New treatment strategy for patients with multiple recurrent Clostridioides difficile infection with bezlotoxumab as first option

The new 2021 European Society for Clinical Microbiology and Infectious Diseases
(ESCMID) guideline recommend treating an initial episode of Clostridioides
difficile (CDI) infection with vancomycin or fidaxomicin, further referred to
as standard CDI antibiotic therapy (CDI ABx). For treatment of a recurrent CDI
episode treatment with fidaxomicin, or addition of an intravenous infusion of
bezlotoxumab to standard CDI ABx are considered. The optimal treatment for
patients with a second or further recurrence of after standard CDI ABx has yet
to be established. Indeed, this is identified as a research gap in the updated
2021 ESCMID guidance document for treatment of CDI. Options include addition of
bezlotoxumab to standard CDI ABx, or fecal microbiota transplantation (FMT)
after standard CDI ABx.

Observational data suggest that bezlotoxumab may prevent FMT in a number of
patients with multiple recurrent CDI, though the exact percentage is unknown. A
point estimate is needed for effective shared decision making and balancing the
risk and benefits of initial bezlotoxumab versus initial FMT for multiple
recurrent CDI. Importantly, offering patients initial bezlotoxumab should not
negatively impact the outcome of a subsequent FMT in case of bezlotoxumab
failure.

We hypothesize that offering patients a treatment strategy with initial
bezlotoxumab has no negative impact on the overall outcome, when compared to a
strategy with initial FMT. We hypothesize that both treatment strategies (both
arms, including rescue therapy) will result in an overall sustained cure of
95%. In addition, we hypothesize that bezlotoxumab result in less AEs and less
IBS-like symptoms and diarrhea than FMT, and that FMT results in an increased
microbiota diversity post treatment when compared to bezlotoxumab treatment.

To investigate whether a treatment strategy offering bezlotoxumab before FMT in
patients suffering from multiple recurrent CDI results in equal efficacy
compared with a treatment strategy with initial FMT. Strategy A includes
bezlotoxumab as ancillary treatment as first option, and FMT in case of
failure. Option B includes FMT as ancillary treatment as first option, and
antibiotic treatment with fidaxomicin in case of failure. A secondary objective
is to provide a point estimate of recurrence after bezlotoxumab for the
treatment of multiple recurrent CDI.

Open label multicentre non-inferiority randomized controlled trial.

Patients will be randomized to one of the following treatment strategies (n=33
each):

Strategy A: bezlotoxumab in addition to standard CDI ABx as first option. 14
days antibiotic therapy with oral vancomycin 250* mg QID + one single
intravenous infusion of bezlotoxumab 10mg/kg over 60 minutes. In case of
treatment failure, i.e. recurrence within 12 weeks, patients will be treated by
fecal microbiota transplantation (FMT, i.e. infusion of 198 cc donor feces
suspension in the gastroduodenum or colon) after 14 days oral vancomycin 250*
mg QID therapy and bowel lavage.

Strategy B: FMT standard CDI ABx as first option. 14 days antibiotic therapy
with oral vancomycin 250* mg QID, followed by FMT on day 15. In case of
treatment failure, patients will be treated with oral fidaxomicin 200 mg BID
for 10 days.

*125 mg vancomycin is administered as suspension, and is also acceptable. 125
mg vancomcyin is considered equally effective as 250 mg tablets in
international guidelines.

Potential issues of concern
This study concerns and investigational medicinal product (bezlotoxumab) that
is approved by the EMA and Dutch CBG for the indication in this study, and an
interventional procedure (FMT). A detailed risk classification can be found in
document K6 and is summarized below.

BEZLOTOXUMAB
Bezlotoxumab may result in mild and transient infusion related reactions
(1-10%). We will exclude patients with a medical history of congestive
heart-failure from the study, due to a potential safety signal in the two
phase-3 clinical trials in this group. Due to limited or absent data we will
also exclude breastfeeding woman, or patients that are pregnant or have a
desire to become pregnant. Potential long-term effects are unknown and are
investigated through post-marketing adverse event registration. The lower
assumed sustained cure rated of bezlotoxumab (60%) comparted with FMT (81%)
means that a proportion of patients in the bezlotoxumab arm do not achieve
sustained cure and will have a delay of treatment with FMT; however, the
benefit is that a considerable portion of patients in this arm a FMT procedure
will be prevented, thereby justifying this trial.

FMT
FMT is an invasive procedure that requires a gastroduodenoscopy or colonoscopy
for donor feces infusion. On the day of FMT patients often experience mild
self-limiting AEs in 2/3 of patients. During follow up 1/3 of patients reports
mild FMT-related (commonly gastro-intestinal) AEs that last for several days.
Because these AEs are mild and self-limiting, we think these are acceptable,
especially given the high sustained cure rate of FMT.

Although FMT is associated with rehospitalization or prolonged hospitalization
(23%) and the occurrence of infections other than CDI (17%), the majority of
SAEs is not (definitely) FMT related and/or due to comorbid conditions.
Possibly related SAEs include bacterial infections. Cases of transmission of
bacteria causing infection in FMT recipients have been described in the US, but
can be prevented by adequate screening protocols for donor feces.

Donors and donor feces provided by the NDFB are extensively screened for
microbiota perturbating risk factors and infectious pathogens. It is however
impossible to screen for unknown pathogens or harmful agents. Therefore,
continuous vigilance by donor stool banks is warranted: for example, in the
beginning of the COVID-19 pandemic NDFB donor activities were halted and
restarted after implementation of SARS-CoV-2 screening. Potential long-term
effects of FMT are unknown and are investigated trough long-term follow-up by
the NDFB and initiatives to establish (inter)national registries.

To minimize the occurrence of (S)AEs after FMT:
- we used extensively screened donor feces, according to NDFB and international
standards
- donor feces will be infused slowly with the patient in the upright position
- patients will be observed after the FMT for at least 2 hours.
- to minimize procedure related risk such as regurgitation and aspiration we
advise to use the coloscopic route for FMT in case of e.g. swallowing problems
or delayed gastric emptying.

In general:
- The patient will be instructed to their treating physician or the
investigators as soon as possible when experiencing a possible (S)AE.