Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial.

Importance: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. Design, Setting, and Participants: This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. Interventions: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. Main Outcomes and Measures: The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. Results: Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). Conclusions and Relevance: In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. Trial Registration: ClinicalTrials.gov identifier: NCT03183141.

Extended Follow-up of Microbiome Therapeutic SER-109 Through 24 Weeks for Recurrent Clostridioides difficile Infection in a Randomized Clinical Trial.

This study examines adverse events and durability of response of SER-109, an investigational microbiome therapeutic comprised of purified Firmicutes spores, compared with placebo for Clostridioides difficile infection.

SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI).

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20−25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.

SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care 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. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).

Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial.

BACKGROUND: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Acute otitis media severity of symptom score in a tympanocentesis study.

We followed symptoms of children with acute otitis media (AOM), who were enrolled in a clinical trial that included a baseline tympanocentesis. We observed marked and rapid improvement in symptom scores after tympanocentesis. Although symptom scores (measured by the AOM-SOS) correlated with overall clinical assessment and bacteriologic outcome, the early effect of tympanocentesis rendered the AOM-SOS less useful as a primary outcome measure.

Treatments for paediatric femoral fractures: a randomised trial.

BACKGROUND: Treatments for femoral fractures in children vary widely and have been investigated only in case series. We did a multicentre randomised trial to compare malunion rates after external fixation and after early application of a hip spica cast for paediatric femoral shaft fractures. METHODS: All children aged 4-10 years with femoral fractures, admitted to four paediatric hospitals, were randomly assigned early application of hip spica or external fixation. The primary outcome was malunion at 2 years after the fracture. Secondary outcomes were scores on the RAND physical function child health questionnaire and the post-hospitalisation behavioural questionnaire, and parents' and children's ratings of overall satisfaction with treatment. Analysis was by intention to treat based on children who reached the 2 year evaluation. FINDINGS: Of 60 children assigned to the hip-spica group, 56 reached the 2-year assessment; of them, six (11%) required other forms of treatment because of unacceptable loss of reduction. Of 48 children assigned external fixation, 45 reached the 2-year assessment; two (4%) had refractures and five (11%) required operative adjustment of the fixator. The rate of malunion was significantly higher in the hip-spica group than in the external-fixator group (25/56 [45%] vs 7/45 [16%]; 95% CI for difference 12-46%; p=0.002). The two groups had similar mean scores for the RAND physical function health questionnaire (0.34 vs 0.45; 95% CI for difference, -0.57 to 0.34; p=0.61), for the post-hospitalisation questionnaire (106.8 vs 106.3; -4.9 to 5.9; p=0.86), and for parents' satisfaction (4.3 vs 4.2; -0.3 to 0.6; p=0.5) and children's ratings of happiness with treatment (6.9 vs 7.7; -2.2 to 0.5; p=0.21). INTERPRETATION: Early application of hip spica has a small role in the treatment of paediatric femoral fractures. Future trials need to compare external fixation with flexible intramedullary nails.

Antibiotic prescribing for upper respiratory tract infection: the importance of diagnostic uncertainty.

OBJECTIVES: Antibiotic misuse for viral upper respiratory tract infections (URI) in children is a significant problem. We determined the influence on antibiotic prescribing of clinical features that may increase concern about possible bacterial infection (age, appearance, fever) in children with URI. STUDY DESIGN: We created 16 scenarios of children with URI and distributed them by mail survey to 540 pediatricians and family practitioners in Ontario, Canada. The association of patient clinical features, parental pressure, and physician characteristics with antibiotic prescribing was determined through the use of logistic regression analysis. RESULTS: A total of 257 physicians responded (48%). Poor appearance (OR, 6.50; 95% CI, 5.06 to 3.84), fever above 38.5 degrees C (OR, 1.48; 95% CI, 1.21 to 1.82), and age older than 2 years (OR, 2.27; 95% CI, 1.85 to 2.78) were associated with prescribing, whereas parental pressure was not. Physician characteristics associated with antibiotic use were family practitioner (OR, 1.54; 95% CI, 1.22 to 1.96), increasing number of patients seen per week (OR, 1.05; 95% CI, 1.01 to 1.08 for every 20-patient increase), and increasing physician age (OR, 1.17; 95% CI, 1.11 to 1.24, 5-year increments). CONCLUSIONS: Clinical factors, which may lead physicians to be concerned about possible bacterial infection in children, are associated with antibiotic use for pediatric URI.

Increasing incidence of hospitalization for bronchiolitis among Canadian children, 1980-2000.

We evaluated temporal trends in hospitalization for bronchiolitis found among Canadian children for 1980-2000. The rate of hospital admission increased in all provinces over the 2 decades for all age groups but was highest in those aged <6 months. The mean length of stay decreased from 5.4 to 3.1 days (mean rate of decrease, 0.13 days/year; P<.0001). Because a concurrent increase in other respiratory diagnostic codes was not seen, it is unlikely that physician practice variation could explain this consistent trend over almost 2 decades, which may indicate a change in disease prevalence or severity.

Tuberculosis among Tibetan refugee claimants in Toronto: 1998 to 2000.

BACKGROUND AND OBJECTIVES: Between 1998 and 2000, approximately 525 Tibetan people previously living in the United States claimed refugee status in Canada, many of whom were referred to our centers for completion of tuberculosis (TB) screening. We reviewed TB-related outcomes in this cohort, to compare our experience with previously published work, and to assess follow-up after a stay in a low-incidence region. METHODS: We performed a retrospective study of all patients of Tibetan origin assessed at our centers (St. Michael's Hospital and West Park Healthcare Centre, both in Toronto) for completion of TB screening, referred because of abnormal chest radiographic findings or positive tuberculin skin test (TST) result. We compared rates of active and drug-resistant TB in our cohort with local and national rates, as well as those previously published in similar groups. RESULTS: One hundred eighty-nine individuals were referred to us for assessment, and 181 records were available for review. The mean duration of stay in Canada prior to presentation was 2.6 months, after having spent a mean of 11 months in the United States. Thirty-two percent of patients gave a history of previous TB, and 97% were TST positive. Culture-positive TB was diagnosed in 24 patients (13%, 4,571 per 100,000), 12 patients had at least one drug resistance (50% of cases), and 4 patients were resistant to at least isoniazid and rifampin (multidrug resistant, 17% of cases). INTERPRETATION: People from highly TB endemic areas retain a very high risk of active TB and drug resistance, despite an intervening period in a low-prevalence country. It is important to maintain a high degree of suspicion for TB in all people from high-incidence areas. Treatment of all cases of latent TB infection or ongoing medical surveillance is likely justified in this population.