A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease.
OBJECTIVE
Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to severe Crohn's disease (CD).


METHODS
A randomised, double-blind, placebo-controlled trial (CD04) was carried out followed by an open-label extension study (CD05). The trial was conducted in international multicentre outpatient clinics and included patients with moderate to severe CD (Crohn's Disease Activity Index (CDAI) 250-400). Placebo was administered for 3 days; 60 mg semapimod intravenously for 1 day with placebo for 2 days; or 60 mg semapimod intravenously for 3 days. Participants who completed CD04 could participate in the open-label extension study, CD05, to receive up to five additional semapimod HCl 60 mg daily doses three times every 6-8 weeks. The main outcome measures were CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Endoscopic Inflammation Score (CDEIS) and serum C-reactive protein (CRP) concentration.


RESULTS
152 patients were randomised in CD04. Responses for 1 and 3 day regimens were similar to placebo for CDAI (p=0.82), IBDQ (p=0.85), CDEIS (p=0.57) and CRP (p=0.40). The only noteworthy treatment-related safety finding was infusion reaction (phlebitis): 7.3, 34.8 and 62.7% for the placebo and 1 and 3 day semapimod treatment groups, respectively (p<0.001). In the open-label CD05 study (included=119 patients) a posthoc analysis showed that the mean CDAI improved in patients receiving 6 compared with < or = 3 cumulative doses (204.1+/-83 vs 251.4+/-103.05, p=0.006).


CONCLUSIONS
Single and 3 day dosing of semapimod (< or = 180 mg) was ineffective for the treatment of moderate to severe CD. However, cumulative dosing > or = 360 mg was associated with decreased CDAI in a limited number of patients.
Dotan
Iris
I
IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel. irisd@tasmc.health.gov.il
Rachmilewitz
Daniel
D
Schreiber
Stefan
S
Eliakim
Rami
R
van der Woude
C Janneke
CJ
Kornbluth
Asher
A
Buchman
Alan L
AL
Bar-Meir
Shimon
S
Bokemeyer
Bernd
B
Goldin
Eran
E
Maaser
Christian
C
Mahadevan
Uma
U
Seidler
Ursula
U
Hoffman
Jörg C
JC
Homoky
Douglas
D
Plasse
Terry
T
Powers
Barbara
B
Rutgeerts
Paul
P
Hommes
Daniel
D
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects; D002097:C-Reactive Protein / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage* / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002097:C-Reactive Protein; D005765:Gastrointestinal Agents; D006835:Hydrazones; D007166:Immunosuppressive Agents; C097256:semapimod; D000813:Anilides; D006146:Guanidines