Final Progress Report
Proposal No. IBD-0005
Principal Investigator: Robert W. Summers, M.D.
Applicant Organization: University of Iowa (Iowa City, U.S.A.)
Project Title: A controlled clinical trial of Trichuris suis in the therapy of active ulcerative colitis
Period of Award: July 1, 2002 - December 31, 2003
A. Summary of project aims.
We investigated the following hypothesis: Trichuris suis is a safe and effective treatment of UC through inhibition of the destructive immunological responses. Because of epidemiological, experimental and clinical observations that supported the hypothesis, we initiated a double blind, placebo-controlled clinical trial to investigate this new therapeutic approach. We administered the eggs of an agent that is not a natural human parasite, Trichuris suis, to patients with active ulcerative colitis (UC). This established an abbreviated, self-limited helminthic colonization of the intestine. We compared the clinical outcomes of these subjects to those of a comparable group of patients given a suitable placebo, using accepted clinical measurements of disease activity as a measure of effect. We were not able to explore mechanisms of action in depth.
B. Accomplishments towards meeting those aims.
We successfully performed and completed a 12-week double blind, placebo-controlled trial in fifty-four patients with active ulcerative colitis, defined by an Ulcerative Colitis Disease Activity Index of ≥ 4. Subjects were given suspensions of 2,500 Trichuris suis ova or placebo at two-week intervals. After the primary trial, the subjects were crossed-over to the alternate therapy for another 12 weeks while maintaining the double blind.
C. List of significant results (positive or negative).
Trichuris suis ova induced major improvement in these patients in comparison with those treated with placebo. Using intention-to-treat, a favorable response (fall in UCDAI ≥ 4) occurred in 13/30 (43.3%) of the subjects treated with ova and 4/24 (16.7%) of the placebo-treated subjects, P=0.04. The initial UCDAI of the 13 patients who responded to ova decreased from 8.8±0.4 to 2.8±0.4 at 12 weeks. The differences in remission rates between the two groups did not achieve statistical significance. Of the 13 ova-treated patients who responded, six attained a UCDAI ≤ 2 compared with two of the four placebo-responders. Subset analysis was limited because of the small sample size, however, there was a suggestion that patients with total colonic involvement and shorter durations of disease activity were more likely to respond to ova therapy. The data from another clinical index, the Simple Index, suggested that the therapeutic response to the agent occurs in about six weeks. In the crossover phase, fewer patients (49) entered because five withdrew and only patients with active disease were analyzed. At the end of this phase, 56.3% given T. suis ova responded, whereas only 13.3% improved with placebo (P=0.02). Combining data from both 12 wk periods showed a 46.8% response with ova and 15.4% with placebo. There were no side effects or complications attributable to the therapeutic agent in either the first or second 12-week phases.
D. Lay summary of this report.
Background:
The cause of inflammatory bowel disease (IBD) likely involves both genetic and environmental factors. Current theories suggest that it results from abnormal immune responses to intestinal bacteria that are initiated by unknown causes. IBD is common in industrialized countries where helminthic colonization is rare. Conversely, it is rare in regions of the world where most people have worms. Helminths could be beneficial in IBD because of their unique capacity to decrease hyper-reactive immune responses. In support of this idea, helminths reduce colonic inflammation in experimental murine IBD. Because of these epidemiological and experimental observations and the clinical improvement observed in patients with ulcerative colitis and Crohn’s disease with Trichuris suis ova therapy, we performed the study outlined below.
Ulcerative colitis double-blind crossover trial:
The primary study was a 12-week double blind, placebo-controlled trial. Fifty-four patients with active ulcerative colitis were enrolled and randomized to either placebo- or ova-treatment groups. The characteristics of the two patient groups at entry were similar. Disease activity was judged using the Ulcerative Colitis Disease Activity Index (UCDAI). The index assess four variables that include stool frequency, severity of bleeding, colonic mucosal appearance, and the physician’s overall assessment of disease activity. Each variable is scored from 0-3 so that the total index score ranges from 0-12. To qualify for this study, subjects needed to have an UCDAI ≥ 4. The patients received 2500 Trichuris suis ova or placebo given every 2-weeks. Clinical improvement was defined as a decrease in the UCDAI of at least 4 points. After the primary trial, the subjects were crossed-over to the alternate therapy for another 12 weeks while maintaining the double blind.
Results:
Fifty-two patients completed the 12-week treatment interval. One patient withdrew from the placebo arm because he received high dose prednisone for lung disease. One patient withdrew from the ova-treated arm because he did not wish to continue. After 12 weeks of Trichuris suis ova therapy, 13 of 30 patients improved (43.3%) compared with 4 of 24 patients given placebo (16.7%), p=0.04 using the two-tailed Fisher’s exact test. The mean initial UCDAI of the responders was 8.8 ± 0.4, which improved to a mean UCDAI of 2.8 ± 0.4 by week 12. The mean improvement was 6.0 ± 0.6. Serial analysis of clinical symptoms suggested that the patients required from 4-6 weeks to achieve maximal improvement.
In the crossover phase, fewer patients (49) entered because three more withdrew; only patients with active disease were analyzed. At the end 24 weeks, 56.3% given T. suis ova responded, whereas only 13.3% improved with placebo (P=0.02). Combining data from both 12 wk periods showed a 46.8% response with ova and 15.4% with placebo. There were no side effects or complications attributable to the therapeutic agent in either the first or second 12-week phases.
Conclusion:
In conclusion, the study described above provides evidence that Trichuris suis ova therapy will be effective in active ulcerative colitis. Ova therapy was effective in patients whose disease was long-standing and refractory to conventional medications and it was effective alone or in conjunction with other IBD drugs. The agent appears to be effective not only in treating active disease, but also in maintaining remission for at least six months. Finally, we have not yet seen any adverse clinical effects that could be ascribed to therapy and thus, safety and tolerability appear to be high. The results support the hypothesis that helminths protect against a dysregulated immune response, like that seen in ulcerative colitis.