key: cord-0078824-qqdh6jcl
authors: Fintzi, Jonathan; Bonnett, Tyler; Tebas, Pablo; Marconi, Vincent C.; Levine, Corri B.; El Sahly, Hana M.; McLellan, Susan L.F.; Benson, Constance A.; Rostad, Christina A.; Ganesan, Anuradha; Huprikar, Nikhil; Frank, Maria G.; Mularski, Richard A.; Atmar, Robert L.; Park, Pauline K.; Short, William R.; Beigel, John H.; Mehta, Aneesh K.; Sweeney, Daniel A.
title: Unravelling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2
date: 2022-04-27
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac219
sha: 3bb5d7f7ed7c5c216a3a1d7de51fffa62bab9884
doc_id: 78824
cord_uid: qqdh6jcl

BACKGROUND: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized COVID-19 patients versus remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. METHODS: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models (MSM) to estimate the effect of BCT on clinical improvement and deterioration, and on utilization of respiratory therapies. RESULTS: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (HR, 0.74; 95% CI, 0.58–0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or non-invasive positive pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99–1.51) while slowing clinical deterioration (HR = 0.71; 95% CI, 0.48–1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8–154) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46–291) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. CONCLUSIONS: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or non-invasive positive pressure ventilation compared with RMT, and may thereby improve care for a patient population.

The Adaptive COVID-19 Treatment Trials (ACTT) were designed in response to the urgent need to test 2 therapeutics for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3

infection. ACTT-1 demonstrated that remdesivir shortened recovery time of patients hospitalized with 4 COVID-19 [1] . Secondary analyses revealed that faster recovery was driven by a reduction in incidence of 5 clinical deterioration, particularly among patients who did not require ICU-level therapies at baseline [1] . 6

In ACTT-2, the Janus kinase (JAK) 1-2 inhibitor baricitinib in combination with remdesivir (baricitinib 7 combination therapy; BCT) reduced recovery time and increased the odds of improvement in clinical 8 status at day 15 without increasing serious adverse events compared to treatment with remdesivir 9 monotherapy (RMT) [3] . The decrease in recovery time was modest (a median time to recovery of 7 days 10 for BCT compared to 8 days in the control group), with the largest effect observed in participants 11 treated with high-flow oxygen or non-invasive positive-pressure ventilation (NIPPV) at baseline (median 12 10 days for BCT compared to 18 days for control). 13

In this secondary analysis, we explore how BCT altered clinical progression of ACTT-2 study participants 14 through the ACTT-2 ordinal scale, which describes their therapy requirements and various demands on 15 hospital resources, such as intensive care nursing and ventilation equipment. We apply a variety of 16 statistical tools, including competing risks and multistate models, to analyze the full clinical trajectories 17 of ACTT-2 study participants and further clarify the effect of BCT on clinical improvement and 18 deterioration. Multistate analyses, in particular, incorporate data on intercurrent events and allow for a 19 more detailed understanding of the dynamics of clinical progression. Our analysis may to help inform 20 treatment guidelines, and has implications for ICU resource utilization, which is an increasingly 21 important consideration during periods of hospital strain as patient outcomes become interdependent 22 due to resource constraints. 23 The ACTT-2 trial randomized COVID-19 patients at 67 trial sites across 8 countries to treatment with BCT 3 or RMT [3] . This analysis is restricted to the 891 ACTT-2 participants who required any level of 4 supplemental oxygen therapy at baseline (Supplementary Table 1 ). Participants in ACTT-2 were assessed 5 daily throughout hospitalization using an 8-category ordinal score (OS) scale (Figure 1 model clinical progression, we combined OS 4 and OS 5 into a single state encompassing standard non-10 intensive hospital therapy. Figure 1A depicts two possible patient trajectories through the ordinal scale 11 used in our analyses. 12

We begin our descriptive analysis by graphically depicting the initial clinical progression and final 14 outcomes of study participants as they transition through the ordinal scale, ignoring the timing of state 15 transitions. We also tabulate incidence of clinical improvement and deterioration relative to baseline, 16 defined respectively by a patient ever reaching an OS of lesser or greater severity than their status at 17 randomization, regardless of their interim or subsequent progression. These events are not exclusive of 18 one another or of eventual recovery or death. As a further descriptive analysis, we summarize the total 19 clinical burden for each patient by the sum of their daily OS levels throughout the study period, 20 assigning a daily value of 1 to OS 1-3, 2 to OS 4-5, 3 to OS 6, 4 to OS 7, and 5 to OS 8, and assess via 21

Wilcoxon-Mann-Whitney U-tests whether participants treated with BCT tended to have a lower total 22 burden over the study period [2] . Differences in expected burden are assessed using the Mann-Whitney 23

parameter (MWP) -the probability that a randomly selected participant treated with BCT will have a 1 higher total burden than a randomly selected participant treated with RMT [3] . Additional details of this 2 test are provided in the Supplementary Methods and sensitivity results from alternative formulations of 3 the total clinical burden score are provided in Supplementary Table 2 . 4

We used competing risk models to estimate the treatment effect on the cumulative incidence of 6 patients who improved or worsened relative to baseline. We assessed the effect of BCT on recovery, 7 death, clinical improvement relative to baseline, and clinical deterioration relative to baseline using 8

Fine-Gray proportional subdistribution hazard models [4] . These models relate the cumulative incidence 9 of each event to the hazard among patients who have not yet experienced that event [5] . We report 10 subdistribution hazard ratios from models fit separately to each baseline OS group, as well as overall 11 estimates from stratified models that allow for separate baseline hazards in each group. Unlike the 12 multistate Markov models (MSMs) described in the next subsection, which consider all observed state 13 transitions, each patient only contributes a single time-to-event observation to each competing risks 14 model. Additional technical details and model diagnostics are provided in the Supplementary Appendix 15 ( Supplementary Figures 4-7) . 16

We used the modified ACTT ordinal scale and time-inhomogeneous MSMs fit to data from each 18 participant's clinical course to describe the effect of BCT on changes in clinical status leading to 19 improvement and deterioration throughout hospitalization. A key advantage of the MSM approach 20 compared to traditional methods is the ability to incorporate patients' full clinical trajectories, including 21 intercurrent events, which allows for a more detailed understanding of the dynamics of progression. The 22 model structure ( Figure 1B ) dictates the states between which a patient may directly transition and 23

reflects clinical practices at the time ACTT-2 was conducted. For example, a patient receiving high-flow 1 oxygen would not be discharged without first receiving non-intensive therapy. We only consider data 2 from each participant's initial course of hospitalization, hence discharge and death are both absorbing 3 states. The model was fit separately for participants in each baseline OS group. For each group, we 4 report common hazard ratios representing the overall treatment effects on transitions leading to either 5 clinical improvement or deterioration, corresponding to the two groups of transitions highlighted in 6 Figure 1B . We also use our MSMs to estimate the expected days of ICU-level respiratory support over 7 the study period per 100 patients in each baseline OS group. Uncertainty about the treatment effects 8 and expected ICU resource utilization is quantified using bootstrap confidence intervals with p-values 9 computed using a rerandomization procedure. Technical details of the model specification and 10 estimation procedures are provided in the Supplementary Appendix along with model diagnostics 11 and sensitivity analyses ( Supplementary Figures 12-14) . 12

Participants receiving low-flow oxygen therapy at enrollment -OS 5 14

The clinical courses of participants receiving low-flow oxygen at baseline (OS 5; n=564) were consistent 15 with a more direct path to recovery and lower total clinical burden among patients treated with BCT 16 than RMT (Table 1; clinical deterioration (HR, 0.78; 95% CI, 0.59-1.03; Figure 2C ), albeit the effect was not statistically 23

significant, but had no effect on transitions leading to clinical improvement (HR, 1.06; 95% CI, 0.91, 1 1.24). The daily proportion of baseline OS 5 participants on mechanical ventilation appears to be lower 2 throughout the study period ( Figure 2B ). We estimate that BCT reduced the expected days of high-flow 3 oxygen/NIPPV therapy per 100 patients over the study period by 20 days (95% CI, -2 days to 39 days; 4 Figure 2D and Supplementary Table 3C ) compared with RMT, and reduced the expected days of 5 mechanical ventilation per 100 patients by 39 days (95% CI, -1 day to 84 days). 6

Participants receiving high-flow oxygen therapy or NIPPV at enrollment -OS 6 7

Participants enrolled on high-flow oxygen or NIPPV (OS 6; n = 216) who received BCT also experienced a 8 more direct path to recovery and had lower total clinical burden compared with participants who 9 received RMT (MWP, 0.40; 95% CI, 0.33 -0.48). The majority of baseline OS 6 participants recovered 10 (152 of 216). However, participants treated with BCT had lower incidence of clinical deterioration to 11 mechanical ventilation or death (Table 1 : BCT, 30.1% vs. RMT, 41.6%; HR, 0.68; 95% CI, 0.43-1.06). 12

Participants treated with BCT were more likely to initially improve as their first transition and less likely 13 to regress after an initial improvement (Supplementary Tables 4A and 4B ). Direct recovery and 14 improvement in respiratory therapy requirements followed by recovery accounted for 58.3% of baseline 15 OS 6 participants treated with BCT versus 42.5% of patients given RMT ( Figure 3A ). The third most 16 common clinical course among baseline OS 6 patients -deterioration to mechanical ventilation with no 17 subsequent change in clinical status over the study period -was more common among patients treated 18 with RMT versus BCT (n=12, 10.6% versus n=5, 4.9%). There was more heterogeneity in clinical 19 trajectories among participants in OS 6 at baseline than those in OS 5, as the three most common paths 20 accounted for only 63.2% of participants in the BCT arm and 53.1% of participants given RMT. Our MSM 21 estimated that BCT slowed clinical deterioration (HR, 0.71; 95% CI, 0.48-1.02; Figure 3C ) and sped 22 improvement (HR, 1.21; 95% CI: 0.99, 1.51). The daily proportion of baseline OS 6 participants receiving 23

ICU-level therapies throughout the study period was lower among BCT participants compared with RMT 1 participants ( Figure 3B ). Based on our MSM, we estimate that BCT reduced the expected days of high-2 flow oxygen/NIPPV therapy per 100 patients over the study period compared with RMT by 74 days (95% 3 CI, -8 days to 154 days; Figure 3D and Supplementary Table 4C ) and the expected days of mechanical 4 ventilation per 100 patients by 161 days (95% CI, 46 days to 291 days). 5

Participants enrolled in OS 7 and treated with BCT did not tend to have lower total burden than baseline 7 OS 7 participants treated with RMT (MWP, 0.44; 95% CI, 0.37-0.55). We also did not find evidence that 8 BCT increased incidence of extubation (HR, 1.27; 95% CI, 0.80-2.01). Although the proportions of BCT 9

and RMT participants who were initially extubated were comparable, BCT patients regressed less 10 frequently following an initial improvement (Supplementary Tables 5A and 5B ). The most common 11 clinical path for participants who were mechanically ventilated at baseline was to remain in OS 7 for the 12 duration of the study ( Figure 4A ; RMT, n=15, 26.3%; BCT, n=7, 13%). Though the second and third most 13 common paths were both consistent with a linear improvement and eventual recovery, a higher fraction 14 of the BCT participants followed the shorter path of extubation to non-ICU respiratory therapy followed 15 by recovery (BCT, n=11, 20.4%; RMT, n=4, 7.0%). The proportion of patients recovered or requiring non-16 ICU level therapies at the end of follow-up was only modestly better compared with patients receiving 17 RMT ( Figure 4B ; BCT, n=30, 56%; RMT, n=24, 42%). In our MSM, BCT was not shown to speed clinical 18 improvement (HR, 1.05; 95% CI: 0.76, 1.49) or slow clinical deterioration (HR, 0.89; 95% CI: 0.46, 1.66) 19 among participants in baseline OS 7 ( Figure 4C ). Correspondingly, we estimate that BCT does not alter 20 expected ICU resource utilization in this group of participants over the study period ( Figure 4D 2 study participants. Descriptive analyses and competing risks models revealed a consistent trend 7 towards a more linear path to recovery among BCT participants who were in OS 5 or OS 6 at baseline, 8 though we did not find evidence that patients on mechanical ventilation at enrollment benefited from 9

BCT. Baseline OS 6 participants experienced the greatest benefit from BCT, and MSMs revealed that BCT 10 had a multifaceted benefit in both speeding clinical improvement and impeding clinical deterioration in 11 this group. Baseline OS 6 participants treated with BCT had a lower total clinical burden and significantly 12 lower expected use of critical care-level respiratory therapy. We conclude that BCT use in OS 5 and OS 6 13 patients has the potential to reduce utilization of ICU-level therapies and alleviate inpatient capacity 14 strain. 15

Hospital capacity strain, particularly on ICU resources, has been shown to worsen clinical outcomes [9] . 16 A similar pattern emerged during the SARS-CoV-2 pandemic, with increased mortality among critically ill 17 COVID-19 patients admitted during periods of increased ICU demand [1, 10, 11] . The prospect of patient 18 outcomes being adversely affected by resource constraints is especially harrowing since demand for ICU 19 beds has exceeded capacity throughout the SARS-CoV-2 pandemic. For example, approximately 1 in 4 20 U.S. hospitals with ICUs reported that at least 95 percent of their ICU beds were full in the midst of the 21 SARS-CoV-2 delta wave of the summer of 2021, and this phenomenon has occurred at multiple times 22 throughout the pandemic [12] . The most straightforward manner of reducing hospital strain is to 23

provide a therapy that prevents hospitalization or results in a shorter inpatient stay. The ACTT-1 study 1 showed that remdesivir reduced the recovery time for hospitalized patients with COVID-19 by 5 days 2 compared with placebo [13] . Secondary analyses of ACTT-1 have shown that remdesivir reduced 3 utilization of ICU-level respiratory therapies for patients with COVID-19 [1]. ACTT-2 demonstrated that 4 the addition of baricitinib to remdesivir therapy further curtailed the recovery time of hospitalized 5 patients with COVID-19 by an additional day [14] . BCT may further improve the care delivered to this 6 patient population by easing demand for scarce ICU-level resources among certain hospitalized patients 7 with COVID-19. 8

The biological mechanisms by which BCT led to a more linear path to recovery and inhibited clinical 9 deterioration among baseline OS 5 and OS 6 participants are not elucidated by this secondary analysis 10 and merit further investigation. In randomized clinical trials, Jak inhibitors have been shown to reduce 11 multiple inflammatory cytokines across a diverse range of disease states [15, 16] . These cytokines, which 12 include IL-6, IFN-γ, and GM-CSF, have been implicated in the pathogenesis of progression to severe and 13 critical COVID-19 [17, 18] . Moreover, a direct-acting anti-viral effect has been proposed for baricitinib, in 14 addition to the anti-inflammatory benefits [19] . Most patients hospitalized with COVID-19 who require 15 minimal to no oxygen support will not progress to severe disease because viral replication is interrupted 16 before the host proceeds to the accelerated cytokine phase. We speculate that baricitinib would have its 17 greatest effect when applied to individuals who have begun this process or some time after the process 18 has started, which likely correlates with patients in OS 5 and OS 6 at baseline. Stopping disease 19 progression short of intubation could reduce the risks of known ICU-and ventilation-associated 20 complications, including nosocomial infections, and might also reduce complications following acute 21 COVID [20] . 22

It is important to acknowledge that standards of care for hospitalized patients with COVID-19 and 1 hospital resource management have shifted over the course of the SARS-CoV-2 pandemic and that some 2 of the choices we made in our analysis reflect clinical practice at the time ACTT-2 was conducted [16] . 3

For example, we refer to high-flow oxygen therapy as an ICU-based treatment, which may not be 4 universally true today. Similarly, most participants in ACTT-2 were not treated with dexamethasone, as 5 this was not part of the standard of care until the final weeks of study enrollment. Results from the 6 STOP-COVID trial suggest that tofacitinib, another Jak inhibitor, could be administered effectively in 7 combination with steroids to reduce the incidence of clinical deterioration to mechanical ventilation 8 among hospitalized patients [17] . Further investigation of co-administering immunomodulatory drugs 9 and steroids, specifically baricitinib and dexamethasone, could have significant implications for the 10 clinical course of hospitalized patients with The decision to deploy a new therapy is based first and foremost on whether the therapy is convincingly 12 shown to be effective at treating an individual patient. We argue that an important secondary benefit of 13 effective COVID-19 therapies is the conservation of limited medical resources as patient outcomes can 14 be highly interdependent during times when healthcare systems are stressed. We conducted a variety of 15 analyses to evaluate how BCT altered the trajectories of respiratory therapy requirements compared 16 with RMT, and quantified the aggregate impact of BCT on utilization of critical care resources. We 17 conclude that the addition of baricitinib therapy for the treatment of hospitalized patients presenting in 18 OS 5 and OS 6 could decrease requirements for expensive critical care support and help alleviate ICU 19 strain. The ACTT-2 trial protocol was reviewed and approved by an institutional review board at each study site 2 and monitored by an independent data safety and monitoring committee. Written informed consent 3 was provided by each study participant, or by their legally authorized representative in the event that 4 the patient could not provide consent. Full details of the ACTT-2 design, conduct, and oversight are 5 available in the ACTT-2 protocol, which is available with the primary manuscript disseminating the study 6 results [3] . Abbreviations: BCT, baricitinib combination therapy; CI, confidence interval; MWP, Mann-Whitney parameter (the probability that a randomly selected participant treated with BCT will have a higher total burden than a randomly selected participant treated with RMT); RMT, remdesivir monotherapy. 

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