Dose ranging pharmacokinetic trial of high‐dose alicaforsen (intercellular adhesion molecule‐1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Natalizumab induction and maintenance therapy for Crohn's disease. Health-Related Quality of Life During Natalizumab Maintenance Therapy for Crohn's Disease Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab Gene polymorphisms and serological markers of patients with active Crohn's disease in a clinical trial of antisense to ICAM‐1 * Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Frequency of glucocorticoid resistance and dependency in Crohn's disease.
Background and aims : To evaluate the safety , pharmacokinetics and clinical efficacy of the intercellular adhesion molecule‐1 antisense phosphorothioate oligonucleotide alicaforsen ( ISIS 2302 ) at 250–350 mg in Crohn 's disease BACKGROUND & AIMS Intercellular adhesion molecule 1 ( ICAM-1 ) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn 's disease . ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression . The aim of this study was to obtain preliminary assessment of tolerability , pharmacology , and efficacy of ISIS 2302 in Crohn 's disease . METHODS Twenty patients with active , steroid-treated Crohn 's disease were r and omized ( 3:1 , ISIS 2302 to placebo ) to receive over 26 days 13 intravenous infusions of ISIS 2302 ( 0.5 , 1 , or 2 mg/kg ) or saline placebo in a double-blinded study . The patients were followed up for 6 months . RESULTS At the end of treatment . 47 % ( 7 of 15 ) of ISIS 2302-treated and 20 % ( 1 of 5 ) of the placebo-treated patients were in remission ( Crohn 's Disease Activity Index [ CDAI ] < 150 ) . At the end of month 6 , 5 of these 7 ISIS 2302-treated remitters were still in remission , and a 6th patient had a CDAI of 156 . Corticosteroid usage was significantly lower ( P = 0.0001 ) in the ISIS 2302-treated patients . These findings were corroborated by significant increases in beta7 and alpha d bearing CD3 + peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period . CONCLUSIONS ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn 's disease BACKGROUND Natalizumab , a humanized monoclonal antibody against alpha4 integrin , inhibits leukocyte adhesion and migration into inflamed tissue . METHODS We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn 's disease . In the first trial , 905 patients were r and omly assigned to receive 300 mg of natalizumab or placebo at weeks 0 , 4 , and 8 . The primary outcome was response , defined by a decrease in the Crohn 's Disease Activity Index ( CDAI ) score of at least 70 points , at week 10 . In the second trial , 339 patients who had a response to natalizumab in the first trial were r and omly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56 . The primary outcome was a sustained response through week 36 . A secondary outcome in both trials was disease remission ( a CDAI score of less than 150 ) . RESULTS In the first trial , the natalizumab and placebo groups had similar rates of response ( 56 percent and 49 percent , respectively ; P=0.05 ) and remission ( 37 percent and 30 percent , respectively ; P=0.12 ) at 10 weeks . Continuing natalizumab in the second trial result ed in higher rates of sustained response ( 61 percent vs. 28 percent , P<0.001 ) and remission ( 44 percent vs. 26 percent , P=0.003 ) through week 36 than did switching to placebo . Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial . In an open-label extension study , a patient treated with natalizumab  died from progressive multifocal leukoencephalopathy , associated with the JC virus , a human polyomavirus . CONCLUSIONS Induction therapy with natalizumab for Crohn 's disease result ed in small , nonsignificant improvements in response and remission rates . Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks . The benefit of natalizumab will need to be weighed against the risk of serious adverse events , including progressive multifocal leukoencephalopathy . ( Clinical Trials.gov numbers , NCT00032786 and NCT00032799 . OBJECTIVES : We evaluated the effects of treatment on health-related quality of life ( HRQoL ) during a r and omized controlled trial of natalizumab maintenance therapy ( ENACT-2 ) using both disease-specific and generic measures . METHODS : Crohn 's disease patients who received natalizumab as induction therapy in ENACT-1 ( N = 724 ) and responded ( N = 339 ) were re-r and omized to ENACT-2 in which they received natalizumab 300 mg ( N = 168 ) or placebo ( N = 171 ) every 4 wk for 48 additional wk . Outcome measures were the change from baseline on the inflammatory bowel disease question naire ( IBDQ ) , the short form-36 ( SF-36 ) , the EuroQol-5D ( EQ-5D ) , and a subject global assessment . RESULTS : At entry into ENACT-1 , scores indicated substantially impaired HRQoL for both the disease-specific and general measures . Natalizumab responders showed clinical ly meaningful improvement in HRQoL over the course of the ENACT-1 study . During maintenance therapy , IBDQ and SF-36 scale scores of patients who responded to natalizumab induction and were re-r and omized to receive the drug in ENACT-2 ( N = 168 ) remained stable , while those re-r and omized to placebo ( N = 171 ) worsened . At week 60 , 48 wk after the initiation of maintenance therapy , the mean change from ENACT-1 baseline of all scales of the IBDQ and the SF-36 was significantly higher for those who continued to receive natalizumab ( P < 0.001 for all scales ) . The scores of patients who received maintenance natalizumab treatment were not statistically different from those of a cross-section of the U.S. population for 6 of 8 scales of the SF-36 . CONCLUSIONS : The substantial improvement in HRQoL experienced by patients who responded to natalizumab induction therapy was maintained during an additional 48 wk of maintenance therapy BACKGROUND & AIMS ISIS-2302 , an antisense oligonucleotide directed against intercellular adhesion molecule 1 , was effective in steroid refractory Crohn 's disease in a pilot trial . The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn 's disease ( CACD ) . METHODS A dose-interval , multicenter , placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD ( Crohn 's Disease Activity Index [ CDAI ] , 200 - 400 ) . The primary endpoint was steroid-free remission ( CDAI < 150 ) at week 14 . RESULTS Only 2 of 60 ( 3.3 % ) ISIS-2302-treated and no placebo patients reached the primary endpoint . Steroid-free remission at week 26 ( secondary endpoint ) was reached in 8 of 60 ( 13.3 % ) active treatment and 1 of 15 ( 6.7 % ) placebo patients . A greater proportion of ISIS-2302-treated than placebo patients achieved a steroid dose < 10 mg/day at weeks 14 and 26 ( 48.3 % vs. 33.3 % and 55.0 % vs. 40.0 % , respectively , and a glucocorticoid dose of 0 mg [ prednisone equivalent ] at week 26 [ 23.3 % vs. 6.7 % , respectively ] ) . Treatment with  ISIS-2302  was safe . The most common side effects were injection site reactions in the active treatment group ( 23 % in ISIS-2302-treated patients vs. none in placebo patients ) . No statistically significant differences in the frequency of side effects were detected between dose groups . CONCLUSIONS The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint . Positive trends were observed in some of the secondary endpoints BACKGROUND & AIMS Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease . This r and omized , double-blind , controlled trial assessed the efficacy and safety of MLN0002 , a monoclonal antibody targeting the alpha4beta7 integrin , in patients with active Crohn 's disease . METHODS Patients were r and omized to receive MLN0002 2.0 mg/kg ( n = 65 ) , MLN0002 0.5 mg/kg ( n = 62 ) , or placebo ( n = 58 ) by intravenous infusion on days 1 and 29 . The primary efficacy end point was clinical response ( > or=70-point decrement in the Crohn 's Disease Activity Index [ CDAI ] score ) on day 57 . Secondary end points were the proportions of patients with clinical remission ( CDAI score < or=150 ) and with an enhanced clinical response ( > or=100-point decrement in CDAI ) . Human anti-human antibody levels were measured . RESULTS Clinical response rates at day 57 were 53 % , 49 % , and 41 % in the MLN0002 2.0 mg/kg , MLN0002 0.5 mg/kg , and placebo groups . Clinical remission rates at day 57 were 37 % , 30 % , and 21 % , respectively ( P = .04 for the 2.0 mg/kg vs placebo comparison ) . At day 57 , 12 % and 34 % of patients in the 2.0- and 0.5-mg/kg groups had clinical ly significant human anti-human antibody levels ( titers > 1:125 ) . There was one infusion-related hypersensitivity reaction . The most common serious adverse event was worsening of Crohn 's disease . CONCLUSIONS This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission .  MLN0002 was well tolerated in patients with active Crohn 's disease Background : Natalizumab , a humanized monoclonal IgG4 antibody to & agr;4 integrin , was investigated as a treatment of active Crohn 's disease ( CD ) . The safety of natalizumab given in combination with infliximab has not previously been studied . Methods : Seventy‐nine adult patients with active CD ( Crohn 's Disease Activity Index [ CDAI ] score ≥ 150 ) despite ongoing infliximab treatment were r and omized 2:1 to receive 3 intravenous infusions of natalizumab  ( 300 mg ; n = 52 ) or placebo  ( n = 27 ) every 4 weeks . Patients received infliximab ( 5 mg/kg ) every 8 weeks for at least 10 weeks before r and omization and throughout the study . The primary objective was to assess the short‐term safety and tolerability  of natalizumab in patients concurrently receiving infliximab . Secondary and tertiary objectives included measures of efficacy , health‐related quality of life ( HRQoL ) , and effects on inflammatory markers . A subset of patients also participated in a pharmacokinetic/pharmacodynamic ( PK/PD ) analysis of the effects of concurrent treatment . Results : Incidence of adverse events ( AEs ) was similar in the treatment groups . AEs frequently reported in both groups were headache , CD exacerbation , nausea , and nasopharyngitis . No patient had a hypersensitivity‐like reaction to natalizumab , whereas 4 patients ( 5 % ) experienced reactions to infliximab . Two patients ( 4 % ) developed anti‐natalizumab antibodies ; 10 patients ( 14 % ) developed anti‐infliximab antibodies . The mean CDAI score  decreased with natalizumab plus infliximab but was unchanged with infliximab alone ( −37.7 versus + 3.5 ; P = 0.084 ) . Patients in both groups showed small increases in HRQoL ( P = 0.811 ) . No drug – drug interactions were noted . Conclusions : The combination of natalizumab plus infliximab was well tolerated . Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone Serological profiles for anti‐Saccharomyces cerevisiae antibodies (ASCA)/ perinuclear antineutrophil cytoplasmic antibodies ( pANCA ) and gene polymorphisms in tumour necrosis factor (TNF)‐α and intercellular adhesion molecule‐1 ( ICAM‐1 ) are associated with occurrence and /or outcome in Crohn 's disease . The aim of the study was to characterize the ASCA/pANCA profile , soluble ICAM‐1 expression and single nucleotide gene polymorphisms ( SNPs ) in TNF‐α and ICAM‐1 genes . Crohn 's patients with moderate disease activity were enrolled in a clinical trial of Alicaforsen ( ISIS 2302 ) .  Peripheral blood sample s were collected prospect ively for serum studies and for potential analysis of gene polymorphisms . A multivariate analysis was performed to compare treatment effect with the biomarkers studied . Serological testing for  ASCA/pANCA was obtained for 257 patients at baseline : 37 % were ASCA+/pANCA– ( Crohn 's pattern ) , 9 % had both markers , 15 % were ASCA–/pANCA+ and 39 % had neither marker . When the data were analysed by multiple regression analysis , a trend was found within the Alicaforsen‐treated groups for greater rates of remission in the ASCA+/pANCA– subgroup versus all other serological profiles ( 25 versus 14 % , P = 0·068 ) , but not versus the placebo remission rate ( 18·8 % ) . Gene polymorphisms were assessed in 64 patients , 21 from the placebo group  . ICAM‐1 assessment revealed no over‐representation . However , three unique TNF‐α SNPs were identified that correlated significantly with remission ; sites 290 ( P = 0·0253 ) , −2735 ( P = 0·0317 ) and −3090 ( P = 0·0067 ) . Although the overall clinical trial was negative , we have identified a trend towards clinical remission  with Alicaforsen therapy in a subgroup of patients with Crohn 's disease expressing ASCA+/pANCA–. Furthermore , we have identified three TNF‐α SNPs that may also predict a positive therapeutic outcome BACKGROUND & AIMS Anti-tumor necrosis factor alpha monoclonal antibody treatment ( infliximab ) reduces clinical signs and symptoms in patients with Crohn 's disease . The effects of infliximab on mucosal histopathologic abnormalities in Crohn 's ileocolitis were studied . METHODS Thirteen patients with steroid-refractory Crohn 's disease were treated with a single infusion of infliximab ( 5 - 20 mg/kg ) , and 5 were treated with placebo . Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy . Severity of inflammation was assessed by a histological score . Immunohistochemical stainings with antibodies against HLA-DR , CD68 , tumor necrosis factor alpha , intercellular adhesion molecule 1 , lymphocyte function-associated antigen , CD4 , CD8 , and interleukin 4 were performed . RESULTS Total histological activity score was reduced significantly in both ileitis and colitis after infliximab . This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells . Mucosal architecture returned to normal in 4 patients at 4 weeks . The number of lamina propria mononuclear cells decreased because of a global reduction of CD4(+ ) and CD8(+ ) T lymphocytes and CD68(+ ) monocytes . Aberrant colonic epithelial HLA-DR expression completely disappeared . The percentage of intercellular adhesion molecule 1 and lymphocyte function-associated antigen 1-expressing and interleukin 4- and tumor necrosis factor-positive lamina propria mononuclear cells sharply decreased . CONCLUSIONS Infliximab dramatically decreases histological disease activity in Crohn 's ileocolitis . Signs of active inflammation nearly disappear accompanied by a profound down-regulation of mucosal inflammatory mediators Background and aims : To evaluate the safety and efficacy of the intercellular adhesion molecule 1 ( ICAM-1 ) antisense phosphorothioate oligonucleotide alicaforsen ( ISIS 2302 ) in Crohn 's disease . Methods : Active ( Crohn 's disease activity index ( CDAI ) 200–350 ) , steroid dependent ( prednisone 10–40 mg ) Crohn 's patients were r and omised into three treatment groups : placebo versus ISIS 2302 ( 2 mg/kg intravenously three times a week ) for two or four weeks . Patients were treated in months 1 and 3 , with steroid withdrawal attempted by week 10 . The primary end point ( steroid free remission ) was a CDAI < 150 off steroids at the end of week 14 . Results : A total of 299 patients were enrolled , with a mean baseline CDAI of 276 and steroid dose of 23 mg/day .  Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups ( 20.2 % and 21.2 % ) and the placebo group ( 18.8 % ) . At week 14 , steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients ( 78 % v 64 % ; p=0.032 ) . Steroid free remission was highly correlated with exposure ( p=0.0064 ) . Other clinical responses were correlated with exposure , with significant results versus placebo being observed in the highest area under the curve subgroup . CDAI scores decreased by 136 ( 112 ) at week 14 versus 52 ( 107 ) for placebo ( p=0.027 ) and inflammatory bowel disease score question naire improved by 43 ( 31 ) versus 15 ( 36 ) for placebo ( p=0.027 ) . Conclusions : Although the primary outcomes failed to demonstrate efficacy , pharmacodynamic modelling suggests that alicaforsen ( ISIS 2302 ) may be an effective therapy for steroid dependent Crohn 's disease BACKGROUND & AIMS A r and omized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn 's disease . METHODS Patients ( N = 509 ) with moderately to severely active Crohn 's disease and active inflammation characterized by elevated C-reactive protein concentrations were r and omized ( 1:1 ) to receive natalizumab 300 mg or placebo intravenously at Weeks 0 , 4 , and 8 . The primary end point was induction of response ( > or = 70-point decrease from baseline in the Crohn 's Disease Activity Index score at Week 8 sustained through Week 12 ) . Additional efficacy end points included the proportion of patients with sustained remission ( Crohn 's Disease Activity Index score < 150 points ) and response or remission over time . RESULTS Response at Week 8 sustained through Week 12 occurred in 48 % of natalizumab-treated patients and 32 % of patients receiving placebo ( P < .001 ) . Sustained remission occurred in 26 % of natalizumab-treated patients and 16 % of patients receiving placebo ( P = .002 ) . Week 4 response rates were 51 % for natalizumab and 37 % for placebo ( P = .001 ) . Responses remained significantly higher at subsequent assessment s ( P < .001 ) in natalizumab-treated patients . Natalizumab-treated patients also had significantly higher remission rates at Weeks 4 , 8 , and 12 ( P < or = .009 ) . The frequency and types of adverse events were similar between treatment groups . CONCLUSIONS Natalizumab induced response and remission at Week 8 that was sustained through Week 12 . Response and remission rates for natalizumab were superior to those for placebo at Weeks 4 , 8 , and 12 , demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn 's disease .  Natalizumab was well tolerated in this study The outcome of the first steroid treatment course was prospect ively studied in a regional cohort of 196 patients with Crohn 's disease diagnosed 1979 - 1987 . The immediate outcome after 30 days , and the prolonged outcome 30 days after treatment had stopped , are described . In all 109 patients treatment was analysed . Complete remission was obtained in 48 % , partial remission in 32 % , and no response in 20 % within 30 days of treatment . Among primary responders ( complete and partial remission ) , 55 % remained in prolonged response after treatment had finished , while 45 % relapsed or could not be withdrawn from treatment within one year . Localisation of disease , age , sex or clinical symptoms did not significantly correlate with outcome , which can be summarised as prolonged steroid response in 44 % , steroid dependency in 36 % , and steroid resistant in 20 % of the patients
OBJECTIVE Due to the crucial role played by adhesion molecules in the pathogenesis of Crohn 's disease ( CD ) , targeting of these molecules has recently been proposed as a new direction for the development of anti-inflammatory strategies for CD .
The aim of this study was to provide up-to- date evidence on the effectiveness and safety of anti-adhesion molecule therapy in treating active CD .
RESULTS Seven RCTs comparing  anti-adhesion molecule therapy with placebo were included in a meta- analysis to evaluate the efficacy and safety of  anti-adhesion molecule strategies in active CD .