Professor of Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A secondary analysis of a Phase III clinical trial found SER-109 improved health-related quality of life for patients with recurrent C. difficile infection compared to placebo through eight weeks.
SOURCE: Garey KW, Jo J, Gonzales-Luna AJ, et al. Assessment of quality of life among patients with recurrent Clostridioides difficile infection treated with investigational oral microbiome therapeutic SER-109: Secondary analysis of a randomized clinical trial. JAMA Netw Open 2023;6:e2253570.
Recurrent Clostridioides difficile infection (rCDI) causes a detrimental impact on the quality of life for many patients. Novel treatments that are potent, safe, and cost-effective are needed. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores (approximately 3 × 107 spore colony-forming units) that has been granted a Breakthrough Therapy designation and Orphan Drug designation for the prevention of rCDI by the Food and Drug Administration (FDA). Garey and colleagues sought to determine the effect of SER-109 on health-related quality of life (HRQoL).
The study was an analysis of a Phase III, randomized, double-blind, placebo-controlled clinical trial done at 56 sites in North America between July 2017 and April 2020 (ECOSPOR III; ClinicalTrials.gov identifier NCT03183128). Eligibility criteria included age 18 years or older and having three or more episodes of CDI within 12 months. After patients completed the standard of care antibiotics with resolution of CDI symptoms, they were randomized 1:1 to receive four oral capsules of SER-109 or placebo daily for three days. The researchers monitored patients for eight weeks for CDI recurrence, a positive C. difficile stool toxin assay, assessment by one of the investigators that antibiotic treatment was warranted, and persistence of diarrhea until initiation of antibiotic therapy. Patients completed the Cdiff32, a questionnaire with 32 items on three major domains (physical, mental, social) with four subdomains (general physical complaints, specific physical complaints, anxiety future, and anxiety current) after resolution of symptoms but before treatment initiation, and weeks 1 and 8 visits after treatment initiation.
There were 182 patients in the intention-to-treat population. Of these, 89 received SER-109 and 93 received placebo. The mean age of participants was 65.5 (standard deviation [SD], 16.5) years; 109 (59.9%) were female, 170 (93.4%) were white, and 180 (98.9%) were outpatients. Baseline characteristics were the same between both groups except there were more females randomized to receive SER-109 (60 [67%] vs. 49 [53%], respectively). Eleven of 89 patients (12%) who received SER-109 had rCDI after treatment compared to 37 of 93 patients (40%) who received placebo (P < 0.001), a relative risk reduction of 68%. Most of the recurrences (41 of 48; 85%) took place on or before week 4.
At week 8, patients who received SER-109 had a significant improvement in their HRQoL, as measured by the Cdiff32, compared to placebo (49.4% vs. 26.9%, respectively; P = 0.012). There were greater improvements in the SER-109 recipients in total and physical domain scores starting in week 1, which continued to increase to week 8. Of note, even patients in the SER-109 group who experienced rCDI had significant improvements from baseline in mental domain and subdomain Cdiff32 scores at week 8.
COMMENTARY
Recurrent CDI can be a devastating disease physically, mentally, and financially for patients and a considerable burden on the healthcare system. The positive results reported by Garey and colleagues are encouraging news in the struggle against rCDI. Physicians treating patients with rCDI primarily think about the disease in clinical terms, such as improvement in signs and symptoms. On the other hand, patients are affected not only by the clinical manifestations, but also by the social and emotional factors that accompany rCDI. Indeed, improving HRQoL is an important objective for the overall management of patients with rCDI.
Another interesting observation was the improvement in the mental domain and subdomain scores at week 8 in the SER-109 group, regardless of their clinical outcome. The investigators hypothesized this might be related to the potential role of the microbiome in disorders related to the gut-brain axis. Many patients with CDI have gut dysbiosis, which has been associated with mood disorders such as anxiety and depression. Prior analysis from the ECOSPOR III clinical trial found engraftment of SER-109 dose species correlated with metabolic changes. It remains unclear whether the purified Firmicutes spores improve the balance of neurotransmitters, which are known to have a role in anxiety and depression. Further investigation seems warranted.
The study had a few limitations. First, eight weeks is not long in terms of clinical follow-up, so a further study that tracks rCDI for a greater time frame (i.e., three to six months) would be beneficial. Second, the baseline estimates of HRQoL were performed after clinical resolution of CDI on antibiotics, which may have affected the ability to see the full spectrum of improvement. Third, the Cdiff32 questionnaire has only been used in a couple of published articles and may require further validation.
If approved for clinical use, SER-109 will be a welcome addition to the therapeutic armamentarium for rCDI. However, areas of uncertainty exist, such as the need for magnesium citrate prior to treatment. This is because oral vancomycin and fidaxomicin can persist for five to seven days after discontinuation, potentially inactivating the Firmicutes spores in SER-109.
