INFLAMMATORY BOWEL DISEASE

A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis

S J H van Deventer¹, J A Tami², M K Wedel² European Colitis Study Group

¹ Academisch Medisch Centrum, Amsterdam, the Netherlands
² Isis Pharmaceuticals, Carlsbad, California, USA

Correspondence to:
Correspondence to:
Professor S J H van Deventer
Academisch Medisch Centrum, Room G2, 129, Poli Inglammatoire Darmzietkten, Meibergdreef 9, NL 1105 AZ, Amsterdam Ziodoost, the Netherlands; S.J.vanDeventer{at}amc.uva.nl

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.

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 received 60 ml of alicaforsen enema (0.1, 0.5, 2, or 4 mg/ml or placebo) once daily for 28 consecutive days. Safety and efficacy (DAI and clinical activity index) scores were evaluated up to six months after initiation of dosing.

Results: At day 29, alicaforsen enema resulted in dose dependent improvement in DAI (overall p = 0.003). Alicaforsen 4 mg/ml improved DAI by 70% compared with the placebo response of 28% (p = 0.004). Alicaforsen 2 and 4 mg/ml improved DAI status by 72% and 68% compared with a placebo response of 11.5% at month 3 (p = 0.016 and 0.021, respectively). Specifically, DAI improved from 5.6 to 1.6 and 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 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 was favourable.

Conclusions: Alicaforsen enema showed promising acute and long term benefit in patients with mild to moderate descending ulcerative colitis. Alicaforsen enemas had a favourable safety profile. These findings require verification in larger randomised controlled clinical trials.

Abbreviations: ICAM-1, intercellular adhesion molecule 1; DAI, disease activity index; CAI, clinical activity index; LLOQ, lower limit of quantitation

Keywords: alicaforsen; enema; ulcerative colitis; intercellular adhesion molecule 1; antisense oligonucleotide

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Robin Spiller
Gut 2004 53: 1549. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Panes, J., Aceituno, M., Gil, F., Miquel, R., Pique, J. M, Salas, A., McLean, P. (2007). Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 293: G739-G748 [Abstract] [Full Text]  
• Bhindi, R., Fahmy, R. G., Lowe, H. C., Chesterman, C. N., Dass, C. R., Cairns, M. J., Saravolac, E. G., Sun, L.-Q., Khachigian, L. M. (2007). Brothers in Arms: DNA Enzymes, Short Interfering RNA, and the Emerging Wave of Small-Molecule Nucleic Acid-Based Gene-Silencing Strategies. Am. J. Pathol. 171: 1079-1088 [Abstract] [Full Text]  
• Matsushita, Y., Hasegawa, M., Matsushita, T., Fujimoto, M., Horikawa, M., Fujita, T., Kawasuji, A., Ogawa, F., Steeber, D. A., Tedder, T. F., Takehara, K., Sato, S. (2007). Intercellular Adhesion Molecule-1 Deficiency Attenuates the Development of Skin Fibrosis in Tight-Skin Mice. J. Immunol. 179: 698-707 [Abstract] [Full Text]  
• De Vry, C. G, Prasad, S., Komuves, L., Lorenzana, C., Parham, C., Le, T., Adda, S., Hoffman, J., Kahoud, N., Garlapati, R., Shyamsundar, R., Mai, K., Zhang, J., Muchamuel, T., Dajee, M., Schryver, B., McEvoy, L. M, Ehrhardt, R. O (2007). Non-viral delivery of nuclear factor-{kappa}B decoy ameliorates murine inflammatory bowel disease and restores tissue homeostasis. Gut 56: 524-533 [Abstract] [Full Text]  
• Pavlick, K. P., Ostanin, D. V., Furr, K. L., Laroux, F. S., Brown, C. M., Gray, L., Kevil, C. G., Grisham, M. B. (2006). Role of T-cell-associated lymphocyte function-associated antigen-1 in the pathogenesis of experimental colitis. Int Immunol 18: 389-398 [Abstract] [Full Text]