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A Randomised, Controlled, Double Blind, Escalating Dose Study of Alicaforsen Enema in Active Ulcerative Colitis

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A Randomised, Controlled, Double Blind, Escalating Dose Study of Alicaforsen Enema in Active Ulcerative Colitis 1646 INFLAMMATORY BOWEL DISEASE Gut: first published as 10.1136/gut.2003.036947 on 11 October 2004. Downloaded from A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis S J H van Deventer, J A Tami, M K Wedel, European Colitis Study Group ............................................................................................................................... Gut 2004;53:1646–1651. doi: 10.1136/gut.2003.036160 Objective: To evaluate the safety and efficacy of an enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule, after 1, 3, and 6 months. See end of article for authors’ affiliations Methods: This was a randomised, placebo controlled, double blind, escalating dose multicentre study in ....................... 40 patients with mild to moderately active distal ulcerative colitis (disease activity index (DAI) 4–10). Patients were assigned to four dosing cohorts of 10 patients each (eight active, two placebo). Each patient Correspondence to: Professor S J H van received 60 ml of alicaforsen enema (0.1, 0.5, 2, or 4 mg/ml or placebo) once daily for 28 consecutive Deventer, Academisch days. Safety and efficacy (DAI and clinical activity index) scores were evaluated up to six months after Medisch Centrum, Room initiation of dosing. G2, 129, Poli Results: At day 29, alicaforsen enema resulted in dose dependent improvement in DAI (overall p = 0.003). Inglammatoire Darmzietkten, Alicaforsen 4 mg/ml improved DAI by 70% compared with the placebo response of 28% (p = 0.004). Meibergdreef 9, NL 1105 Alicaforsen 2 and 4 mg/ml improved DAI status by 72% and 68% compared with a placebo response of AZ, Amsterdam Ziodoost, 11.5% at month 3 (p = 0.016 and 0.021, respectively). Specifically, DAI improved from 5.6 to 1.6 and the Netherlands; S.J.vanDeventer@ from 6.3 to 2.5 in the 2 and 4 mg/ml groups compared with placebo (7.5 to 6.1). None of the patients in amc.uva.nl the 4 mg/ml group compared with 4/8 placebo patients required additional medical or surgical intervention over baseline during the six month period after starting the enema treatment. The safety profile Revised version received was favourable. 2 April 2004 Accepted for publication Conclusions: Alicaforsen enema showed promising acute and long term benefit in patients with mild to 3 April 2004 moderate descending ulcerative colitis. Alicaforsen enemas had a favourable safety profile. These findings ....................... require verification in larger randomised controlled clinical trials. esalamine, administered orally or as an enema, is the associated antigen 1, and Mac-1, all expressed on leuco- mainstay of therapy for patients with mild to cytes.67ICAM-1 serves multiple functions in the propagation Mmoderate ulcerative colitis. Meta-analyses of thera- of inflammatory processes, including facilitating roles in http://gut.bmj.com/ peutic trials in patients with left sided colitis or proctitis have leucocyte activation and migration from the intravascular reported that topical mesalamine treatment is superior to oral space in response to inflammatory stimuli.8–10 Several studies mesalamine, results in higher remission rates than rectal have reported increased ICAM-1 expression within the corticosteroid administration, and is safe.12 Hence topical inflamed gut mucosa as well as increased circulating mesalamine treatment is currently the preferred therapy for concentrations of soluble ICAM-1 in experimental colitis patients with mild to moderate left sided ulcerative colitis. and in inflammatory bowel disease.11 The functional impor- However, 50–60% of patients treated with mesalamine enema tance of ICAM-1 expression for recruitment of neutrophils on September 25, 2021 by guest. Protected copyright. do not achieve complete endoscopic remission within was demonstrated in intervention studies in experimental 4–8 weeks of therapy. A smaller fraction of patients are colitis that reported therapeutic benefit from administration completely resistant to mesalamine therapy necessitating of either antibodies or antisense oligonucleotides targeting treatment with corticosteroids or immunosuppressives, both ICAM-1.12 13 These observations indicate that ICAM-1 inhibi- of which are associated with significant toxicity. Therefore, tion is an attractive target for the development of new agents there is a continuing need for new effective and non-toxic for ulcerative colitis. therapies for left sided ulcerative colitis. Alicaforsen (ISIS 2302; Isis Pharmaceuticals, Inc., Recruitment of neutrophils from the intravascular space Carlsbad, California, USA) is a 20 base phosphorothioate into local sites of inflammation is a multistep process oligodeoxynucleotide antisense molecule designed to down- resulting from selectin dependent slowing of the neutrophil regulate messenger RNA for ICAM-1. Antisense inhibition of on the endothelial surface (‘‘rolling’’) and activation of ICAM-1 via retention enema is a means of achieving topical neutrophil b-integrins, in particular CD11b/CD18 (Mac-1), by drug delivery to the involved colon while minimising platelet activating factor and CXC chemokines (a chemokines systemic bioavailability. This study is the first clinical that have one amino acid residue separating the first two evaluation of alicaforsen enema. The objective of the study conserved cysteine residues), a process which leads to firm was to evaluate the acute and long term safety and efficacy of adherence. four different doses of alicaforsen enema administered once a Intercellular adhesion molecule 1 (ICAM-1), a member of day for 28 consecutive days. the immunoglobulin superfamily, is an inducible transmem- brane glycoprotein that is constitutively expressed at low levels on vascular endothelial cells and a subset of leucocytes.3–5 In response to proinflammatory mediators, many cell types, including colonic epithelium, upregulate Abbreviations: ICAM-1, intercellular adhesion molecule 1; DAI, expression of ICAM-1 on their surface. The primary counter- disease activity index; CAI, clinical activity index; LLOQ, lower limit of ligands for ICAM-1 are the b2-integrins, leucocyte function quantitation www.gutjnl.com Alicaforsen in ulcerative colitis 1647 MATERIALS AND METHODS without significant toxicity. Each patient self administered a Institutional ethics committees approved the protocol and 60 ml retention enema in the evening for 28 consecutive consent forms, and the study was conducted in accordance days. Patients who responded to treatment were followed Gut: first published as 10.1136/gut.2003.036947 on 11 October 2004. Downloaded from with local and national regulatory guidelines. Candidates for until recurrence or six months after treatment had begun. the study were patients with active distal ulcerative colitis Patients who did not respond to treatment were followed for extending 5–50 cm from the anal verge (confirmed by safety data until two months after dosing started and were endoscopy) who were at least 18 years old, had a disease allowed to exit the trial to pursue alternative treatment. activity index (DAI)14 score of 3–10, and were receiving either Efficacy was measured by DAI (table 1) and clinical activity a stable oral dose of 5-ASA (1500–3000 mg) for at least two index (CAI) (table 2).14 15 months prior to the study or no background oral therapy The intent to treat population (n = 40) was used for (except antidiarrhoeals and analgesics) for two months prior analysis of the primary efficacy end points, DAI and CAI. DAI to the study. is a composite score based on the daily number of stools, Protocol exclusions included: current use of other treat- visible blood in stool, appearance of the colonic mucosa at ments for ulcerative colitis (for example, steroids, 5-ASA endoscopy, and the investigator’s global assessment. DAI was enema, immunosuppressants) except oral 5-ASA, antidiar- assessed at baseline (day 1), day 29, and at months 3 and 6. rhoeal, and analgesic agents during the study dosing period; CAI is a composite score based on the number of daily stools, concomitant use of non-steroidal anti-inflammatory drugs or nocturnal diarrhoea, visible blood in stool, faecal incon- antibiotics effective against gastrointestinal organisms; com- tinence, abdominal cramping, general well being, abdominal plications of ulcerative colitis such as bowel stricture, toxic tenderness, and the need for antidiarrhoeal medication. CAI megacolon, or colon carcinoma; a history of colonic resection; is an unvalidated clinical scoring system for the severity of a positive stool culture for enteric pathogens or C difficile toxin symptoms and quality of life related to ulcerative colitis. in stool; other infectious, ischaemic or immunological Because it is entirely subjective and provided for the diseases with gastrointestinal involvement; active infection; collection of more frequent data points, this non-invasive active malignancy; uncontrolled haematological, hepatic, and subjective assessment was included as an exploratory renal, pulmonary, or cardiovascular disease; severe infection end point. CAI was assessed at screening, baseline (day 1), or a major surgical procedure within one month prior to days 8, 15, 22, and 29, and again at months 2, 3, 4, 5, and 6. dosing; and significant laboratory abnormalities. Secondary efficacy end points include the four individual A central pharmacy assigned patients sequentially to four components of the DAI score and alicaforsen drug concen- cohorts of 10 patients
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