Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.

BACKGROUND: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19. METHODS: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS. FINDINGS: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2). INTERPRETATION: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. FUNDING: Intermountain Research and Medical Foundation.

Hydroxychloroquine versus Azithromycin for Hospitalized Patients with Suspected or Confirmed COVID-19 (HAHPS). Protocol for a Pragmatic, Open-Label, Active Comparator Trial.

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832).

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial.

RATIONALE: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. OBJECTIVE: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. METHODS: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. RESULTS: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. CONCLUSIONS: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial.

Importance: This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease. Objectives: To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. Design, Setting, and Participants: This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease. Interventions: Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period. Main Outcomes and Measures: It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. Results: Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups. Conclusions and Relevance: In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. Trial Registration: ClinicalTrials.gov identifier: NCT02954978.

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease.

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.