Phase 1 Trial Demonstrates Safety, Tolerability of Autologous FMT

Capsulized frozen autologous fecal microbiota transplantation (FMT) may offer a safe and well-tolerated alternative to traditional FMT for prophylactic treatment of Clostridioides difficile infection (CDI).

Johan Ursing, MD, PhD

Credit: Karolinska Institute

Results from a randomized, double-blind, phase 1 clinical trial at the Department of Infectious Diseases at Danderyd Hospital in Stockholm, Sweden showed no serious side effects and no significant difference in time to normalized intestinal habits among patients treated with autologous FMT compared to those treated with placebo.¹

“The main obstacles are identification of donors, the complexity of FMT administration via colonoscopy or gastroscopy, and the process of capsulizing faecal samples,” wrote investigators.¹ “Moreover, though FMT is considered safe, there is a risk of transmitting pathogenic organisms and the long-term effects of heterogenic microbiota on the recipient are not known. Replacing donors with autologous faeces circumvents some of these difficulties”

An estimated 500,000 people in the US are affected by CDI each year.² It is one of the most common healthcare-associated infections in the US, with an estimated two-thirds of cases originating in hospitals, long-term care facilities, or other healthcare settings. Recurrent CDI occurs in about 20% of patients.³ FMT is frequently used to treat persistent CDI and is 80% to 95% successful in preventing CDI from recurring, but several barriers to treatment have prompted the exploration of alternative treatment options.⁴

To assess the safety and tolerability of autologous FMT, Johan Ursing, MD, PhD, senior lecturer and senior physician at Karolinska Institute in Sweden, and colleagues randomized healthy volunteers in a 1:1 ratio to autologous FMT capsules or placebo capsules and recorded data on patient-reported treatment experience, general and gastrointestinal health, stool habits, and adverse events. Healthy volunteers were identified by advertisements in the Karolinska Trial Alliance and Studentkanin databases, sites managing registers of individuals reporting an interest in participating in research projects.¹

For inclusion, patients were required to be aged 18–40 years, able to swallow study capsules, provide a negative pregnancy test at inclusion, use an approved method to prevent pregnancy during the study period, and provide written informed consent. Patients were excluded from the study if they had a previous or current bowel disorder, delayed gastric emptying syndrome, recurrent aspirations, swallowing dysfunction, antibiotic treatment during the previous 3 months, regular intake of any medication, body mass index <18.5 and >30, any other significant medical history, and identification of CDI in a stool sample prior to the start of the study.¹

A total of 33 people were screened for participation in the study, 9 of whom investigators excluded based on the study criteria. In total, 24 participants with an average age of 28 (interquartile range, 25-35) years and 50% (n = 12) male were enrolled in the study. Upon enrollment, participants donated a fecal sample and took clindamycin capsules to disrupt intestinal microbiota. After a 2-day washout, participants were randomized 1:1 to treatment with autologous fecal matter or placebo and took 2 frozen capsules containing autologous fecal matter or placebo twice daily for 5 days.¹

Participants underwent a medical visit prior to the start of the study and then on days 1, 10, and 15. At each visit, participants were examined and questioned about adverse events. Patients completed an electronic questionnaire on days 1–28, 60, and 180.¹

​​The primary outcome of interest was safety and tolerability by day 28. Secondary outcomes included time to normalized intestinal habits and time to normalization of intestinal microbiota up to 180 days after the start of the study.¹

Results revealed positive scores for general health and intestinal well-being throughout the study, although investigators pointed out general health appeared to be slightly lower during treatment with clindamycin and improved significantly with time when assessed in a univariate fixed effect quantile regression (P < .001). Reported stool scores were greater during treatment with clindamycin, and stopping clindamycin treatment was associated with a decreasing stool score (P = .02). Time (P = .09) and treatment with placebo compared to autologous FMT (P = .77) were not significantly associated with the stool score.¹

Investigators noted the median time taken to reach stable intestinal habits was 17 (95% confidence interval [CI], 16–21) days for the placebo group and 19 (95% CI, 15–20) days for the autologous FMT group, with no significant difference between the groups (0.9; 95% CI, 0.39–2.06; P = .8).¹

Although 2 participants reported serious fatigue during clindamycin treatment, investigators deemed these cases to be of low seriousness because the affected patients did not seek medical care or inform the study staff. A total of 13 participants reported fatigue as an adverse event during the first 7 days, 11 still reported fatigue during days 10–14, and 9 continued to have fatigue during the follow-up period, with a similar proportion of affected patients across both groups.¹

Additionally, 9 patients reported diarrhea as an adverse event during clindamycin treatment and 4 reported it during the capsule treatment, including 3 participants in the autologous FMT group and 1 in the placebo group. All other reported adverse events in both groups were minor to moderate without significant differences (P > .05) between the placebo and treatment groups.¹

“The apparent safety, potential beneficial metabolic effects, ability to restore antibiotic-induced dysbiosis, and low risk of pathogen spread from donors suggests that auto-FMT may become an effective and safe treatment,” concluded investigators.¹

References:

1. Stefansson M, Bladh O, Flink, O, et al. Safety and tolerability of frozen, capsulized autologous faecal microbiota transplantation. A randomized double blinded phase 1 clinical trial. PLOS ONE 18(9): e0292132. https://doi.org/10.1371/journal.pone.0292132
2. Centers for Disease Control and Prevention. What is C. Diff? Clostridioides difficile (C. diff). September 7, 2022. Accessed October 17, 2023. https://www.cdc.gov/cdiff/what-is.html
3. Yale Medicine. Clostridium Difficile (C. Diff). Accessed October 17, 2023. https://www.yalemedicine.org/conditions/c-diff-infection
4. Cleveland Clinic. Fecal Transplant. Treatments & Procedures. Accessed October 17, 2023. https://my.clevelandclinic.org/health/treatments/25202-fecal-transplant