A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit.

BACKGROUND: Community-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP). METHODS: In addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20-30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20-30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union's Horizon 2020 Research and Innovation Program. DISCUSSION: SEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination. TRIAL REGISTRATION: NCT03158727 , retrospectively registered on 9 May 2017.

Development of a new patient-reported outcome measure for complex cryptoglandular fistulas (20-Item complex cryptoglandular fistula questionnaire™): a qualitative study.

BACKGROUND: There are limited tools to measure the burden of disease and effectiveness of medical/surgical interventions in patients with cryptoglandular fistulas. The aim of this study was to explore concepts that are relevant and important to patients with complex cryptoglandular fistulas (CCF) and to develop a patient-centred, disease-specific, patient-reported outcome measure (PROM) to assess symptom burden and impacts of CCF. METHODS: A targeted literature review was conducted, followed by one-to-one telephone interviews with five colorectal surgeons (USA, n = 3; UK, n = 1; Spain, n = 1) and 20 US adult patients with CCF to inform the development of a conceptual model and a CCF-specific PROM. The targeted literature review informed the development of the preliminary conceptual model and identified a PROM in the literature that was used as a reference to generate the draft CCF-specific PROM. The colorectal surgeon interviews provided insights on the experience of patients with CCF to refine the conceptual model, formulate probing questions for use in patient interviews, and to develop the draft CCF-specific PROM. Patients' descriptions of their experiences with symptoms and the impacts on their lives and evaluation of the draft CCF-specific PROM in concept elicitation and cognitive interviews were used to develop the final conceptual model and final CCF-specific PROM. RESULTS: Ten symptoms (odour, pain during bowel movement, abscess, post-operative pain, discharge/drainage/leakage, anal/perianal pain, inflammation/swelling, skin irritation, bleeding and itchiness) and 11 impacts (discomfort, inability to exercise, embarrassment, difficulty sitting, worry about disease, adapted life to maintain hygiene, negatively impacted social life/isolation, inability to perform daily activities, reduced interest in sex, negatively impacted intimate relationships and negatively impacted mood) were reported as most salient by patients. The patient experience, clinician perspective, and literature review provided input to item generation. Evaluation of relevance and patient understanding through cognitive interviews with patients provided evidence for the content validity of the new patient-reported outcome measure: the 20-item Complex Cryptoglandular Fistula Questionnaire™ (CCFQ-20™). CONCLUSION: The CCFQ-20™ is a new clinician-guided, patient-validated, disease-specific patient-reported outcome measure that measures disease impact and quality of life in patients with CCF.

The safety and efficacy of stem cells for the treatment of severe community-acquired bacterial pneumonia: A randomized clinical trial.

PURPOSE: Evaluate the safety profile of expanded allogeneic adipose-derived mesenchymal stem cell (eASC) for the treatment of severe community-acquired bacterial pneumonia (CABP). MATERIALS AND METHODS: Randomized, multicenter, double-blind, placebo-controlled, phase 1b/2a trial. Patients with severe CABP were enrolled to receive intravenous infusions of Cx611 or placebo. The primary objective was safety including hypersensitivity reactions, thromboembolic events, and immunological responses to Cx611. The secondary endpoints included the clinical cure rate, ventilation-free days, and overall survival (Day 90). RESULTS: Eighty-three patients were randomized and received infusions (Cx611: n = 42]; placebo: n = 41]. The mean age was similar (Cx611: 61.1 [11.2] years; placebo: 63.4 [10.4] years). The number of AEs and treatment-emergent AEs were similar (243; 184 and 2; 1) in Cx611 and placebo respectively. Hypersensitivity reactions or thromboembolic events were similar (Cx611: n = 9; placebo: n = 12). Each study arm had similar anti-HLA antibody/DSA levels at Day 90. The clinical cure rate (Cx611: 86.7%; placebo: 93.8%), mean number of ventilator-free days (Cx611: 12.2 [10.29] days; placebo: 15.4 [10.75] days), and overall survival (Cx611: 71.5%; placebo: 77.0%) did not differ between study arms. CONCLUSION: Cx611 was well tolerated in severe CABP. These data provide insights for future stem cell clinical study designs, endpoints and sample size calculation. TRIAL REGISTRATION: NCT03158727 (retrospectively registered: May 09, 2017). Full study protocol: https://clinicaltrials.gov/ProvidedDocs/27/NCT03158727/Prot_000.pdf.