scholarly journals 1042. Safety of Investigational Microbiota-Based Live Biotherapeutic RBX2660 in Individuals with Recurrent Clostridioides difficile Infection: Data from Five Prospective Clinical Studies

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S611-S611
Author(s):  
Tricia Braun ◽  
Beth Guthmueller ◽  
Adam J Harvey
Keyword(s):  
Clinical Studies ◽  
Ad Hoc ◽  
Safety Data ◽  
Standard Of Care ◽  
Oral Antibiotic ◽  
Open Label ◽  
Two Phase ◽  
Oral Antibiotic Therapy ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable safety data are needed to support regulatory approvals and broaden patient access. Here we provide cumulative safety data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI. Methods This analysis included three Phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two Phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). Participants were ≥18 years old with documented rCDI who completed standard-of-care oral antibiotic therapy prior to treatment with RBX2660. PUNCH CD3-OLS allowed participants with comorbidities of irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 (or placebo), administered rectally. Participants whose CDI recurred within 8 weeks were eligible for additional RBX2660 treatment. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; CD2 and CD Open Label recorded TEAEs for 24 months. Results Among 620 participants who received at least one RBX2660 dose (assigned treatment or after recurrence), 324 (52.3%) received 1, 270 (43.5%) received 2, 14 (2.3%) received 3, and 12 (1.9%) received 4. 83 participants received blinded placebo only. A total of 1980 TEAEs were reported from 432 (69.7%) RBX2660-treated participants, compared to 174 TEAEs in 50 (60.2%) placebo-only treated participants. Most TEAEs were mild or moderate in severity, with diarrhea common in all treatment groups. No potentially life-threatening TEAEs were considered related to RBX2660. Study discontinuation due to TEAEs was minimal (< 1%) with none related to RBX2660. There were no reported infections for which the causative pathogen was traced to RBX2660. Conclusion Across five clinical studies with consistent investigational product, RBX2660 was well-tolerated in rCDI participants. In aggregate, this data provides compelling and consistent safety data for RBX2660. Disclosures Tricia Braun, PharmD, Rebiotix, a Ferring Company (Employee) Beth Guthmueller, AS, Rebiotix Inc, A Ferring Company (Employee) Adam J. Harvey, PhD, Rebiotix, A Ferring Company (Employee)

scholarly journals 167. Efficacy of Investigational Microbiota-Based Live Biotherapeutic RBX2660 in Individuals with Recurrent Clostridioides difficile Infection: Data from Five Prospective Clinical Studies

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
Lindy Bancke ◽  
Xin Su
Keyword(s):  
Clinical Studies ◽  
Ad Hoc ◽  
Treatment Success ◽  
Standard Of Care ◽  
Oral Antibiotic ◽  
Success Rates ◽  
Open Label ◽  
Two Phase ◽  
Clinical Endpoints ◽  
Clostridioides Difficile

Abstract Background Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable clinical efficacy data are needed to support regulatory approvals that broaden patient access. Here we provide cumulative data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI recurrence. Methods This analysis included three phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). All participants were ≥18 years old with documented rCDI who completed standard-of-care (SOC) oral antibiotic therapy prior to treatment with RBX2660. Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 or placebo, with Treatment Success (TS) defined as remaining recurrence-free for 8 weeks after treatment. Treatment responders were monitored for additional recurrence through at least 6 months after receiving the last RBX2660 dose. Treatment non-responders were administered SOC antibiotic treatment and/or additional RBX2660 treatment and monitored for recurrence for 8 weeks after the last received RBX2660 treatment. Results Among the 5 trials with a total of 629 participants, RBX2660 consistently reduced the recurrence of rCDI, with TS rates ranging from 50 to 78.9% (Figure 1). Among primary non-responders, additional RBX2660 treatments further reduced recurrence and overall rates of TS ranged from 75.0% to 84.4% (Figure 2). Among CD, CD3, and CD3-OLS, a majority of primary responders remained CDI-free to 6 and up to 24 months with success rates ranging from 74.4% to 92.1%. Conclusion Among 5 trials with consistent investigational product and clinical endpoints, RBX2660 consistently reduced rCDI recurrence, with a majority of treatment responders remaining CDI-free for at least 6 and up to 24 months. Further, initial lack of response to RBX2660 did not preclude clinical benefit of additional RBX2660 treatment. Collectively, these data demonstrate consistency and reliability of the potential benefit of RBX2660 across an entire clinical program. Disclosures Lindy Bancke, PharmD, Rebiotix, a Ferring Company (Employee) Xin Su, MD, Rebiotix/Ferring (Employee)

Vancomycin Versus Metronidazole for Nonsevere Clostridioides difficile Infection: Are the Data Adequate to Change Practice?

2019 ◽  
Vol 53 (8) ◽  
pp. 845-852
Author(s):  
Katherine V. Sarna ◽  
Alan E. Gross
Keyword(s):  
Cost Effectiveness ◽  
Clinical Studies ◽  
Statistical Significance ◽  
Outcome Data ◽  
Tolerability Profile ◽  
National Guidelines ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Meta Analyses ◽  
Oral Metronidazole

Objective: To compare oral metronidazole and vancomycin for the treatment of mild-to-moderate Clostridioides difficile infection (mmCDI). Data Sources: A MEDLINE literature search (inception to November 2018) was performed using the search terms metronidazole, vancomycin, and Clostridium/Clostridioides difficile. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: All English-language clinical studies (interventional and observational), meta-analyses, and cost-effectiveness analyses comparing the efficacy of metronidazole and vancomycin for mmCDI were evaluated. Data Synthesis: Nine clinical studies, 5 meta-analyses, and 1 cost-effectiveness analysis provided comparative data for metronidazole and vancomycin for the treatment of mmCDI. Improved treatment response with vancomycin as compared with metronidazole in adults with mmCDI reached statistical significance in a few studies; albeit, most studies and pooled analyses have results that numerically favor vancomycin. Furthermore, the cost per case treated appears to be lower with vancomycin compared with metronidazole based on data from hospitalized patients. Relevance to Patient Care and Clinical Practice: Recent updates to national guidelines now give preference to vancomycin over metronidazole for mmCDI; however, this has been a source of controversy. This review provides an appraisal of direct and indirect comparisons of oral metronidazole and vancomycin for mmCDI, including recent literature published after the release of current guidelines. Conclusions: The available outcome data suggesting that vancomycin is more effective than metronidazole, combined with the more favorable pharmacokinetics, safety, and tolerability profile of vancomycin, provide adequate clinical rationale for the preferential use of this agent for the treatment of mmCDI.

A novel phase I/IIa open-label study of IMM-101 in combination with selected standard of care regimens in patients with metastatic cancer or unresectable cancer at study entry.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14627-e14627
Author(s):  
David Cunningham ◽  
Jean-Yves Blay ◽  
Aurelien Marabelle ◽  
David Stanbury ◽  
Satvinder Mudan ◽  
...  
Keyword(s):  
T Regulatory Cells ◽  
Metastatic Cancer ◽  
Safety Data ◽  
Standard Of Care ◽  
Intradermal Injection ◽  
Primary Objective ◽  
In Vivo Model ◽  
Open Label ◽  
T Effector Cells

e14627 Background: The MODULATE (IMM-101-011, EUDRACT 2016-001459-28) trial recruits patients with metastatic or unresectable cancer considered for a new line of recognised SOC (1st, 2nd or 3rd line and beyond). IMM-101 is a heat-killed whole cell Mycobacterium obuense (National Collection of Type Cultures [NCTC] 13365) for intradermal injection. Methods: The primary objective of the study is to provide safety data for IMM-101 in combination with several selected SOC regimens. The secondary objectives of the study are to provide safety and tolerability data for extended administration (beyond 28 weeks) of the immunomodulator IMM-101 in combination with a number of selected SOC regimens. A particular focus of the study is to evaluate safety data for the combination of IMM 101 with anti PD1 and with anti-CTLA 4. Pre-clinical data suggests that IMM-101 increases the response to PD1 in a syngeneic in vivo model of EMT6 breast cancer. Furthermore, in a syngeneic B16 melanoma tumour model the combination of IMM-101 with anti-PD1 antibodies increased T effector cells in the tumour and reduced the numbers of T-regulatory cells; significantly shifting the T-cell ratio towards anti-tumour efficacy. Results: The study aims through its translational programme to evaluate the best combination partner for IMM-101 due to the SOCs immunogenic cell death capabilities and supportive immunological activities. MODULATE will monitor selected markers of tumour burden and immunological status in patients taking IMM-101. Conclusions: The MODULATE study will initially recruit patients in the UK and France with US sites added in Q4 2017. Clinical trial information: NCT03009058. [Table: see text]

scholarly journals Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

2020 ◽  
Vol 9 (3) ◽  
pp. 481-494 ◽  
Author(s):  
Daniele Roberto Giacobbe ◽  
Silvia Dettori ◽  
Stefano Di Bella ◽  
Antonio Vena ◽  
Guido Granata ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Narrative Review ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

scholarly journals Evaluation of new or repurposed treatments for COVID-19: protocol for the phase Ib/IIa DEFINE trial platform

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e054442
Author(s):  
Erin Gaughan ◽  
Tom Quinn ◽  
Annya Bruce ◽  
Jean Antonelli ◽  
Vikki Young ◽  
...  
Keyword(s):  
Safety Data ◽  
Standard Of Care ◽  
Assisted Ventilation ◽  
Early Warning Score ◽  
Ordinal Scale ◽  
Experimental Therapy ◽  
Experimental Medicine ◽  
Open Label ◽  
Link Type ◽  
Hospitalised Patients

IntroductionCOVID-19 is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS-CoV-2. At present, there are few proven effective treatments. This early-phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety data in patients with COVID-19, pharmacokinetic (PK)/pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of patients positive for COVID-19.Methods and analysisDefine is an ongoing exploratory multicentre-platform, open-label, randomised study. Patients positive for COVID-19 will be recruited from the following cohorts: (a) community cases; (b) hospitalised patients with evidence of COVID-19 pneumonitis; and (c) hospitalised patients requiring assisted ventilation. The cohort recruited from will be dependent on the experimental therapy, its route of administration and mechanism of action. Randomisation will be computer generated in a 1:1:n ratio. Twenty patients will be recruited per arm for the initial two arms. This is permitted to change as per the experimental therapy. The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Secondary analysis will assess the following variables during treatment period: (1) the response of key exploratory biomarkers; (2) change in WHO ordinal scale and National Early Warning Score 2 (NEWS2) score; (3) oxygen requirements; (4) viral load; (5) duration of hospital stay; (6) PK/PD; and (7) changes in key coagulation pathways.Ethics and disseminationThe Define trial platform and its initial two treatment and standard of care arms have received a favourable ethical opinion from Scotland A Research Ethics Committee (REC) (20/SS/0066), notice of acceptance from The Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2020-002230-32) and approval from the relevant National Health Service (NHS) Research and Development (R&D) departments (NHS Lothian and NHS Greater Glasgow and Clyde). Appropriate processes are in place in order to be able to consent adults with and without capacity while following the necessary COVID-19 safe procedures. Patients without capacity could be recruited via a legal representative. Witnessed electronic consent of participants or their legal representatives following consent discussions was established. The results of each study arm will be submitted for publication in a peer-reviewed journal as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including the Randomised Evaluation of COVID-19 Therapy trial (RECOVERY), and to other partners for rapid roll-out in larger patient cohorts.Trial registration numberISRCTN14212905, NCT04473053.

scholarly journals Evaluation of the Ototoxicity Potential of OnceDaily, Single-Entity Hydrocodone in Patients with Chronic Pain: Results of Two Phase-3 Clinical Studies

2017 ◽  
Vol 1 (21;1) ◽  
pp. E183-E193
Author(s):  
Ellie He
Keyword(s):  
Hearing Loss ◽  
Clinical Studies ◽  
Pure Tone ◽  
The United States ◽  
Controlled Study ◽  
Open Label ◽  
Phase 3 ◽  
Two Phase ◽  
Single Entity ◽  
Air Conduction

Background: Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients’ overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated. Objective: In this report, we aimed to evaluate the potential ototoxicity of a novel, singleentity, once-daily, extended-release hydrocodone tablet (Hysingla® ER; HYD). Study Design: Clinical study. Setting: Audiology clinics in US. Methods: Results from 1207 patients in two phase 3 clinical studies were evaluated: A placebo-controlled study with an enriched enrollment, randomized withdrawal design in patients with chronic low back pain, and an open-label, long-term, safety study in patients with chronic nonmalignant and non-neuropathic pain. Comprehensive audiologic assessments (comprising pure-tone air-conduction audiometry in the conventional [0.25-8 kHz] and ultra-high [10-16 kHz] frequencies, pure-tone boneconduction audiometry, tympanometry, speech reception thresholds, and word recognition) were conducted at baseline and end-of-studies; air-conduction audiometry was conducted periodically during the studies. All audiologic assessments were performed in audiology clinics in the United States by licensed audiologists. The primary endpoint was changes from baseline in pure-tone air-conduction thresholds in the conventional frequencies during the studies. These trials are registered with ClinicalTrials.gov, identifiers NCT01400139 and NCT01452529 Results: During the studies, mean changes from baseline in air-conduction thresholds were clinically unremarkable. Bidirectional variability across all test frequencies was observed; 82% of patients did not experience significant threshold changes during the studies, 7% had potential hearing decrement, and 10% experienced hearing sensitivity improvement. No notable differences were observed between patients receiving HYD and placebo or between different HYD doses. Conclusion: No ototoxic signal was observed for single-entity hydrocodone tablets at the dosages and treatment durations investigated. Key words: Audiologic monitoring, clinical trials, hydrocodone, opioids, ototoxicity monitoring, sensorineural hearing loss

scholarly journals Optimizing preoperative antibiotics in patients with β-lactam allergies: A role for pharmacy

2021 ◽  
Author(s):  
Shaina Kwiatkowski ◽  
Surafel Mulugeta ◽  
Susan Davis ◽  
Rachel Kenney ◽  
James Kalus ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Surgical Site Infections ◽  
Standard Of Care ◽  
Pharmacist Intervention ◽  
Decision Algorithm ◽  
Allergy Testing ◽  
Telephone Interviews ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Preoperative Antibiotics

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Patients with a reported β-lactam allergy (BLA) are often given alternative perioperative antibiotic prophylaxis, increasing risk of surgical site infections (SSIs), acute kidney injury (AKI), and Clostridioides difficile infection (CDI). The purpose of this study was to implement and evaluate a pharmacist-led BLA clarification interview service in the preoperative setting. Methods A pharmacist performed BLA clarification telephone interviews before elective procedures from November 2018 to March 2019. On the basis of allergy history and a decision algorithm, first-line preoperative antibiotics, alternative antibiotics, or allergy testing referral was recommended. The pharmacist intervention (PI) group was compared to a standard of care (SOC) group who underwent surgery from November 2017 to March 2018. Results Eighty-seven patients were included, with 50 (57%) and 37 (43%) in the SOC and PI groups, respectively. The most common surgeries included orthopedic surgery in 41 patients (47%) and neurosurgery in 17 patients (20%). In the PI group, all BLA labels were updated after interview. Twenty-three patients were referred for allergy testing, 12 of the 23 (52%) completed BLA testing, and penicillin allergies were removed for 9 of the 12 patients. Overall, 28 of the 37 (76%) pharmacy antibiotic recommendations were accepted. Cefazolin use significantly increased from 28% to 65% after the intervention (P = 0.001). SSI occurred in 5 (10%) patients in the SOC group and no patients in the PI group (P = 0.051). All of these SSIs were associated with alternative antibiotics. Incidence of AKI and CDI was similar between the groups. No allergic reactions occurred in either group. Conclusion Implementation of a pharmacy-driven BLA reconciliation significantly increased β-lactam preoperative use without negative safety outcomes.

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