VE303 for C. Difficile Infection
(RESTORATiVE303 Trial)
Recruiting in Palo Alto (17 mi)
+149 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Vedanta Biosciences, Inc.
Must be taking: Standard antibiotics
Must not be taking: Antidiarrheals, Bezlotoxumab
Disqualifiers: Chronic diarrhea, Celiac, others
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?The overall objective of the RESTORATiVE303 study is to evaluate the safety and the Clostridioides difficile infection (CDI) recurrence rate at Week 8 in participants who receive a 14-day course of VE303 or matching placebo. The objectives and endpoints are identical for Stage 1 (recurrent CDI) and Stage 2 (high-risk primary CDI).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you must complete a course of standard antibiotic therapy for CDI before starting the study drug. You cannot use antidiarrheal drugs within 3 days before the first dose of the study drug, and you should not expect to take antibiotics for other conditions during the trial.
What makes the drug VE303 unique for treating C. difficile infection?
VE303 is unique because it is a microbiome-based treatment designed to restore the natural balance of gut bacteria, which can help prevent the recurrence of C. difficile infections, unlike traditional antibiotics that may disrupt gut flora.
12345Eligibility Criteria
This trial is for adults, especially those over 65 or with kidney issues, who have had Clostridioides difficile infection (CDI) recently or in the past year. It's also for people with weakened immune systems, organ transplant recipients, and regular users of stomach acid reducers. Children over 12 with CDI history can join too.Inclusion Criteria
I am 12 or older and have had at least two episodes of C. diff infection in the last 6 months.
I am over 75 with CDI or over 12 with CDI and have at least two risk factors like being over 65, kidney issues, regular PPI use, a past CDI episode, immunosuppression, or an organ transplant.
I had a recent severe diarrhea episode treated successfully with antibiotics for C. diff.
Exclusion Criteria
For both Stage 1 and Stage 2: History of chronic diarrhea, Laboratory-confirmed infectious diarrhea other than CDI, Known or suspected toxic megacolon or small bowel ileus, History of confirmed celiac disease, inflammatory bowel disease, microscopic colitis, short gut, GI tract fistulas, or a recent episode of intestinal ischemia or ischemic colitis, Receipt of bezlotoxumab during the course of SoC antibiotic treatment, Receipt of genetically modified live bacterial, fungal, viral, or bacteriophage isolates, fecal-derived live bacterial isolates, or other LBPs for CDI-associated diarrhea within 6 months prior to randomization, Use of antidiarrheal drugs within 3 days prior to the planned first dose of study drug, Anticipated administration of oral or parenteral antibacterial therapy for a non-CDI indication after randomization
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a 14-day course of VE303 or placebo after completing 10 to 21 days of standard antibiotic treatment
14 days
Follow-up
Participants are monitored for CDI recurrence and safety until Week 8
6 weeks
Participant Groups
The RESTORATiVE303 study tests VE303 against a placebo to see if it prevents CDI from coming back within eight weeks after treatment. Participants will take either VE303 or a placebo for two weeks and be monitored for safety and recurrence.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: VE303Experimental Treatment1 Intervention
Subjects assigned to the VE303 arm will take 3 capsules containing VE303 per day for 14 days after completing 10 to 21 days of standard of care antibiotic treatment for the qualifying CDI episode.
Group II: PlaceboPlacebo Group1 Intervention
Subjects assigned to the placebo arm will take 3 placebo capsules per day for 14 days after completing 10 to 21 days of standard of care antibiotic treatment for the qualifying CDI episode.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Advanced Gastroenterology, P.C.Chandler, AZ
South Jersey Infectious DiseaseSomers Point, NJ
Toledo Institute of Clinical ResearchToledo, OH
North America Research InstituteSan Dimas, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Vedanta Biosciences, Inc.Lead Sponsor
References
New types of toxin A-negative, toxin B-positive strains among Clostridium difficile isolates from Asia. [2022]A total of 56 C. difficile strains were selected from 310 isolates obtained from different hospitals in Japan and Korea and from healthy infants from Indonesia. Strains that had been previously typed by pulsed-field gel electrophoresis and PCR ribotyping, were characterized by toxinotyping and binary toxin gene detection. When toxinotyped, 35 strains were determined to be toxinotype 0, whereas 21 strains showed variations in toxin genes and could be grouped into 11 variant toxinotypes. Six of the toxinotypes had been described before (I, III, IV, VIII, IX, and XII). In addition, five new toxinotypes were defined (XVI to XX). Three of the new toxinotypes (XVIII, XIX, and XX) vary only in repetitive regions of tcdA and produce both toxins. In two strains from toxinotypes XVI and XVII, the production of TcdA could not be detected with commercial immunological kits. Strain J9965 (toxinotype XVII) was in PaLoc similar but not identical to another known A(-)B(+) strain, C. difficile 8864. Strain SUC 36 (toxinotype XVI), on the other hand, was similar to well-defined group consisting of toxinotypes V, VI, and VII, which thus far includes only A(+)B(+) strains. Toxinotypes XVI and XVII represent two new groups of A(-)B(+) strains. Strains of the well-known A(-)B(+) group from toxinotype VIII have a nonsense mutation at the beginning of tcdA gene, and the introduction of a stop codon at amino acid position 47 results in nonproduction of TcdA. The 5'-end sequence of tcdA in two newly described A(-)B(+) strains does not contain an identical mutation. The prevalence of variant C. difficile strains varied greatly among nine hospitals. Only five strains from four different hospitals were positive in PCR for amplification of the binary toxin gene.
Protection from Clostridium difficile infection in CD4 T Cell- and polymeric immunoglobulin receptor-deficient mice. [2021]Clostridium difficile rivals methicillin-resistant Staphylococcus aureus as the primary hospital-acquired infection. C. difficile infection (CDI) caused by toxins A and/or B can manifest as mild diarrhea to life-threatening pseudomembranous colitis. Although most patients recover fully from CDI, ~20% undergo recurrent disease. Several studies have demonstrated a correlation between anti-toxin antibody (Ab) and decreased recurrence; however, the contributions of the systemic and mucosal Ab responses remain unclear. Our goal was to use the CDI mouse model to characterize the protective immune response to C. difficile. C57BL/6 mice infected with epidemic C. difficile strain BI17 developed protective immunity against CDI and did not develop CDI upon rechallenge; they generated systemic IgG and IgA as well as mucosal IgA Ab to toxin. To determine if protective immunity to C. difficile could be generated in immunodeficient individuals, we infected CD4(-/-) mice and found that they generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge, with protection dependent on major histocompatibility complex class II (MHCII) expression; no IgG anti-toxin Ab was found. We found that protection was likely due to neutralizing mucosal IgA Ab. In contrast, pIgR(-/-) mice, which lack the receptor to transcytose polymeric Ab across the epithelium, were also protected from CDI, suggesting that although mucosal anti-toxin Ab may contribute to protection, it is not required. We conclude that protection from CDI can occur by several mechanisms and that the mechanism of protection is determined by the state of immunocompetence of the host.
Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium difficile infection. [2021]Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy.
Predictors of 30-Day Mortality in Hospitalized Patients with Clostridium difficile Infection. [2020]Label="OBJECTIVES"> Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality and is the most common nosocomial infection in the United States, with associated annual costs of approximately $3 billion. The epidemiology of CDI has changed with the identification of novel risk factors for incident and recurrent CDI. The aim of this study was to identify the predictors of 30-day mortality in hospitalized patients with CDI.
Emergence of Clostridium difficile-associated disease in North America and Europe. [2022]The clinical spectrum of Clostridium difficile-associated disease (CDAD) ranges from diarrhoea to severe life-threatening pseudomembranous colitis. Although not always associated with previous antibiotic exposure, it is in the majority of cases. CDAD is recognised increasingly in a variety of animal species and in individuals previously not considered to be predisposed. C. difficile can be transmitted via personal contact or environmentally. The role of patients and healthcare workers who are symptom-free but colonised with C. difficile in the intestinal tract is unclear. C. difficile, with more than 150 PCR ribotypes and 24 toxinotypes, has a pathogenicity locus (PaLoc) with genes encoding enterotoxin A (tcdA) and cytotoxin B (tcdB). Genes for the binary toxin are located outside the PaLoc, but the role of this toxin is unclear. The recently completed genome sequence of C. difficile 630 revealed a large proportion of 11% of mobile genetic elements, mainly in the form of conjugative transposons. Diagnostic assays include tests for the detection of C. difficile products or genes and culture methods for isolation of a toxin-producing bacterium. Enzyme immunoassays to detect toxin in faeces are widely available, with varying sensitivities and specificities. Despite practical drawbacks and sensitivity less than 100%, the cell cytototoxicity assay is still considered to be the standard. Rapid diagnostic assays are available on a limited scale and require much improvement. Molecular tests enable the detection of carriers of toxigenic and non-toxigenic strains, as does culture. It is highly recommended to culture C. difficile from toxin-positive faeces samples and to store isolates for future characterisation and typing. The financial impact of CDAD on the healthcare system is substantial (5-15,000 euro/case in England and $1.1 billion/year in the USA). Assuming a European Union population of 457 million, the potential cost of CDAD can be estimated to be 3000 million euro/year, and is expected to almost double over the next four decades. In North America, increasing rates of CDAD have been reported in Canada and the USA since March 2003, involving a more severe course, higher mortality, increased risk of relapse and more complications. This increased virulence is presumably associated with higher levels of toxin production by fluoroquinolone-resistant strains belonging to PCR ribotype 027, pulsed-field gel electrophoresis (PFGE) type NAP1, REA (restriction endonuclease analysis) type BI and toxinotype III. In Europe, outbreaks of CDAD due to the new, highly virulent strain of C. difficile PCR ribotype 027, toxinotype III have been recognised in 75 hospitals in England, 16 hospitals in The Netherlands, 13 healthcare facilities in Belgium and nine healthcare facilities in France. These outbreaks are very difficult to control, and preliminary results from case-control studies indicate a correlation with fluoroquinolones and cephalosporins. Information concerning community-acquired cases of ribotype 027 is lacking, and data concerning its incidence in nursing homes are limited. European countries should first develop early-warning and response capabilities at a national level. Depending on the nature of the notifications received, countries should implement laboratory-based or patient-based surveillance systems in specific, targeted populations.