Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial

Background Baricitinib has shown efcacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifcally on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/ critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modifed intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute diference and 95% CI −0.1% [−8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (−3.2% [−9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a signifcant interac‑ tion between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated partici‑ pants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to con‑ clude on a potential survival beneft of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these fnd‑ ings warrant further investigation in other trials and real-world studies

Chronic fatigue in long-term survivors of Hodgkin’s lymphoma after contemporary risk-adapted treatment

Chronic fatigue (CF), substantial fatigue for ≥ six months, can manifest as a late effect (LE) after cancer treatment, and may affect several aspects of life. In a Norwegian cohort of Hodgkin’s lymphoma survivors (HLS), more than a decade after contemporary risk-adapted treatment regimens with limited use of radiotherapy (RT), we assessed: (1) Prevalence of, (2) factors associated with (3) and implications of CF on socioeconomic status (SES) and work ability (WA). HLS treated between 1997–2006, aged 8–49 years at diagnosis, were invited to participate in a population-based cross-sectional study on late effects in 2018–2019. In a mailed questionnaire, HLS responded to a fatigue questionnaire (FQ), work ability score (WAS) and short-form health survey (SF-36). Disease- and treatment data were extracted from hospital records. Factors associated with CF were identified by uni- and multivariate analysis. To study the implications of CF on SES and WA, a multinomial regression analysis was performed. Invitations were extended to 518 HLS and 298 (58%) responded to FQ, of whom 42% had CF with mean (standard deviation [SD]) physical- and mental fatigue scores of 10.2 (4.3) and 5.5 (2.1) respectively. Median age at survey was 45 years, 47% were females. In multivariate analysis female sex (p = 0.03), lower education (p = 0.03), body mass index ≥30 kg/m2 (p = 0.04), and an increasing number of comorbidities (p = 0.01) were associated with CF. No association with disease stage, chemotherapy or RT was found. CF was associated with poorer WAS scores at survey (p p = 0.03), and receiving disability pension (p = 0.003). After risk-adapted treatment, CF is still a frequent LE among long-term HLS, without apparent association with disease or treatment-related parameters. CF is associated with reduced WA and SES. As no apparent risk reduction is seen with contemporary treatment, further studies should emphasize etiological factors of CF and treatment to alleviate this common LE.</p

Accelerating Clinical Trial Implementation in the Context of the COVID-19 Pandemic: Challenges, Lessons Learned and Recommendations from DisCoVeRy and the EU-SolidAct EU Response Group

No abstract availabl

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

Abstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )