A new formulation of tolevamer, a novel nonantibiotic polymer, is safe and well‐tolerated in healthy volunteers: a randomized phase I trial

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clostridium difficile‐associated diarrhoea (CDAD), which affects about 1% of hospitalized patients whose intestinal flora have been altered by the administration of antimicrobial agents such as the cephalosporins, accounts for 10% to 20% of all cases of antibiotic‐associated diarrhoea. • The incidence and severity of CDAD is rising in a number of countries, including the United States, United Kingdom, and Canada, where recent outbreaks of CDAD have been associated with increased mortality. • Since both antibiotics that are currently used for treating CDAD (vancomycin, the only treatment approved by the US Food and Drug Administration for this indication, and metronidazole, the most widely recommended first‐line therapy) have serious limitations, including recurrence rates of about 20%, systemic adverse events, and the emergence of drug resistance, there is a large unmet need for the development of novel therapeutic modalities with unique mechanisms of action for the prevention of the disease and/or management of patients with CDAD. WHAT THIS STUDY ADDS • The results of the phase I study demonstrate that a new phase III formulation of tolevamer, a novel, high‐molecular weight, anionic polymer with a unique mechanism of action based on noncovalent binding to C. difficile toxins A and B, may eliminate the increased risk of hypokalaemia observed with the phase II formulation and allow further clinical development of an alternative therapeutic approach to antibiotics for this antibiotic‐induced disease. • The results demonstrate that a potassium sodium oral liquid formulation of tolevamer given over a 9 day treatment period is generally safe and well‐tolerated. • The information contained herein provides a basis for selection of the appropriate dosing and scheduling of this formulation of tolevamer in future trials. AIMS To evaluate the safety and tolerability of a new oral solution formulation of tolevamer potassium sodium, a nonantibiotic polymer that binds Clostridium difficile toxins A and B. METHODS This phase 1 randomized, double‐blind, placebo‐controlled study evaluated four doses of tolevamer potassium sodium in 40 healthy volunteers using a sequential dose escalation paradigm and doses of 6, 9, 12 and 15 g day−1 for 9 days. Within each 10 patient cohort, eight patients received active treatment and two matching placebo. Placebo subjects were pooled to provide eight per arm. All subjects received three times daily dosing on days 2–8 as well as a loading dose (a single dose equal to the total daily dose) either on day 1 or day 9. RESULTS All 40 subjects completed the study per protocol. Treatment‐emergent adverse events (TEAEs) were generally mild, transient, and resolved without sequelae. There were no serious AEs or deaths. There was no relationship detected between dose and the incidence of TEAEs, whether drug‐related (all gastrointestinal disorders) or not. No clinically significant changes in laboratory parameters, including serum and urinary potassium concentrations, vital signs, and results of physical examination, were observed. A small but statistically significant reduction in 24 h urine potassium excretion was seen in the 15 g day−1 dose group, and on day 10 in the 6 g day−1 group. CONCLUSIONS Tolevamer oral solution administered for 9 days at total daily doses up to 15 g, with loading doses of up to 15 g, was generally safe and well‐tolerated in healthy volunteers.

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