Recruitment for a phase 2 trial of a novel antibiotic against Clostridium difficile (C diff) is proceeding after phase 1 demonstrated safety and tolerability.
A novel antibiotic against Clostridium difficile is advancing to a phase 2 clinical trial, after demonstrating safety and tolerability of single or multiple ascending doses in phase 1 testing.
The investigational agent, CRS3123, is a small molecule protein which inhibits synthesis of methionyl-tRNA synthetase (MetRS). According to the manufacturer, Crestone, the unique mechanism of action is not affected by resistance to any existing classes of antibiotics.The lack of absorption from oral administration should also preclude interference with systemic antibiotic treatments.
In an additional statement, the manufacturer indicates that the agent has already demonstrated several advantages, including:high potency against all clinical isolates of C difficile and a narrow spectrum, which could reduce the disruption of the normal intestinal biome; inhibition of toxin production, potentially leading to lower associated morbidity and mortality; and inhibition of sporulation, anticipated to reduce rates of transmission and recurrence.
In phase 1 testing, 5 cohorts of 8 subjects each received CRS3123 or placebo in a 3:1 ratio; with 100mg, 200mg, 400mg, 800mg and 1,200mg.The investigators reported no serious adverse events or immediate allergic reactions.They concluded that the study drug was well tolerated over that range of doses, and that the safety profile supports progressing to clinical study of its effectiveness for C difficile infections.
The investigators are now recruiting 108 adult patients with clinically documented C difficile infection at 30 sites in the US to participate in the phase 2 clinical trial to evaluate CRS3123 against oral vancomycin.Funding for the trial is provided by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Urs Ochsner, PhD, a co-founder and vice president, research and development at Crestone, is the designated principle investigator.
“We are excited to initiate the phase 2 trial of CRS3123, a narrow-spectrum agent that is highly selective for the target pathogen with minimal disruption of healthy gastrointestinal microbiota,” Ochsner stated.
The randomized, blinded trial will include three 10-day treatment arms of twice daily doses of 200mg or 400mg CRS3123, compared to vancomycin 125mg four times daily.The trial design has quadruple blinding: for participant, care provider, investigator and outcomes assessor.The estimated study completion date is February 2022.
Eligibility criteria include stool positive for C difficile and Toxin A and/or B in the primary episode or first recurrence of infection, marked by 3 or more diarrheal stools/day in 24 hours prior to randomization; and concurrence of the investigator that C difficile is the likely cause.
The study drug CRS3123 will be administered 200mg or 400mg orally twice daily for 10 days, against the active comparator, vancomycin orally 125mg four times daily. The primary outcome measure is clinical cure at day 12-14. One of the secondary measures is rate of early recurrence of C diff infection, in follow-up visit occurring within 12 to 40 days after primary study period. Other secondary measures include rate of total relief of symptoms, and time to resolution of diarrhea.
“A key unmet need…is treatment or prevention of relapse, which requires additional antibiotic treatment and often re-hospitalization,” the manufacturer emphasizes in a statement announcing the new trial.