Controlled Hookworm Infection for Medication-free Maintenance in Patients with Ulcerative Colitis: A Pilot, Double-blind, Randomized Control Trial

Abstract

Background: Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC.

Methods: Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection.

Results: At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL.

Conclusions: A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible.

Keywords: clinical trial; helminth; hookworm; inflammatory bowel disease; ulcerative colitis.

Graphical Abstract

Figure 1.

Consort flow diagram showing recruitment and participant progress. Abbreviations: IMM, immunomodulator; 5-ASA, 5-aminosalicylic acid.

Figure 2.

Proportion of participants remaining in remission (Simple Clinical Colitis Activity Index ≤5 and fecal calprotectin <200 μg/g) in the hookworm and placebo groups. Dotted line indicates when the participants ceased 5-aminosalicylic acid.

Figure 3.

Peripheral blood eosinophils in participants randomized to (A) hookworm and (B) placebo groups.

Figure 4.

Symptoms as shown by heatmapping in participants that received (A) hookworm and (B) placebo. Color of each cell indicates the average score of all participants in each group at a particular week postrandomization as shown in legend. Symptoms were assessed using a modified version of the Talley gut symptom questionnaire. Symptoms were self-graded by the participant as 0 = absent, 1 = mild (nagging or annoying), 2 = moderate (strong negative influence on daily living), and 3 = severe (disabling).

Figure 5.

Comparison of short inflammatory bowel disease questionnaire (SIBDQ) scores for the hookworm group and placebo group after adjusting for baseline scores. Mean, 95% CI.

Figure 6.

Fecal calprotectin (fCal), fecal eosinophil derived neurotoxin (EDN), and fecal human neutrophil lipocalin (HNL) levels at baseline, weeks 4 and 8 postrandomization, and at time of ulcerative colitis flare measured by enzyme-linked immunosorbent assay (ELISA). Mean, 95% CI. Line, fCal = 200 μg/g. *P < .05.