Dataset Information

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

ABSTRACT:

Importance

COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear.

Objective

To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation.

Design, setting, and participants

The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021.

Interventions

Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously.

Main outcomes and measures

The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis.

Results

A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99).

Conclusions and relevance

In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia.

Trial registration

ClinicalTrials.gov Identifier: NCT04443881.

SUBMITTER: Fanlo P

PROVIDER: S-EPMC10082404 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

Fanlo Patricia P Gracia-Tello Borja Del Carmelo BDC Fonseca Aizpuru Eva E Álvarez-Troncoso Jorge J Gonzalez Andrés A Prieto-González Sergio S Freire Mayka M Argibay Ana Belén AB Pallarés Lucio L Todolí José Antonio JA Pérez Mercedes M Buján-Rivas Segundo S Ibáñez Berta B

JAMA network open 20230403 4

<h4>Importance</h4>COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear.<h4>Objective</h4>To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation.<h4>Design, setting, and participants</h4>The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 ( ...[more]

PMID: 37027155

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Project description:BackgroundAmong interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19.MethodsIn this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76).FindingsBetween May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths.InterpretationThe efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results.FundingThis study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

Project description:BackgroundSARS-CoV-2 infections still have a significant impact on the global population. The existing vaccinations have contributed to reducing the severe disease courses, decreasing hospitalisations, and lowering the mortality rate. However, due to the variability of COVID-19 symptoms, the emergence of new variants and the uneven global distribution of vaccines there is still a great need for new therapy options. One promising approach is provided by host-directed therapies. We assessed here the efficacy and safety of MP1032, a host-directed anti-viral/anti-inflammatory drug in hospitalised patients with moderate to severe COVID-19.MethodsIn a randomised, double-blind, placebo-controlled, Phase IIa study, patients were randomised 2:1 to receive either 300 mg MP032 bid + Standard-of-Care (SoC) or placebo bid + SoC for 28 days. Eligible patients were ≥18 years old, tested positive for SARS-CoV-2, and had moderate to severe COVID-19 symptoms. The study spanned 20 sites in six countries (Bulgaria, France, Hungary, Italy, Romania, Spain), assessing disease progression according the NIAID scale as the primary outcome on day 14. Secondary objectives included disease progression (day 28), disease resolution (days 14 and 28), mortality rate, COVID-19 related parameters and safety. Exposure-response analyses were performed, linking MP1032 to COVID-19 biomarkers (eGFR, D-dimer).Findings132 patients were enrolled to receive MP1032 + SoC (n = 87) or placebo + SoC (n = 45). The patients were all white or Caucasian with a mean (median) age of 60.5 (63) years. Overall, only 10 patients were vaccinated, 5 in each group. No significant risk difference of disease progression could be detected between groups on both day 14 (9.8% MP1032 vs. 11.6% placebo) and day 28 with MH common risk differences of -0.276% (95% CI, -11.634 to 11.081; p = 0.962) and 1.722% (95% CI, -4.576 to 8.019; p = 0.592), respectively.The treatment with MP1032 + SoC was safe and well-tolerated. Overall, 182 TEAEs including 10 SAEs were reported in 53.5% (46/86) of patients of the verum group and in 57.8% (26/45) of patients of the placebo group; the SAEs occurred in 5.8% (5/86) and 6.7% (3/45) of verum and placebo patients, respectively. None of the SAEs was considered as related.InterpretationDespite the study's limitation in size and the variation in concurrent SoCs, these findings warrant further investigation of MP1032 as a host-directed anti-viral drug candidate.FundingThe study was funded by the COVID-19 Horizon Europe work programme and MetrioPharm AG.

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Project description:ImportanceFrontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms.ObjectiveTo investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19.Design, setting, and participantsThis prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection.InterventionsCannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days.Main outcomes and measuresThe primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel.ResultsA total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [ηp2] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; ηp2 = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; ηp2 = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery.Conclusions and relevanceIn this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings.Trial registrationClinicalTrials.gov Identifier: NCT04504877.

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Dataset Information

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

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