A randomized, placebo-controlled, phase II study of tetomilast in active ulcerative colitis.
OBJECTIVE
Tetomilast (OPC-6535), a novel thiazole compound, inhibits phosphodiesterase-4 and proinflammatory functions of leukocytes including superoxide production and cytokine release.


METHODS
One hundred eighty-six patients with mildly to moderately active ulcerative colitis (Disease Activity Index [DAI] 4-11 points) from 35 centers were randomized to receive an oral, once-daily dose of placebo or tetomilast 25 mg or 50 mg for 8 weeks.


RESULTS
Percentages of patients reaching the primary end point (improvement as defined by reduction in DAI > or =3 at week 8) were not significantly different between placebo (35%) and either the 25 mg tetomilast (52%) or the 50 mg tetomilast (39%) groups (intent-to-treat population). Remission rates (DAI 0-1) were 7%, 16%, and 21%, respectively (not significant). Mean reduction in DAI at week 8 was greater in the 25-mg group than under placebo (2.8 +/- 0.4 vs 1.7 +/- 0.36, respectively, P = .041) and approached statistical significance in the 50-mg group (2.8 +/- 0.46, P = .056). A post hoc analysis focusing on patients with high activity scores (baseline DAI 7-11) suggested differences between tetomilast and placebo that will require further investigation. No significant safety concerns were raised. Main adverse effects included gastrointestinal problems (nausea, vomiting) and were preferentially seen in the 50-mg tetomilast group.


CONCLUSIONS
This phase II trial of tetomilast in ulcerative colitis did not achieve statistical significance for the primary end point. Secondary end points indicate a potential clinical activity of tetomilast. The post hoc analysis suggests that further clinical development should focus on patients with objective parameters of inflammation.
Schreiber
Stefan
S
Department of General Internal Medicine, Christian-Albrechts University, Schittenhelmstrasse 12, Kiel Schleswig-Holstein 24105, Germany. secretary@mucosa.de
Keshavarzian
Ali
A
Isaacs
Kim L
KL
Schollenberger
John
J
Guzman
Juan P
JP
Orlandi
Cesare
C
Hanauer
Stephen B
SB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000473:pathology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D012074:Remission Induction; D012812:Sigmoidoscopy; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D010726:Phosphodiesterase Inhibitors; D010919:Placebos; D013844:Thiazoles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C108965:tetomilast