Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

Abstract Background In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality. Methods We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels. Results Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24–0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12–0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84). Conclusion In patients with severe COVID-19 pneumonia, early administration of prolonged, low dose MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.

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Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia

10.1101/2020.06.17.20134031 ◽

2020 ◽

Cited By ~ 4

Author(s):

Francesco Salton ◽

Paola Confalonieri ◽

Pierachille Santus ◽

Sergio Harari ◽

Raffaele Scala ◽

...

Keyword(s):

Primary Endpoint ◽

Low Dose ◽

Research Question ◽

Invasive Mechanical Ventilation ◽

Rapid Improvement ◽

Clinical Trial Registration ◽

Multicenter Observational Study ◽

Randomized Controlled Studies ◽

High Dependency ◽

Composite Primary Endpoint

AbstractBackgroundIn hospitalized patients with COVID-19 pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism.Research QuestionWill early prolonged methylprednisolone (MP) treatment accelerate disease resolution, decreasing the need for ICU and mortality?Study Design and MethodsWe conducted a multicenter, observational study to explore the association between exposure to prolonged, low-dose, MP treatment and need for ICU referral, intubation or death within 28 days (composite primary endpoint) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.ResultsFindings are reported as MP (n=83) vs. control (n=90). The composite primary endpoint was met by 19 vs. 40 [adjusted hazard ratio (HR) 0.41; 95% confidence interval (CI): 0.24-0.72]. Transfer to ICU and need for invasive MV was necessary in 15 vs. 27 (p=0.07) and 14 vs. 26 (p=0.10), respectively. By day 28, the MP group had fewer deaths (6 vs. 21, adjusted HR=0.29; 95% CI: 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs. 17.5 ± 12.8; p=0.001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the two groups (p=0.84).InterpretationIn patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Randomized controlled studies are needed to confirm these findings.Clinical trial registrationClinicalTrials.gov. Identifier: NCT04323592.

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Effect of Micronutrient Powder (MNP) with a Low-Dose of Iron on Hemoglobin and Iron Biomarkers, and Its Effect on Morbidities in Rural Bangladeshi Children Drinking Groundwater with a High-Level of Iron: A Randomized Controlled Trial

Nutrients ◽

10.3390/nu11112756 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2756 ◽

Cited By ~ 1

Author(s):

Sabuktagin Rahman ◽

Patricia Lee ◽

Rubhana Raqib ◽

Anjan K. Roy ◽

Moududur R. Khan ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Side Effects ◽

Low Dose ◽

Controlled Trial ◽

Randomized Controlled ◽

End Point ◽

Micronutrient Powder ◽

Iron Parameters ◽

Rate Ratios ◽

High Level

Micronutrient Powder (MNP) is beneficial to control anemia, but some iron-related side-effects are common. A high level of iron in the groundwater used for drinking may exacerbate the side-effects among MNP users. We conducted a randomized controlled trial examining the effect of a low-dose iron MNP compared with the standard MNP in children aged 2–5 years residing in a high-groundwater-iron area in rural Bangladesh. We randomized 327 children, who were drinking from the “high-iron” wells (≥2 mg/L), to receive either standard (12.5 mg iron) or low-dose iron (5.0 mg iron) MNP, one sachet per day for two months. Iron parameters were measured both at baseline and end-point. The children were monitored weekly for morbidities. A generalized linear model was used to determine the treatment effect of the low-dose iron MNP. Poisson regressions were used to determine the incidence rate ratios of the morbidities. The trial was registered at ISRCTN60058115. Changes in the prevalence of anemia (defined as a hemoglobin level < 11.0 g/dL) were 5.4% (baseline) to 1.0% (end-point) in the standard MNP; and 5.8% (baseline) to 2.5% (end-point) in the low-dose iron MNP groups. The low-dose iron MNP was non-inferior to the standard MNP on hemoglobin outcome (β = −0.14, 95% CI: −0.30, 0.013; p = 0.07). It resulted in a lower incidence of diarrhea (IRR = 0.29, p = 0.01, 95% CI: 0.11–0.77), nausea (IRR = 0.24, p = 0.002, 95% CI: 0.09–0.59) and fever (IRR = 0.26, p < 0.001, 95% CI: 0.15–0.43) compared to the standard MNP. Low-dose iron MNP was non-inferior to the standard MNP in preventing anemia yet demonstrated an added advantage of lowering the key side-effects.

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COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

10.1101/2020.07.20.20157503 ◽

2020 ◽

Cited By ~ 2

Author(s):

Garth W Strohbehn ◽

Brian L Heiss ◽

Sherin J Rouhani ◽

Jonathan A Trujillo ◽

Jovian Yu ◽

...

Keyword(s):

Low Dose ◽

Controlled Trial ◽

Pulmonary Infiltrate ◽

Primary Objective ◽

Dose Finding ◽

Repeat Dose ◽

Rapid Improvement ◽

Phase 2 Trial ◽

Biological Studies ◽

Epidemiologic Risk

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.

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Effects of photobiomodulation therapy combined with static magnetic field (PBMT-sMF) in patients with severe COVID-19 requiring intubation: a pragmatic randomized placebo-controlled trial

10.1101/2020.12.02.20237974 ◽

2020 ◽

Author(s):

Thiago De Marchi ◽

Fabiano Frâncio ◽

João Vitor Ferlito ◽

Renata Monteiro Weigert ◽

Cristiane Aparecida de Oliveira ◽

...

Keyword(s):

Mechanical Ventilation ◽

Length Of Stay ◽

Primary Outcome ◽

Controlled Trial ◽

Invasive Mechanical Ventilation ◽

C Reactive Protein ◽

Reactive Protein ◽

Secondary Outcomes ◽

Fraction Of Inspired Oxygen ◽

Inspired Oxygen

ABSTRACTBackgroundPhotobiomodulation therapy (PBMT) when used isolated or combined with static magnetic field (PBMT-sMF) has been proven benefits on skeletal muscle increasing performance and reducing fatigue, increasing oxygen saturation, and modulating inflammatory process. However, it is unknown whether the effects observed with this therapy on respiratory muscles will be similar to the effects previously observed on skeletal muscles.ObjectiveWe aimed to investigate whether PBMT-sMF is able to decrease the length of stay in the intensive care unit (ICU) and to reduce the mortality rate of patients with severe COVID-19 requiring invasive mechanical ventilation, increasing the respiratory function and modulating the inflammatory process.MethodsWe conducted a prospectively registered, pragmatic, triple-blinded (patients, therapists and outcome assessors), randomized, placebo-controlled trial of PBMT-sMF in patients with severe COVID-19, requiring invasive mechanical ventilation, admitted to the ICU. Patients were randomly assigned to receive either PBMT-sMF (6 sites at the lower thorax – 189 J total, and 2 sites at the neck area – 63 J total) or placebo PBMT-sMF daily during all the ICU stay. The primary outcome was length of stay in the ICU defined by either discharge or death. The secondary outcomes were survival rate, muscle function of diaphragm, change in blood tests, change in mechanical ventilation parameters and change in arterial blood gas analysis.ResultsA total of 30 patients underwent randomization (with 15 assigned to PBMT-sMF and 15 to placebo) and were analyzed. The length of stay in the ICU for the placebo group was 23.06 days while for the PBMT-sMF group was 16.26. However, there was no statistically difference between groups for the length of stay in the ICU (mean difference - MD = - 6.80; 95% CI = - 18.71 to 5.11). Regarding the secondary outcomes were observed statistically differences in favor of PBMT-sMF for diaphragm thickness, fraction of inspired oxygen, partial pressure of oxygen/fraction of inspired oxygen ratio, C-reactive protein, lymphocytes count, and hemoglobin (p<0.05).ConclusionAmong patients with severe COVID-19 requiring invasive mechanical ventilation, PBMT-sMF was not statistically different than placebo to the length of stay in the ICU. However, it is important to highlight that our sample size was underpowered to detect statistical differences to the primary outcome. In contrast, PBMT-sMF increased muscle function of diaphragm, improved ventilatory parameters, decreased C-reactive protein levels and hemoglobin count, and increased lymphocytes count.

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EARLY LENZILUMAB TREATMENT OF COVID-19 PATIENTS USING C-REACTIVE PROTEIN AS A BIOMARKER IMPROVES EFFICACY: RESULTS FROM THE PHASE 3 LIVE-AIR TRIAL

10.1101/2021.12.30.21267140 ◽

2022 ◽

Author(s):

Zelalem Temesgen ◽

Colleen F. Kelley ◽

Frank Cerasoli ◽

Adrian Kilcoyne ◽

Dale Chappell ◽

...

Keyword(s):

Mechanical Ventilation ◽

Adverse Events ◽

Controlled Trial ◽

Invasive Mechanical Ventilation ◽

Tertiary Care ◽

Baseline Risk ◽

C Reactive Protein ◽

Phase 3 ◽

Gm Csf ◽

Reactive Protein

Objective: The LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab. Design: LIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28. Setting: Secondary and tertiary care hospitals in the US and Brazil. Participants: 520 hospitalized COVID-19 participants with SpO2≤94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. Interventions: Lenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measures: A multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values. Results: The multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP≥150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade ≥ 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab. Conclusion: These finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention. Trial Registration: ClinicalTrials.gov NCT04351152

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