
`
`18 (41.9%)
`25 (58.1%)
`112.4 ⫾ 102.6
`
`93 (44.9%)
`114 (55.1%)
`124.7 ⫾ 93.4
`
`311.9 ⫾ 51.4
`300.5 ⫾ 37.7
`
`307.2 ⫾ 48.2
`297.8 ⫾ 46.2
`
`312.2 ⫾ 52.4
`341.0 ⫾ 64.0
`
`325.3 ⫾ 44.0
`324.7 ⫾ 51.9
`
`315.8 ⫾ 49.6
`308.8 ⫾ 47.3
`
`314.7 ⫾ 48.4
`314.4 ⫾ 51.9
`
`2.7 ⫾ 3.3
`.9 ⫾ .7
`
`29 (76.3%)
`14 (36.8%)
`13 (34.2%)
`2 (5.3%)
`3 (7.9%)
`5 (13.2%)
`
`13 (34.2%)
`9 (23.7%)
`5 (13.2%)
`19 (50.0%)
`
`1.5 ⫾ 1.7
`2.2 ⫾ 2.9
`
`31 (72.1%)
`19 (44.2%)
`22 (51.2%)
`1 (2.3%)
`1 (2.3%)
`4 (9.3%)a
`
`12 (27.3%)
`9 (20.5%)
`9 (20.5%)
`21 (47.7%)
`
`2.5 ⫾ 2.3
`1.2 ⫾ 1.1
`
`25 (59.5%)
`20 (47.6%)
`19 (45.2%)
`1 (2.4%)
`0
`6 (14.3%)
`
`14 (33.3%)
`11 (26.2%)
`8 (19.0%)
`18 (42.9%)
`
`3.8 ⫾ 5.1
`.6 ⫾ .5
`
`30 (75.0%)
`22 (55.0%)
`19 (47.5%)
`3 (7.5%)
`0
`3 (7.5%)
`
`13 (32.5%)
`11 (27.5%)
`12 (30.0%)
`18 (45.0%)
`
`2.6 ⫾ 1.7
`2.0 ⫾ 2.0
`
`34 (79.1%)
`24 (55.8%)
`14 (32.6%)
`1 (2.3%)
`1 (2.3%)
`5 (11.6%)
`
`21 (48.8%)
`10 (23.3%)
`11 (25.6%)
`20 (46.5%)
`
`2.6 ⫾ 3.2
`1.4 ⫾ 1.8
`
`149 (72.3%)
`99 (48.1%)
`87 (42.2%)
`8 (3.9%)
`5 (2.4%)
`23 (11.2%)
`
`73 (35.3%)
`50 (24.2%)
`45 (21.7%)
`96 (46.4%)
`
`34 (89.5%)
`
`32 (72.7%)
`
`32 (76.2%)
`
`34 (85.0%)
`
`35 (81.4%)
`
`167 (80.7%)
`
`NOTE. Results are presented as mean ⫾ SD, except for sex, disease location, and concomitant medications.
`aData on disease location were not available for 1 patient in this group.
`
`points or analysis of variance on the ranks could be performed.
`Adjustment by region was performed if feasible. In addition,
`95% confidence intervals were calculated, where appropriate,
`for secondary end points.
`Times to event (remission, clinical response, relapse) end
`points were estimated using the Kaplan–Meier procedure and
`tested for a significant difference between the active treatments
`and placebo using the log-rank test.
`
`Measurement of Antibodies to Onercept
`and Autoimmunity
`
`to TNF-binding protein 1
`antibodies
`Levels of
`(TBP-1) in serum were determined using a semiquantitative
`radioimmunoprecipitation assay.
`Antinuclear antibodies were determined by an indirect im-
`munofluorescence technique on Sjögren’s syndrome A–trans-
`fected Hep2 cells. Sera expressing antinuclear antibodies at a
`dilution of at least 1:80 were examined further for double-
`stranded DNA.
`
`Results
`Participants
`
`The study began in November 2001 and finished
`in February 2003. A total of 230 patients were screened
`
`for participation in the study, of whom 23 were excluded
`and 207 were randomized. The majority of randomized
`patients (201/207 [97.1%]) were classified as Caucasian,
`3 patients (1.4%) were Asian, and 3 (1.4%) belonged to
`other racial groups. The randomized groups were well
`matched for most baseline demographic and disease char-
`acteristics (Table 1). The mean baseline CRP levels dif-
`fered between treatment groups, being lowest in the
`onercept 10-mg group (1.5 ⫾ 1.7 mg/dL) and highest in
`the onercept 35-mg group (3.8 ⫾ 5.1 mg/dL).
`
`Efficacy Results
`
`For the primary efficacy end point in the intent-
`to-treat population there was no significant trend across
`dose groups for the proportion of patients in remission at
`week 8 (P ⫽ .78, Cochran–Armitage trend test). The
`same was true for the AACD group (P ⫽ .98) and the
`CACD group (P ⫽ .66). Similarly, there were no signif-
`icant differences in remission rates at week 8 between the
`placebo group and any onercept-treated group for both
`the AACD and the CACD disease types. Other efficacy
`end points also failed to show statistically significant
`effects of onercept treatment (Table 2), although the
`
`

`

`July 2006
`
`ONERCEPT IN CROHN’S DISEASE 891
`
`Table 2. Summary of Key Efficacy Results (Intent-to-Treat Population)
`
`Onercept
`
`Placebo (n ⫽ 38)
`
`10 mg (n ⫽ 44)
`
`25 mg (n ⫽ 42)
`
`35 mg (n ⫽ 40)
`
`50 mg (n ⫽ 43)
`
`Total (n ⫽ 207)
`
`AACD
`(n ⫽ 17)
`
`CACD
`(n ⫽ 21)
`
`AACD
`(n ⫽ 23)
`
`CACD
`(n ⫽ 21)
`
`AACD
`(n ⫽ 20)
`
`CACD
`(n ⫽ 22)
`
`AACD
`(n ⫽ 23)
`
`CACD
`(n ⫽ 17)
`
`AACD
`(n ⫽ 21)
`
`CACD
`(n ⫽ 22)
`
`AACD
`(n ⫽ 104)
`
`CACD
`(n ⫽ 103)
`
`4 (23.5%)
`2 (11.8%)
`
`5 (23.8%)
`4 (19.0%)
`
`8 (34.8%)
`5 (21.7%)
`
`5 (23.8%)
`2 (9.5%)
`
`4 (20.0%)
`3 (15.0%)
`
`2 (9.1%)
`1 (4.5%)
`
`6 (26.1%)
`5 (21.7%)
`
`6 (35.3%)
`5 (29.4%)
`
`6 (28.6%)
`4 (19.0%)
`
`3 (13.6%)
`2 (9.1%)
`
`28 (26.9%)
`19 (18.3%)
`
`21 (20.4%)
`14 (13.6%)
`
`7 (41.2%)
`
`7 (33.3%)
`
`10 (43.5%)
`
`6 (28.6%)
`
`10 (50.0%)
`
`7 (31.8%) 11 (47.8%)
`
`9 (52.9%)
`
`7 (33.3%)
`
`7 (31.8%)
`
`45 (43.3%)
`
`36 (35.0%)
`
`3 (17.6%)
`
`5 (23.8%)
`
`3 (13.0%)
`
`7 (33.3%)
`
`3 (15.0%)
`
`6 (27.3%) 11 (47.8%)
`
`2 (11.8%)
`
`7 (33.3%)
`
`7 (31.8%)
`
`27 (26.0%)
`
`27 (26.2%)
`
`Remission at week 8
`Remission at weeks 8
`and 10
`Response (100-point
`decrease in CDAI)
`at week 8
`Treatment failure
`
`CACD group treated with 35 mg of onercept consis-
`tently achieved numerically better results than the pla-
`cebo group.
`Logistic regression analysis indicated that patients
`with lower baseline CDAI were more likely to be in
`remission at week 8 than those with higher baseline
`values, regardless of treatment group or disease type.
`Based on this analysis, the primary end point of remis-
`sion at week 8 was adjusted for baseline CDAI. For the
`CACD population, the odds of being in remission at
`week 8 were 3-fold higher for patients who received 35
`mg of onercept compared with the placebo group after
`adjustment for baseline CDAI (Table 3).
`Changes in CRP levels during the study showed no
`significant trends across dose groups for the study pop-
`ulation as a whole or in patients with increased CRP
`
`levels (defined as ⱖ 1.5 mg/dL) at baseline. Similarly, no
`trends in CRP evolution were noted in the AACD or
`CACD subpopulations. High CRP levels at baseline did
`not predict better response and did not separate the
`active treatment groups from the placebo group.
`
`Safety Results
`
`Overall, 147 (71.0%) of the 207 patients experi-
`enced at least 1 adverse event during the study. The
`incidence of adverse events, of drug-related adverse
`events, and of adverse events possibly related to the
`effects of anti-TNF agents (including infections, malig-
`nancies, autoimmune disorders, and blood dyscrasias) did
`not increase with an increased dose of onercept (Table 4).
`The most commonly reported adverse events were head-
`ache
`(41 patients
`[19.8%]), nausea
`(23 patients
`
`Table 3. Logistic Regression Analysis for Remission at Week 8 (Intent-to-Treat Population)
`
`Onercept
`
`Statistic
`
`10 mg
`
`25 mg
`
`35 mg
`
`50 mg
`
`As-stratified AACD group
`Remission rate
`Unadjusted odds ratio (95% CI)a
`Odds ratio adjusted for baseline
`CDAI (95% CI)a
`As-stratified CACD group
`Remission rate
`Unadjusted odds ratio (95% CI)a
`Odds ratio adjusted for baseline
`CDAI (95% CI)a
`P valuea for unadjusted odds ratio
`P valuea for adjusted odds ratio
`Expanded CACD group
`Remission rate
`Unadjusted odds ratio (95% CI)a
`Odds ratio adjusted for baseline
`CDAI (95% CI)a
`P valuea for unadjusted odds ratio
`P valuea for adjusted odds ratio
`
`CI, confidence interval.
`aComparison of active treatment vs placebo.
`
`8/23 (35%)
`1.73 (.42–7.11)
`1.75 (.39–7.94)
`
`4/20 (20%)
`.81 (.17–3.90)
`.80 (.16–4.04)
`
`6/26 (26%)
`1.15 (.27–4.92)
`1.32 (.29–5.93)
`
`6/21 (29%)
`1.30 (.30–5.64)
`1.35 (.31–6.01)
`
`5/21 (24%)
`1.25 (.28–5.53)
`1.15 (.25–5.30)
`
`2/22 (9%)
`.40 (.07–2.47)
`.58 (.09–3.80)
`
`7/18 (39%)
`2.55 (.60–10.84)
`3.36 (.72–15.68)
`
`3/22 (14%)
`.63 (.12–3.25)
`.61 (.11–3.53)
`
`.2062
`.1239
`
`8/36 (23%)
`1.5 (.43–5.13)
`1.55 (.43–5.52)
`
`4/35 (11%)
`.67 (.16–2.76)
`.86 (.20–3.71)
`
`10/28 (36%)
`2.89 (.84–9.89)
`4.29 (1.12–16.37)
`
`6/34 (18%)
`1.11 (.30–4.09)
`1.29 (.33–4.97)
`
`.0910
`.0331
`
`

`

`892 RUTGEERTS ET AL
`
`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 7
`
`Table 4. Summary of Frequency of Adverse Events (Safety Population)
`
`Onercept
`
`Patients experiencing at least 1
`Adverse event
`Drug-related adverse event
`Adverse event possibly
`related to anti-TNF therapy
`
`Placebo (n ⫽ 37)
`
`10 mg (n ⫽ 44) 25 mg (n ⫽ 42) 35 mg (n ⫽ 42) 50 mg (n ⫽ 42)
`
`Total (n ⫽ 207)
`
`26 (70.3%)
`19 (51.4%)
`12 (32.4%)
`
`31 (70.5%)
`25 (56.8%)
`11 (25.0%)
`
`28 (66.7%)
`22 (52.4%)
`14 (33.3%)
`
`30 (71.4%)
`27 (64.3%)
`12 (28.6%)
`
`32 (76.2%)
`25 (59.5%)
`16 (38.1%)
`
`147 (71.0%)
`118 (57.0%)
`65 (31.4%)
`
`[11.1%]), and injection-site erythema (22 patients
`[10.6%]). Injection-site erythema did not occur in any of
`the placebo-treated patients but was found in 2 (4.5%),
`4 (9.5%), 9 (21.4%), and 7 (16.7%) patients in the
`onercept 10-mg, 25-mg, 35-mg, and 50-mg dose
`groups, respectively. Unspecified injection-site reactions
`and injection-site pruritus also occurred more frequently
`in the onercept-treated patients than in the placebo
`group.
`The majority of adverse events (576/611 [94.3%])
`were mild or moderate in intensity. The incidence of
`severe adverse events was highest in the placebo group
`and did not increase with dose in the onercept-treated
`groups. Six (2.9%) of the 207 patients experienced at
`least 1 serious adverse event, including 1 patient each in
`the placebo, onercept 10-mg, and onercept 25-mg
`groups, and 3 patients in the onercept 35-mg group.
`Each event was reported just once and no particular
`trends were observed.
`Ten patients (4.8%) withdrew from the study because
`of adverse events: 3 patients each in the placebo and
`onercept 10-mg groups and 2 patients each in the oner-
`cept 35-mg and 50-mg groups. No clinically meaningful
`differences were noted across
`treatment groups
`in
`changes from baseline in hematology or biochemistry
`parameters, including thyroid function tests, or in vital
`signs.
`A total of 13 (7.9%) of the 165 onercept-treated
`patients with data available at baseline and postbaseline
`tested positive for antibodies to TBP-1 at 1 or more
`postbaseline time point, including 2 (4.9%), 1 (2.4%), 4
`(9.8%), and 6 (14.3%) patients in the 10-, 25-, 35-, and
`50-mg groups, respectively.
`At baseline, 57 (28.2%) of the 202 patients with the
`test performed were positive for antinuclear antibodies;
`an identical proportion of patients (28.2%; 46 of 163)
`was positive at the week 8/end-of-treatment visit. No
`differences were noted across the treatment groups in the
`proportions of patients who tested positive between the
`baseline and week 8/end-of-treatment visits.
`A total of 36 (18.5%) of the 195 patients with the test
`performed were positive for anti– double stranded DNA
`
`antibody at baseline; at week 8/end of treatment a total
`of 35 (22.3%) of 157 patients with the test performed
`were positive. None of the patients treated in this study
`had lupus or lupus-like syndrome reported as an adverse
`event.
`
`Discussion
`The results of this study did not show any efficacy
`of onercept for induction of remission in patients with
`active CD. There was no linear relationship between dose
`of onercept and remission at week 8 in patients with
`either AACD or CACD. Onercept did not show a sta-
`tistically significant superiority over placebo for any ef-
`ficacy outcome at any of the doses applied. These results
`do not confirm the promising data obtained in a previous
`open 2-dose study with onercept in active CD.7
`Onercept was well tolerated at all of the doses used in
`this study. The only adverse events that were more
`common with onercept than with placebo were injection-
`site reactions and these were mild or moderate.
`Based on their clinical history and baseline data, pa-
`tients were stratified into AACD and CACD popula-
`tions. The disease course did not appear to have any effect
`on response to therapy with onercept.
`The reason why onercept was not efficacious in the
`present study is unclear.
`First, the mechanism of action of an anti-TNF strategy
`may be of importance to determine its efficacy. Both
`infliximab and adalimumab induce apoptosis of T lym-
`phocytes and monocytes and are efficacious to treat
`CD,10 –14 whereas etanercept is not effective to treat CD
`at doses used in rheumatoid arthritis. Etanercept does
`not induce apoptosis. There are no experimental data on
`the induction of apoptosis by onercept. Inefficacy of
`onercept to induce apoptosis of monocytes and T cells
`might explain the current negative results.
`Second, the potency of TNF inhibition might be
`important. Another anti-TNF agent, certolizumab pegol
`(a pegylated Fab= fragment to TNF) that does not induce
`apoptosis,15 is effective for the treatment of CD.16 There-
`fore, the capacity for induction of apoptosis and clinical
`
`

`

`July 2006
`
`ONERCEPT IN CROHN’S DISEASE 893
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`Aliment
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`Pharmacol
`
`Ther
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`8. Best W. Development of a Crohn’s Disease Activity Index. Gas-
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`9. Committee for Proprietary Medicinal Products. Points to consider
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`ment of Crohn’s disease. London: European Agency for the Eval-
`uation of Medicinal Products, 2001.
`10. Lugering A, Schmidt M, Lugering N, et al. Infliximab induces
`apoptosis in monocytes from patients with chronic active Crohn’s
`disease by using a caspase-dependent pathway. Gastroenterol-
`ogy 2001;121:1145–1157.
`11. ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab
`treatment induces apoptosis of lamina propria T lymphocytes in
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`12. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab
`but not etanercept induces apoptosis in lamina propria T-lympho-
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`2003;124:1774 –1785.
`13. Ringheam M, Markowitz J, Chawla A, et al. Effects of Infliximab on
`apoptosis and reverse signaling of monocytes. Gastroenterology
`2003;124:A101.
`14. Shen C, Assche GV, Colpaert S, et al. Adalimumab induces
`apoptosis of human monocytes: a comparative study with inflix-
`imab and etanercept. Aliment Pharmacol Ther 2005;21:251–
`258.
`15. Fossati G, Nesbitt A. Effect of the anti-TNF agents adalimumab,
`etanercept, infliximab, and certolizumab pegol (CDP870) on the
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`Am J Gastroenterol 2005;100(Suppl):
`S298 –S299.
`16. Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Certolizumab
`pegol, a humanized anti-TNF pegylated Fab= fragment, is safe and
`effective in the maintenance of response and remission following
`induction in active Crohn’s disease: a phase III study (PRECiSE).
`Gut 2005;54:A82.
`17. Nesbitt AM, Henry AJ. High affinity and potency of the pegylated
`FAB= fragment CDP870 —a direct comparison with other anti-TNF
`agents. Am J Gastroenterol 2004;99:S253.
`18. Scallon B, Cai A, Solowski N, et al. Binding and functional com-
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`
`pilot
`
`study.
`
`efficacy of TNF binding proteins may not be linked. An
`alternative hypothesis to explain the differential efficacy
`between infliximab, adalimumab, and certolizumab pe-
`gol on one hand, and etanercept and onercept on the
`other, is differences in potency of TNF inhibition.17,18 A
`third explanation might be the choice of the onercept
`dose. A recent double-blind, placebo-controlled, clinical
`trial of onercept 150 mg 3 times weekly in patients with
`psoriasis showed a significant improvement in the Pso-
`riasis Area and Severity Index score after 12 weeks of
`treatment with onercept; onercept at doses of 50 and 100
`mg 3 times weekly also has been shown to be signifi-
`cantly more effective than placebo in the treatment of
`psoriatic arthritis (Menter A. Safety and efficacy of oner-
`cept in psoriasis and psoriatic arthritis. Paper presented
`at the 9th International Psoriasis Symposium, New
`York, NY, June 19 –22, 2003). Hence, it is possible that
`higher doses of onercept than were used in this study
`may be necessary to show efficacy in the treatment of CD.
`In conclusion, this dose-finding study with onercept
`did not identify an effective dose for inducing remission
`in patients with active CD. The effects of onercept on
`inflammatory cells in vitro and the potency of onercept
`for TNF inhibition need to be studied. It also needs to be
`determined if onercept has efficacy at higher doses in
`patients with CD.
`
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`5. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity
`on the long-term efficacy of infliximab in Crohn’s disease. N Engl
`J Med 2003;348:601– 608.
`6. Trinchard-Lugan I, Ho-Nguyen Q, Bilham WM, et al. Safety, phar-
`macokinetics and pharmacodynamics of recombinant human tu-
`mour necrosis factor-binding protein-1 (Onercept) injected by in-
`travenous, intramuscular and subcutaneous routes into healthy
`volunteers. Eur Cytokine Netw 2001;12:391–398.
`7. Rutgeerts P, Lemmens L, Van Assche G, et al. Treatment of
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`
`Address requests for reprints to: Professor Paul Rutgeerts, University
`Hospital Gasthuisberg, Leuven, Belgium. e-mail: Paul.Rutgeerts@uz.
`kuleuven.ac.be; fax: (32) 16-344-419.
`Supported by Serono International SA, Geneva, Switzerland. William
`J. Sandborn is a Consultant for and has received research support from
`Serono. Claudia Pena Rossi and Monia Zignani are employees of
`Serono.
`The authors thank the following members of the Onercept Study
`Group for their contributions to the study: Professor Dr. Tomica
`Milosavljevic (Yugoslavia), Professor Simon Bar-Meir (Israel), Dr. Bill
`Connell (Australia), Dr. Julián Panés-Díaz (Spain), Dr. Yvonne Dörffel
`(Germany), Professor Pierre Michetti (Switzerland), Dr. Paul Pavli (Aus-
`tralia), Professor Eran Goldin (Israel), Dr. A. Hillary Steinhart (Canada),
`Dr. Gerd Kullak-Ublick (Switzerland), Professor Ben-Zion Novis (Israel),
`Dr. Julio García-Paredes (Spain), Dr. AAM Geraedts (Netherlands),
`Professor Dr. Med. Wolfgang Kreisel (Germany), Dr. Choon Jin Ooi
`(Singapore), Dr. Russell Cohen (United States), and Dr. Wai-Keung
`Leung (Hong Kong, China).
`
`