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Comparative efficacy/clinical trial data for fecal transplantation in the treatment of recurrent C. difficile infections
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Abbreviations: AE: adverse event; ANC: absolute neutrophil count; CDI: Clostridioides difficile infection; COR: class (strength) of recommendation; FMT: fecal microbiota transplant; GI: gastrointestinal; IBD: irritable bowel disease; IBD-D: inflammatory bowel disease with diarrhea; IBS: irritable bowel syndrome; ICER: incremental cost-effectiveness ratio; LOE: level (quality) of evidence; OL: open label; QALY: quality-adjusted life year; RBL: Rebyota (fecal microbiota, live-jslm); rCDI: recurrent Clostridioidesdifficile infection; SAE: serious adverse event; SOC: standard of care; SER-109: Vowst™ (fecal microbiota, live-brpk)
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Trial Description
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Study Design
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Methods
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Outcomes
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Results
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Conclusions
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Sims et al., 2023
ECOSPOR IV
To evaluate safety and rate of rCDI after administration of investigational microbiome therapeutic SER-109 through 24 weeks
Vowst (Ser-109)
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Phase-3, open-label (OL), single-arm trial
N= 263
Cohort 1 (n= 29)
Cohort 2 (n= 234)
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Inclusion/ exclusion criteria:
Cohort 1: Nonpregnant patients (≥ 18 years old), previously enrolled in ECOSPOR III study, rCDI within 8 weeks after treatment of SER-109 or placebo and met ECOSPOR III rCDI protocol definition were included.
Cohort 2: Newly enrolled patients ≥ 18 years old with one or more CDI recurrences and responded to a course of antibiotic treatment. Same exclusion criteria as Cohort 1 plus not previously enrolled in a SERES clinical study except for those screened in ECOSPOR III and did not receive SER-109 or previously roll-over to ECOSPOR III.
Intervention:
SER-109 is administered orally as 4 capsules per day for 3 days after the onset of symptom remission following CDI antibiotic treatment.
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Primary outcome:
Rate of TEAEs;
rCDI through week 24
Secondary/safety outcomes:
Time to recurrence of CDI; Sustained clinical response and rCDI in cohort 1 at week-8 and cohort 2 at weeks 8 and 12 after treatment
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Primary outcome:
141 patients (53.6%) had TEAEs. CDI rates through 24 weeks (36 patients [13.7%; 95% CI, 9.8% to 18.4%])
Secondary outcomes:
23 patients (8.7%; 95% CI, 5.6% to 12.8%) had CDI recurrence up to week 8 (4 of 29 [13.8%; 95% CI, 3.9% to 31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0% to 12.4%] in cohort 2. recurrent. Sustained clinical response rates at weeks 8 and 24 were 91.3% (95% CI, 87.2% to 94.4%) and 86.3% (95% CI, 81.6% to 90.2%), respectively. By week 24, 36 patients (13.7%; 95% CI, 9.8% to 18.4%) had a rCDI episode.
Safety outcomes:
33 patients (12.5%) had major TEAEs, and there were 8 deaths (3%), none of which the researchers believed to be attributable to the medication.
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Authors’ conclusions:
In this trial, oral SER-109 was well tolerated in a patient population with rCDI and prevalent comorbidities. The rate of rCDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.
Limitations:
Due to OL study design, all patients received SER-109, which limited the ability to assess for efficacy.
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Cohen et al., 2022
ECOSPOR III extended f/u
To evaluate the safety and efficacy of SER-109 compared with placebo for the treatment of rCDI through 24 weeks
SER-109 or placebo
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Phase III, multicenter, randomized, double-blind, placebo-controlled trial
N= 182
SER-109 (n= 89)
Placebo (n= 93)
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Inclusion/ exclusion criteria:
Identical to the ECOSPOR trial
Intervention:
Patients who had ≥ 3 episodes of C. difficile infection were randomized to receive SER-109 (approximately 3×107 spore colony-forming units) or placebo 4 capsules daily for 3 days after SOC antibiotic treatment.
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Secondary/safety outcomes:
CDI rates at 4, 12, and 24 weeks and time to recurrence, positive C. difficile test result for toxin production, and investigator decision to treat
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Secondary outcomes:
-63 of 182 patients had rCDI through 24 weeks (SER-109: 19, placebo: 44)
- SER-109 group had lower rCDI rates at weeks 4, 8, 12, and 24 (p< 0.001)
- The median time of rCDI was 3.3 (0.6 to 23.4) weeks for SER-109 and 1.6 (0.6 to 18.1) weeks for placebo
Safety outcome
- Treatment-emergent AEs (TEAEs) in ≥5%: abdominal distension, constipation, diarrhea, urinary tract infection (SER-109 vs placebo)
- Serious AEs: SER-109 15 patients, placebo 19; none drug-related
- 3 patients discontinued SER-109 due to preexisting condition worsening
- 1 patient in each group withdrew due to serious treatment-emergent AEs
- 3 deaths in SER-109 group (days 15, 60, 164 after intervention); none drug-related
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Authors’ conclusions:
SER-109 demonstrated efficacy in reducing the rate of rCDI and was well-tolerated through 24 weeks in patients with prevalent comorbidities.
Limitations:
The study’s focus on the 24-week time frame may not capture potential longer-term effects or late recurrences beyond this point.
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Feuerstadt et al., 2022
ECOSPOR III
To show superiority of SER-109 compared to placebo in reducing the risk of C. difficileinfection recurrence up to 8 weeks after treatment
SER-109 or placebo
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Phase III, multicenter, randomized, double-blind, placebo-controlled trial
N= 182
SER- 109 (n= 89)
Placebo (n= 93)
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Inclusion/ exclusion criteria:
Identical to the ECOSPOR trial
Intervention:
Patients who had ≥ 3 episodes of C. difficile infection were randomly assigned 1:1 to receive SER-109 (approximately 3×107 spore colony-forming units) or placebo 4 capsules daily for 3 days after SOC antibiotic treatment
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Primary outcome:
Risk of C. difficile infection recurrence up to 8 weeks after treatment
Secondary/safety outcomes:
AEs observed through week 8
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Primary outcome:
- SER-109 was found to be superior to placebo in reducing the risk of C. difficile infection recurrence.
- The percentage of patients with recurrence was significantly lower in the SER-109 group than in the placebo group (12% and 40%, respectively; relative risk, 0.32; 95% CI, 0.18 to 0.58; p< 0.001)
Secondary/ safety outcomes:
- No SAEs were observed through week 8
- Most common AEs were mild to moderate GI disorders with similar numbers in both groups
- Three deaths occurred in the SER-109 group; none were drug-related
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Authors’ conclusions:
In patients with symptom resolution of C. difficile infection after treatment with SOC antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo.
Limitations:
The limitations of this study include lack of stool specimens before antibiotic treatment and low representation of minority populations in the trial.
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McGovern et al., 20214
ECOSPOR
To evaluate the safety and efficacy of SER-109 in rCDI
SER-109 or placebo
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Phase II, multicenter, randomized, double-blind, placebo-controlled trial
N= 89
SER- 109 (n= 59)
Placebo (n= 30)
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Inclusion/ exclusion criteria:
Patients ≥ 18 years old, qualifying episode of CDI, and documented history of ≥ 3 episodes of CDI within the previous 9 months inclusive of the current episode. Key exclusion criteria include pregnant patients, known or suspected toxic megacolon or known small bowel ileus, active IBD-D within the previous 24 months, major GI surgery within 3 months before enrollment, IBD, untreated celiac disease or gluten enteropathy, history of FMT, received an investigational vaccine against C. difficile, and ANC < 500 cells/mm3
Intervention:
Randomly assigned (2:1) to single dose SER-109 or placebo
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Primary outcome:
The relative risk (RR) of rCDI among subjects randomized to placebo versus SER-109 up to 8 weeks after treatment
Secondary/safety outcomes:
Safety outcomes: adverse events
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Primary outcome:
In the overall population rCDI rates were lower in the SER-109 arm than placebo but did not meet statistical significance 44.1% vs 53.3%; RR, 1.2; 95% CI, 0.8 to 1.9). However, SER-109 significantly reduced recurrence compared with placebo among patients aged ≥ 65 years or older (45.2% vs 80%, respectively; RR, 1.8; 95% CI, 1.1 to 2.8)
Secondary/safety outcomes:
- AEs occurred in 76.7% subjects on SER-109 and 69.0% subjects on placebo
- AEs were generally mild to moderate in severity
- Six subjects (10%) on SER-109 experienced a severe AE but none were considered related to study drug
- GI AEs were the most reported but did not differ significantly by treatment arm (55% SER-109 vs 44.8% placebo; p= 0.44)
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Authors’ conclusions
Early SER-109 engraftment was associated with reduced rCDI and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current phase III trial.
Limitations:
The age-related differences in treatment response may have influenced the overall study outcome
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Lee et al., 2023
To provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) for preventing recurrent Clostridioides difficile infections rCDI in adults
REBYOTA™ Fecal microbiota, live-jslm (RBL) or placebo
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Integrated safety analysis including three phase II trials (PUNCH CD, PUNCH CD2, PUNCHCD3-OLS) and two phase III (PUNCH CD3, PUNCH CD3 OLS) trials of RBL
N= 1061
RBL only (n= 763)
Placebo + OL RBL (n= 48)
RBL + OL RBL (n= 167)
Any RBL (n= 978)
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Inclusion/ exclusion criteria:
Patients ≥ 18 years old with rCDI and completed standard antibiotic course prior to RBL treatment. All RBL trials excluded patients with fulminant CDI and life expectancy of less than 12 months, all trials except PUNCH CD3-OLS also excluded patients with IBD
Intervention:
Depending on trial design, assigned study treatment regimen consisted of one or two rectally administered doses of RBL 150 mL (or placebo). In four of the five trials, participants with rCDI within 8 weeks after RBL or placebo administration were eligible for treatment with OL RBL.
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Safety outcomes:
Rate of TEAEs; TEAE severity
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Rate of TEAEs:
TEAEs were reported in 60.2% of placebo only participants, 55.1% of RBL + OL and 66.4% of RBL only participants
TEAE Severity:
- Mild: Placebo only (15.7%); RBL+ OL (19.2%); RBL only (23.7%)
- Moderate: Placebo only (34.9%); RBL+ OL (21%); RBL only (28.8%)
- Severe: Placebo only (8.4%); RBL+ OL (14.4%); RBL only (11.3%)
Safety outcomes:
No infections were reported for which RBL could be attributed. Rarely (3.0%) did participants experience potentially fatal TEAEs.
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Authors’ conclusions:
Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.
Limitations:
This analysis is constrained by the exclusion of patients with fulminant CDI and life expectancy of less than 12 months from all RBL trials, as well as IBD patients from all trials with the exception of PUNCH CD3-OLS. RBL's safety in these populations has yet to be determined
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Dubberke et al., 2023
PUNCH CD2
To evaluate the efficacy and safety of RBL for the reduction of rCDI compared to placebo
RBL or placebo
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Phase IIb, prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm trial
N= 128
Group A (n= 42)
Group B (n= 44)
Group C (n= 42)
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Inclusion/ exclusion criteria:
Adults, at least three episodes of CDI, at least two rounds of SOC antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Key exclusion criteria include ongoing or anticipated antibiotic therapy for a condition other than CDI, known or suspected causes of diarrhea other than CDI, a compromised immune system, a history of IBD, or pregnancy
Intervention:
Patients were randomized 1:1:1 to receive 2 doses of RBL (Group A), 2 doses of placebo (Group B), or 1 dose of RBL and 1 dose of placebo (Group C), all administered 7 ± 2 days apart
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Primary outcome:
Treatment success at 8 weeks in the ITT and treatment success at 8 weeks in the per-protocol population
Secondary/safety outcomes:
Assessment of safety through symptom reporting, AEs, and SAEs at follow-up visits throughout 24 months
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Primary outcome:
- Treatment success at 8 weeks ITT:
Group A (55.6%), Group B (43.2%), Group C (56.8%)
No significant difference between RBL and placebo (p= 0.2)
- Treatment success at 8 weeks per-protocol:
Group A (75%) vs Group B (58.1) p= 0.17
Group C (87.5%) vs Group B p= 0.017
Secondary outcomes/safety outcomes:
- TEAEs: 82.0% with similar rates across groups
- Most TEAEs were mild or moderate and gastrointestinal disorder related.
- Three SAEs: constipation, recurrent acute myeloid leukemia, abdominal pain: (2.3%)
- Sixteen reported deaths with none attributed to treatment or administration procedure
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Authors’ conclusions:
While the PUNCH CD2 clinical trial did not meet its pre-defined primary efficacy endpoint of treatment success at 8 weeks after two doses of RBL vs two doses of placebo in the ITT population, meaningful data were obtained from the single dose regimen in the mITT and PP populations to justify moving forward with the phase III clinical trial, PUNCH CD3, using a single dose regimen
Limitations:
Being a phase IIb trial, this study might not fully represent the efficacy and safety of RBL as compared to larger and more comprehensive phase III trials
Authors’ conclusions:
While the PUNCH CD2 clinical trial did not meet its pre-defined primary efficacy endpoint of treatment success at 8 weeks after two doses of RBL vs two doses of placebo in the ITT population, meaningful data were obtained from the single dose regimen in the mITT and PP populations to justify moving forward with the phase III clinical trial, PUNCH CD3, using a single dose regimen
Limitations:
Being a phase IIb trial, this study might not fully represent the efficacy and safety of RBL as compared to larger and more comprehensive phase III trials
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Khanna et al., 2022
PUNCH CD3
To Evaluate Efficacy and Safety of RBL (Microbiota Suspension) for Prevention of Clostridium Difficile Infection
RBL or placebo
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Phase III Prospective, Randomized, Double-blinded, Placebo-controlled Clinical Study
N= 267
RBL (n= 180)
Placebo (n= 87)
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Inclusion/ exclusion criteria:
Nonpregnant adults (≥ 18 years old), CDI recurrence after primary episode and has completed at least one course of antibiotics or at least two episodes resulting in hospitalization within the last year, positive stool test within 30 days prior to enrollment, currently taking or was just prescribed antibiotics to control CDI related diarrhea at the time of enrollment, ANC > 1000 cells/mm3, no major GI surgery, history of active IBD, irritable bowel syndrome or microscopic colitis.
Intervention:
Patients were randomly assigned 2:1 to receive a single-dose enema of RBL or placebo
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Primary outcome:
Treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment
Secondary/safety outcomes:
Sustained clinical response, defined as the absence of new CDI episodes for more than 8 weeks following the conclusion of study treatment and the successful treatment of the presenting rCDI; incidence and severity of AEs and SAEs.
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Primary outcome:
The mITT population's treatment success rates were 70.4% for RBL and 58.1% for placebo, a difference of 12.3 percentage points. The superiority threshold of 0.975 exceeding posterior probability of superiority of 0.986.
Secondary outcomes:
For both treatment groups across analysis populations, the percentage of participants with treatment success at 8 weeks who did not experience a CDI recurrence was around 90% (mITT: RBL, 92.1% (n= 116/126); placebo, 90.6% (n= 48/53)).
Safety outcomes:
A higher rate of AEs was reported in the RBL group through 6 months after blinded treatment (55.6% (n= 100/180)) compared to the placebo group (44.8%, (n= 39/87)).
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Authors’ conclusions: RBL is a safe and effective treatment to reduce recurrent C. difficileinfection following SOC antibiotics with a sustained response through 6 months.
Limitations:
Patients with the first recurrence of C. difficile infection were excluded, which may narrow the scope of the study's findings.
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Kelly et al., 2016
FMT landmark trial
To determine the efficacy and safety of FMT for treatment of recurrent CDI
Heterologous (donor) or autologous FMT
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Randomized, controlled, double-blind clinical trial
N= 46
Heterologous (donor) FMT (n= 22)
Autologous FMT (n= 24)
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Inclusion/ exclusion criteria:
Adult outpatients with ≥ 3 documented rCDI and unable to maintain cure after course of tapered or pulsed vancomycin or unable to taper or discontinue vancomycin without experiencing recurrent diarrhea necessitating anti-CDI treatment, completed ≥ 10 days of vancomycin therapy and continued therapy until two to three days before procedure. Age ≥ 75 years, IBD, IBS, chronic diarrheal disorder, any immunocompromised state or immunodeficiency, prior FMT, untreated, in situ colorectal cancer, and inability to undergo colonoscopy were main exclusion criteria.
Intervention:
FMT with donor stool (heterologous) or patient’s own stool (autologous) administered by colonoscopy
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Primary outcome: Resolution of diarrhea without need for further anti-CDI therapy during the 8-week follow-up. Clinical cure was defined as the absence of CDI recurrence with maintenance of resolution (i.e., >3 unformed stools per day) for eight weeks without the need for further antibiotics (metronidazole, vancomycin, or fidaxomicin).
Secondary/safety outcomes:
AEs, SAEs, and new medical conditions for 6 months after FMT
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Primary outcome:
In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]).
Secondary outcomes:
After a subsequent Heterologous (donor) FMT, none of the 9 patients who experienced recurrent CDI after autologous FMT experienced it again. Heterologous (donor) FMT restored the diversity and composition of the gut bacterial community to that of healthy donors.
Safety outcome
There were no SAEs related to FMT.
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Authors’ conclusions:
Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes.
Limitations
Only patients with ≥ 3 recurrences were included in the study; patients with immunocompromised conditions or those 75 years of age or older were not included.
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