A randomised trial in patients with early C. difficile infection (CDI), faecal microbiota transplant (FMT)-based therapy was found to be highly effective and superior to standard-of-care antibiotic treatment.
Swiss biopharmaceutical company Ferring Pharmaceuticals’ investigational FMT-based therapy is the first to be given a positive note by the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the US Food and Drug Administration (FDA).
VRBPAC voted 13 to 4 that the data from the biologics licensc application were adequate to support the effectiveness of RBX2660 (Rebyota) to reduce the recurrence of Clostridioides difficile infection (CDI) in adults after antibiotic treatment, and 12 to one that the data were adequate to support safety of the microbiota-based live therapeutic treatment, which is delivered via an enema, reported the company in a press release.
The advisory committee provides recommendations to the FDA, which the agency may consider but is not required to follow, when making its decision.
FMT therapy involves transplanting beneficial bacteria into the gut of a patient with recurrent CDI, which is traditionally treated with antibiotics. FMT has been found in several studies to be an effective treatment for recurrent CDI, and the most recent treatment guidelines from the Infectious Diseases Society of America recommend it for patients who've had several bouts of recurrent CDI and have not been cured by antibiotics.
Up to 35% of CDI cases recur after initial diagnosis, and patients who have recurrent CDI have a significantly higher risk of further infection.
“The vote represents an important milestone in Ferring’s efforts to address the unmet need for interventions that can reduce the incidence of recurrent C. difficile infection, which represents a significant health burden for patients,” said Dr Mirjam Mol-Arts, executive vice president and chief medical officer of Ferring Pharmaceuticals.
Bearing out the effectiveness of the therapy, a recent randomised clinical trial in Denmark found that in patients with a first or second C. difficile infection, FMT was far superior to standard-of-care antibiotic treatment in achieving sustained resolution of symptoms, said the researchers.
Their study was reported in The Lancet Gastroenterology & Hepatology.
Conducted at a university hospital in Aarhus, Denmark, the double-blind, placebo-controlled trial enrolled adult patients with a first or second C difficile infection and randomly assigned them to receive either FMT or placebo after receiving 10 days of vancomycin, the standard antibiotic treatment. Treatments were administered on day one and between days three and seven, and patients were followed for eight weeks or until recurrence.
The primary outcome was resolution of C difficile–associated diarrhoea (CDAD) after eight weeks.
A total of 42 patients were assigned to FMT (21) or placebo (21) from 21 June 2021, to 1 April 2022. Interim analysis on 7 April showed that 19 of 21 patients in the FMT group had resolution of CDAD at eight weeks, compared with seven of 21 in the placebo group, for an absolute risk reduction of 57%. Because of the significantly lower resolution rate in the placebo group, the trial was stopped for ethical reasons.
“In rare cases, it can happen that you discover that the treatment you are investigating is so effective that it is ethically indefensible to continue,” said first author Dr Simon Dahl Baunwall from Aarhus University.
“Our study is one example, in that the new FMT treatment is so much better than the standard treatment with antibiotics that it would be unethical to continue, because the patients in the control group would risk not receiving the FMT treatment.”
Overall, 204 adverse events were reported, with one or more reported in 20 of 21 patients in the FMT group and all 21 in the placebo group. The most common adverse events were diarrhoea and abdominal pain.
Study details
Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial
Simon Mark Dahl Baunwall, Sara Ellegaard Andreasen, Mette Mejlby Hansen, Jens Kelsen, Katrine Lundby Høyer, Nina Rågård, et al.
Published in The Lancet Gastroenterology & Hepatology on 21 September 2022
Summary
Background
Clostridioides difficile infection is an urgent antibiotic-associated health threat with few treatment options. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C difficile. We compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C difficile infection.
Methods
We did a randomised, double-blind, placebo-controlled trial (EarlyFMT) at a university hospital in Aarhus, Denmark. Eligible patients were aged 18 years or older with first or second C difficile infection (defined as ≥3 watery stools [Bristol stool chart score 6–7] per day and a positive C difficile PCR test). Patients were randomly assigned (1:1) to faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125 mg oral vancomycin four times daily for 10 days. Randomisation was done by investigators using a computer-generated randomisation list provided by independent staff. Patients and investigators were masked to the treatment group. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) 8 weeks after treatment. We followed up patients for 8 weeks or until recurrence. We planned to enrol 84 patients with a prespecified interim analysis after 42 patients. The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients.
Findings
Between June 21, 2021, and April 1, 2022, we consecutively screened 86 patients, of whom 42 were randomly assigned to faecal microbiota transplantation (n=21) or placebo (n=21). The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because a significantly lower rate of resolution was identified in the placebo group compared with the faecal microbiota transplantation group (Haybittle-Peto boundary limit p<0·001). 19 (90%; 95% CI 70–99) of 21 patients in the faecal microbiota transplantation group and seven (33%, 95% CI 15–57) of 21 patients in the placebo group had resolution of CDAD at week 8 (p=0·0003). The absolute risk reduction was 57% (95% CI 33–81). Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the faecal microbiota transplantation group and all 21 patients in the placebo group. Diarrhoea (n=23 in the faecal microbiota transplantation group; n=14 in the placebo group) and abdominal pain (n=14 in the faecal microbiota transplantation group; n=11 in the placebo group) were the most common adverse events. Three serious adverse events possibly related to study treatment occurred (n=1 in the faecal microbiota transplantation group; n=2 in the placebo group), but no deaths or colectomies during the 8-week follow-up.
Interpretation
In patients with first or second C difficile infection, first-line faecal microbiota transplantation is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C difficile.
Ferring statement (Open access)
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