Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension

Background: The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure. Method(s): In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposureadjusted incidence rates per 100 patient-years (PY) were calculated. Result(s): The average age of TN OLE study participants was 41.7 years (+/-13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious;TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%;EAIR 0.1/100 PY;2 in TN and 1 in OLE;no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%;EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%];EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events. Conclusion(s): Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure). (Table Presented).

Providing preventative care during the SARS-CoV-2 pandemic: Street medicine interventions amongst those experiencing unsheltered homelessness in the City of Detroit

Background. In 2021, there were approximately 1300 people on a given day who have experienced homelessness within the city of Detroit, Michigan. Sheltered beds within the 24 homeless shelters in the city were drastically cut in half during the COVID-19 pandemic due to concerns of overcrowding perpetuating SARS-CoV-2 outbreaks. We aimed to describe the outreach efforts made by Street Medicine Organizations (SMO) of Detroit during the SARS-CoV-2 pandemic, highlighting infection prevention and control strategies, and promotion of COVID-19 vaccinations amongst the unsheltered homeless. Methods. Health promotion interventions were directed at individuals who were unsheltered (defined as those living on the streets of Detroit, encampment sites and abandoned buildings). Education, which was provided through in-person sessions, as well as targeted COVID-19 informational pamphlets were distributed with every street-based run. Hygiene kits, which included masks, hand sanitizer and gloves were distributed thrice weekly at shelters and encampment sites. Since access to hand hygiene was drastically limited, the SMO constructed 10 hand washing stations throughout the city. COVID-19 vaccination in people experiencing homelessness started in April 2021. Results. SMO prioritized a 60 square mile range within the city of Detroit, providing care to approximately 500 persons over the months of April 2020 to April 2021. Demographics for this population varied;age ranged from 23 to 76 years old, sex was 70% males, race were 67% Black, 29% White and 4% Hispanic. More than 2000 hygiene kits were distributed throughout this period. Ninety-one individuals experiencing unsheltered homelessness were provided the COVID-19 vaccine in April 2021. Conclusion. Individuals experiencing unsheltered homelessness face unique challenges to accessing timely medical care, which has been further exacerbated during the pandemic. These individuals have limited or no access to necessary measures needed to prevent the spread and severity of diseases of SARS-CoV-2. We describe a focused and effective approach to preventing infection among these individuals as a model for organizations nationally.

TREATMENT-EMERGENT COVID-19 INFECTIONS IN OZANIMOD ULCERATIVE COLITIS AND MULTIPLE SCLEROSIS CLINICAL TRIALS

Introduction: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients in active phase 3 open-label extension studies. Methods: A database search identified COVID-19 infection reports in ozanimodtreated patients with UC in the True North open-label extension and MS in the DAYBREAK open-label extension. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all patients with ³1 event was analyzed. Results: Among 2792 ozanimod-treated patients with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most patients with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated patients with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Figure 1). A majority of UC patients with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC patient with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC patients. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Figure 2). Most MS patients with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Figure 1). No MS patients with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC patients (Figure 1) and 30 additional MS patients (Figure 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. Conclusion: In the UC and MS open-label extension studies, most patients with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (case-fatality rate 1.6% in MS, 1.2% overall). (Figure Presented)(Figure Presented)

The Role of Anaesthesiologists in the COVID-19 Pandemic: Practical lessons from Groote Schuur Experience

Clinicians worldwide have been called to action against COVID-19, requiring development of effective systems to respond to the surge of pandemic cases. Anaesthesiologists are equipped to fulfil many roles in the operating room, critical care and retrieval settings. However, it was anticipated that the case load could overwhelm our existing referral structures, and put staff and patients at increased risk. We describe, using the “4S” components of surge capacity development, how systems, staff, space and stuff were utilised to create a COVID Anaesthesia, Intubation and Retrieval (CAIR) Team at Groote Schuur Hospital, Cape Town, South Africa. The primary aims of the team are to provide safe anaesthesia for patients with known or suspected COVID-19, and perform intubation and transfer in COVID wards or high care areas to intensive care units. Concurrently, promotion of strict infection control practices and risk mitigation through the use of a dedicated group of low-risk, highly trained individuals was achieved. Staff support systems, protocols for streamlined patient management, reallocation of spaces within the hospital, the capital and disposable equipment required for the service, and use of continual audit and iterative improvement are discussed in this article. © World Federation of Societies of Anaesthesiologists 2022.

Treatment-emergent COVID-19 infections in ozanimod ulcerative colitis and multiple sclerosis clinical trials

Background: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients (pts) in active phase 3 openlabel extension (OLE) studies. Methods: A database search identified COVID-19 infection reports in ozanimod-treated pts with UC in the True North OLE and MS in the DAYBREAK OLE. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all pts with ≥1 event was analyzed. Results: Among 2792 ozanimod-treated pts with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most pts with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated pts with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Fig 1). A majority of UC pts with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC pt with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC pts. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Fig 2). Most MS pts with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Fig 1). No MS pts with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC pts (Fig 1) and 30 additional MS pts (Fig 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. One pt died from a presumed pulmonary embolism;this pt had received high-dose corticosteroids for MS relapse immediately before COVID-19 symptom onset. Another pt died from suspected COVID-19-related respiratory failure. One tetraplegic, cachectic pt died from a lung abscess following COVID-19 infection. Conclusion: In the UC and MS OLE studies, most pts with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (casefatality rate 1.6% in MS, 1.2% overall).

Sustained endothelial, coagulation and inflammatory cytokine activation without macrovascular dysfunction at 3 months after COVID-19: A reflection on SARS-CoV-2 induced thrombo-inflammation

Background: Endothelial damage caused by COVID-19 may imperil the cardiovascular health of millions. More than a year since WHO declared the COVID-19 pandemic, information on the lasting effects of this infection on the cardiovascular system beyond the acute phase is still lacking. Purpose: To study macrovascular endothelial dysfunction and activation, coagulation and inflammation, 3 months after resolution of acute COVID- 19 symptoms. Methods: A cross-sectional observational cohort study was conducted including 203 patients with PCR confirmed COVID-19 disease, 6-20 weeks after acute COVID-19. The primary endpoint was macrovascular endothelial function, assessed by the carotid artery reactivity (CAR) test. The CAR measures the carotid artery diameter in response to hand in icewater immersion. A historic cohort of 313 subjects served as controls. Propensity score matching was used to correct for baseline differences. Plasma endothelin-1 (ET-1), interleukin (IL)-1ra, IL-6, IL-18 were measured by ELISA. ET-1 levels were also measured in a partially overlapping COVID-19 cohort of which plasma samples were available during the acute phase. Coagulation enzyme:inhibitor complexes for thrombin:antithrombin (TAT), factor (F) IXa:AT, FVIIa:AT, FXIa:AT, FXIa:alpha 1 antitrypsin (a1AT), FXIa:C1 esterase inhibitor (C1inh), kallikrein(PKa):C1inh and von Willebrand Factor:antigen (vWF:Ag), were assessed by in house developed ELISA. Results: After propensity score matching, the prevalence of macrovascular dysfunction did not differ between the COVID-19 (22.5%) versus the historical control cohort (18.6%, RD -3.92%, 95%-CI -15 to 7.19, p=0.49). Plasma concentrations of markers for endothelial activation were elevated (>1 SD above normal);ET-1 (64.9%), and vWF:Ag (80.8%). In controls, ET- 1 levels were significantly lower as compared to COVID-19 patients during the acute phase and after 3 months. ET-1 levels were significantly higher 3 months after COVID-19 as compared to the acute phase. Cytokines were high in a majority of patients: IL-18 (73.9%), IL-6 (51.2%), and IL- 1ra (48.9%). TAT and FIXa:AT, reflecting a prothrombotic state, were high in 48.3% and 29.6% of the patients, respectively. FVIIa:AT, as marker of the extrinsic pathway, was elevated (35%). Markers of contact activation were also increased: PKa:C1inh (16.3%), FXIa:AT (16.3%), FXIa:a1AT (20.7%), and FXIa:C1inh (17.7%) (picture 1). Conclusions: At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction as compared to matched historic controls;there was evidence, however, of sustained thrombo-inflammation, indicated by high circulating concentrations of ET-1, vWF:Ag, proinflammatory cytokines, and markers of coagulation (picture 2). Elevated IL-18 levels could potentially induce arterial inflammation and subsequent atherogenesis. Our data highlight the importance of further studies on SARS-CoV-2 related thrombo-inflammation, as well as longer follow-ups in recovered patients. (Figure Presented).

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Diabetes and COVID-19: psychosocial consequences of the COVID-19 pandemic in people with diabetes in Denmark-what characterizes people with high levels of COVID-19-related worries?

AIM: To map COVID-19-specific worries and overall psychosocial health among people with diabetes in the initial phase of the COVID-19 pandemic in Denmark, and to explore characteristics of people with diabetes and high levels of worries related to the COVID-19 pandemic. METHODS: A cross-sectional survey was conducted by distributing online questionnaires to 2430 adult members (> 18 years) of two user panels consisting of people with diabetes who have volunteered to share information about their life with diabetes. The questionnaire included items on COVID-19-specific worries as well as such worries related to diabetes, sociodemographic and health status, social relations, diabetes-specific social support, diabetes distress and changes in diabetes-specific behaviours. Responses were analysed with descriptive statistics and logistic regressions. RESULTS: People with diabetes have COVID-19-specific worries related to their diabetes. More than half were worried about being overly affected due to diabetes if infected with COVID-19, about one-third about being characterized as a risk group due to diabetes and not being able to manage diabetes if infected. Logistic regressions showed that being female, having type 1 diabetes, diabetes complications and diabetes distress, feeling isolated and lonely, and having changed diabetes behaviours were associated with being more worried about COVID-19 and diabetes. CONCLUSION: People with diabetes have COVID-19-specific worries related to their diabetes which is associated with poorer psychosocial health. These worries should be addressed through support targeting specific questions and needs of individuals with diabetes as well as frequent updates on new knowledge regarding COVID-19 and diabetes.