Protecting clinical trials in cystic fibrosis during the SARS-CoV-2 pandemic: risks and mitigation measures.

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks.

"Il faut continuer à poser des questions" patient reported outcome measures in cystic fibrosis: An anthropological perspective.

BACKGROUND: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool. METHODS: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers. CONCLUSIONS: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

Disease-specific clinical trials networks: the example of cystic fibrosis.

UNLABELLED: This article describes the steps of the development and the structure of a disease-specific clinical trials network for cystic fibrosis in Europe. Activities such as reviewing study protocols, feasibility assessments, training and standardizing of procedures, and outcome measurements help to bring high-quality clinical trials to the patients. Cooperation with the pharmaceutical industry, other research networks, patient organizations, and regulatory agencies is very important throughout all activities. CONCLUSION: The European Cystic Fibrosis Society-Clinical Trials Network facilitates the development of new treatments for a rare disease and could be a prototype for other diseases. WHAT IS KNOWN: • Clinical research has led to the first approved treatments targeting the basic Cystic Fibrosis defect. • For a rare disease like Cystic Fibrosis, multicenter international collaboration is needed to obtain solid evidence when testing possible new treatments. What is New: • The Clinical Trials Network established by the European Cystic Fibrosis Society has grown to a fully operational network with well-defined structures, procedures and partnerships. • Standardization of outcome parameters, protocol review, feasibility assessment and other activities help to develop high quality, efficient, relevant and feasible clinical trials, with the aim to bring new treatments to the patients.

Effects of T cell-induced colonic inflammation on epithelial barrier function.

BACKGROUND: Epithelial barrier disturbance is thought to contribute to the pathogenesis of inflammatory bowel diseases; however, it remains unclear whether it is a primary defect participating to the onset of inflammation or only a consequence of sustained inflammation. METHODS: A time course study of epithelial barrier functions and immune mediators was performed in the CD4(+)CD45RB(hi) T cell transfer model of colitis using Ussing chambers. RESULTS: In nonreconstituted severe combined immunodeficiency (SCID) mice, no epithelial dysfunction was observed. However, after transfer of CD4(+)CD45RB(hi) T cells or total CD4(+) T cells, colon of SCID mice displayed a decreased epithelial resistance, even before overt microscopic inflammation had occurred. Sustained colitis of CD4(+)CD45RB(hi) T cell reconstituted mice was also associated with enhanced subepithelial resistance, enhanced paracellular permeability, and decreased net ion transport. All these reflect a disturbance of barrier function and may contribute to diarrhea. Epithelial resistance was positively correlated with interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF-alpha) levels, pointing to the protective effect of IL-10 and TGF-beta and to a damaging effect of TNF-alpha. Indomethacin, a nonselective COX inhibitor, decreased epithelial resistance independent of T cells and inflammation, but its effect was more pronounced in inflamed colon. CONCLUSIONS: Induction of colitis by transfer of CD4(+)CD45RB(hi) T cells in SCID mice leads to changes in the colonic epithelium before colitis develops. Decreased epithelium resistance might contribute to the development of colitis; however, it is not sufficient to lead to chronic inflammation.

Pouchitis, similar to active ulcerative colitis, is associated with impaired butyrate oxidation by intestinal mucosa.

BACKGROUND: Healthy colonic mucosa uses butyrate as the major energy source. In ulcerative colitis (UC) butyrate oxidation has been shown to be disturbed, but it remains unclear whether this is a primary defect. The aim of this study was to measure mucosal butyrate oxidation in UC (involved and noninvolved colon) and in pouchitis and to study the relationship with endoscopic as well as histological disease activity. METHODS: Butyrate oxidation was measured in 73 UC patients, 22 pouchitis patients, and 112 controls (95 colon, 17 ileum) by incubating biopsies with 1 mM 14C-labeled Na-butyrate and measuring the released 14CO2. RESULTS: Compared with that in normal colon, butyrate oxidation was significantly impaired in endoscopically active but not in quiescent disease or uninvolved colon segments. The severity of the metabolic defect was related to histological disease activity and decreased epithelial cell height. In active pouchitis, butyrate oxidation was significantly decreased compared with that in normal ileum and excluded pouches without inflammation. The histological pouchitis score correlated significantly with butyrate oxidation. CONCLUSIONS: Active UC and pouchitis show the same inflammation-related metabolic defect. Our data suggest that the defect is a consequence of inflammation and that pouchitis is metabolically similar to active UC.

Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent.

BACKGROUND: Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti-tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti-inflammatory drug intake in patients with CD. METHODS: Thirty-one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for Cr-EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty-five patients carried out a baseline and indomethacin-mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of Cr-EDTA after oral intake. RESULTS: Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92-5.72) was restored to normal values (2.47%; IQR, 1.97-2.78) by anti-TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti-TNF: 6.50%; IQR, 4.84-10.38; after anti-TNF: 5.50%; IQR, 3.97-10.09) compared with the healthy subjects (4.66%; IQR, 3.51-5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti-TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission. CONCLUSIONS: Although anti-TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease.

OBJECTIVES: A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. METHODS: Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. RESULTS: The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively). CONCLUSION: Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.