Baricitinib in Hospitalized Covid-19 Patients With Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
To date, some of the most promising drugs used in the treatment of COVID pneumonia are systemic corticosteroids, remdesivir and baricitinib. Dexamethasone has been found efficacious in reducing mortality in patients requiring supplemental oxygen and mechanical ventilation. There is a trend towards reduced mortality in patients who receive remdesivir and dexamethasone combination, supporting the hypothesis that an antiviral drug combined with an anti-inflammatory agent improve outcomes in COVID-19. Baricitinib plus remdesivir is superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen non-invasive ventilation. Diabetes mellitus increases the risk for COVID-19 morbidity and mortality. Patients with diabetes have coexisting morbidities and already immune-compromised. Steroids cause further immunosuppression and may contribute to uncontrolled blood glucose in this group of patients, resulting in worse outcomes. Baricitinib can be an alternative to corticosteroids in diabetic patients. This open-label multi-centre non-inferiority randomized controlled trial will be conducted in seven hospitals in Bangladesh. The primary objective is to evaluate the clinical efficacy of baricitinib plus remdesivir compared to dexamethasone plus remdesivir in hospitalized COVID-19 patients with diabetes mellitus, as assessed by the proportion of patients, need rescue treatment between two groups by day 29. Hospitalized adult (≥18 years) diabetic patients with confirmed SARS-CoV-2 infection have ordinal scale category 5 will be included in the study. Subjects will be randomized in a 1:1 (by tossing a coin) ratio in two groups. The total sample size is 362. Group 1 subjects will receive 200 mg of remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily dose of remdesivir while hospitalized for up to 5 days and 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to 14 days. Group 2 will receive the same dose of remdesivir plus 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to 10 days. Subjects will be assessed daily while hospitalized. Discharged subjects will be evaluated on days 15, 22 and 29 (in person; if not possible, over the telephone). Assessment will be done clinically using an 8-point Ordinal Scale and National Early Warning Score.

Detailed Description
-----------------
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first identified during an outbreak of a respiratory illness in Wuhan City of Hubei Province, China, in December 2019. On March 11, WHO declared COVID-19 a global pandemic. COVID-19 situation is sprouting rapidly with increasing case counts and deaths. So far (June 29, 2021), 182.2 million cases have been detected, with 3.95 million deaths worldwide. . High infection and case fatality rates warrant ongoing research to find safe and effective treatment protocols for hospitalized patients. To date, some of the most promising drugs used in treating COVID pneumonia are systemic corticosteroids, remdesivir and baricitinib. The first randomized clinical trial of remdesivir did not show an absolute decrease in mortality. Subsequently, the ATCC-1 trial conclusively demonstrated a benefit. A third open-label trial involvingCOVID-19 with moderate severity had a low overall mortality (<2%) and did not provide further insight. Finally, data from the SOLIDARITY trial, the largest remdesivir trial to date with 5451 patients (WHO Solidarity Trial Consortium, 2021), did not show a significant decrease in mortality for remdesivir alone (rate ratio 0.95, 95% CI 0.81-1.11) or their embedded meta-analysis of all available trials (rate ratio 0.91, 95% CI 0.79-1.05).Though remdesivir showed promising clinical benefit, the high mortality in the ATCC-1 trial underscored using an immunomodulator combined with remdesivir to achieve the desired outcome . There was a trend towards reduced mortality in patients who received remdesivir and dexamethasone combination. This observation supports the hypothesis that the combination of antiviral and anti-inflammatory agents could improve the outcomes of COVID-19. Baricitinib is an inhibitor of Janus kinase (JAKs) 1 and 3, with partial selectivity to JAK 2. Baricitinib suppresses pro-inflammatory signals that may be pathogenetically important in the progression to more severe lung disease and ARDS in patients with COVID-19. So far, dexamethasone and baricitinib are the only two anti-inflammatory treatment options; those have been shown to be effective in large randomized clinical trials in treating adults with COVID-19 in hospitals. However, differences in study populations, mortality rates, and endpoint data collected in the ACTT-2 and RECOVERY studies make it difficult to draw firm conclusions about the value of interventions in different patient populations. A comparison between baricitinib and dexamethasone for treating patients with COVID-19 pneumonia who require supplemental oxygen is now a fascinating topic for clinical research, mentioned in an editorial in the New England Journal of Medicine. ACTT-2showed that baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen or non-invasive ventilation. The combination was associated with fewer serious adverse events like serious infections.Baricitinib was most effective in patients with an ordinal scale of 5 and 6, allowing expansion of therapeutic armament against COVID-19 pneumonia, mainly in patients receiving oxygen support without invasive mechanical ventilation.Evidence in favour of baricitinib is emerging; a recent meta-analysis and systematic review of five studies with a total of 1190 patients showed that the use of JAK inhibitors was significantly associated with a reduced risk of mortality (OR=0.51; 95% CI, 0.28 to 0.93; P = 0.02; I2: 7.8%, P = 0.354) and clinical improvement (OR=1.76; 95% CI, 1.05 to 2.95; P = 0.032; I2: 26.4%, P = 0.253) . Another systematic review of 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N = 3) or baricitinib (N = 8) found a potential role for JAK-inhibitors in reducing the risk of death in persons with COVID-19. Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; 95% CI, 0.47 to 0.84; P = 0.002) and had borderline impact on rates of ICU admission (RR = 0.24; 95% CI, 0.06 to 0.02; P = 0.05) and ARDS (RR = 0.50; 95% CI, 0.19 to1.33; P = 0.16). Relative risks of death for both drugs were 0.42; 95% CI, 0.30 to 0.59; P < 0.001, for ruxolitinib, RR = 0.33; 95% CI, 0.13 to 0.88; P = 0.03) and for baricitinib RR = 0.44; 95% CI, 0.31 to 0.63; P < 0.001). A recent Brazilian study found that tofacitinib resulted in a lower risk of death or respiratory failure than placebo in patients hospitalized with Covid-19 pneumonia. Dexamethasone has been established as life-saving by reducing mortality in patients needing supplemental oxygen and mechanical ventilation . Dexamethasone was evaluated at the University of Oxford-sponsored Global Study on the Randomised Evaluation of COVID-19 Therapy (RECOVERY). The study results showed that patients receiving dexamethasone had a lower death rate than patients receiving usual treatment. However, in this study, no ordinal stratification was used. The mortality benefit of dexamethasone was greater in patients receiving invasive mechanical ventilation. (assumed ordinal scale of 7). Nevertheless, no indication of the level of oxygen support was given; therefore, it is unknown whether dexamethasone was effective in patients who received low flow oxygen (ordinal scale 5) or in patients who received high flow oxygen (ordinal scale 6). To date, ACTT-4 is the only head to head study comparing these two drugs in a similar population. The preliminary report of this study is equivocal. No differences in efficacy or adverse reactions were found between the two groups; no drugs were found to be superior or inferior to one another. Dexamethasone is associated with high blood glucose levels, especially in patients with diabetes, and often gets out of hand. Recent retrospective analyses of hospitalized patients have strongly suggested that diabetes increases the risk for COVID-19 morbidity and mortality. Another study found that patients with COVID-19 who have elevated blood glucose levels without a previous diagnosis of diabetes may be at a high risk of death and an increased risk of severe complications. The recent surge of mucormycosis in diabetic COVID-19 is supposed to be a consequence of using high dose steroids in this patient population. Diabetic patients often have other concomitant comorbidities and are already immunosuppressed. High dose steroids lead to additional immunosuppression with uncontrolled blood glucose in this group of patients, leading to a worse outcome. Baricitinib may be a reasonable alternative to dexamethasone in diabetic patients. This drug has already been recommended for COVID-19 patients with grossly uncontrolled diabetes. The present study aims to compare the outcome between patients treated with dexamethasone plus remdesivir and baricitinib plus remdesivir in the diabetic population. This study will help clinicians contextualize the evidence and practice sane medicine when selecting drugs to treat COVID-19 patients with coexisting diabetes mellitus. Research question: Is baricitinib plus remdesivir as effective as dexamethasone plus remdesivir in hospitalized diabetic patients with COVID-19? Hypothesis: Baricitinib plus remdesivir is not less effective than dexamethasone plus remdesivir in hospitalized diabetic patients with COVID-19. Study design: Open-label, multi-centre randomized controlled non-inferiority trial. Randomization: 1:1 (by tossing a coin). Non-Inferiority margin: M1=1.0309, M2=1.0153. Assessment procedure: Subjects will be assessed daily while hospitalized. For discharged subjects Day 15 and 29 (in person; if not possible, over the telephone) Physical and biochemical examination The Day 22 (over the telephone) Only clinical data Al patient-related data will be updated in a web-based structured form instantly Assessment tools Clinical 8-point Ordinal scale activities and no new or increased oxygen use. National Early Warning Score 2 (NEWS 2, table 2) Laboratory: CBC, HbA1c, fasting blood glucose, CRP, serum ferritin, LDH, D-dimer, serum creatinine, SGPT, SGOT, PT/APTT, serum procalcitonin, serum electrolytes, serum fibrinogen, IL-6 level, blood and sputum culture and sensitivity, imaging. Assessment frequency Clinical: daily during hospitalization, after discharge on day 15, 22, and 29. Biochemical: CRP: 24 hourly for 1st48 hours of randomization, then on day 3, 5, 8, 11, 15, and 29. CBC, serum ferritin, LDH, D-dimer, serum creatinine, SGPT, SGOT, fasting blood glucose on randomization and day 3, 5, 8, 11, 15, and 29. HbA1c, PT/APTT, serum procalcitonin, total serum bilirubin, on the day of randomization then as relevant. Serum fibrinogen level, serum IL-6 level, serum electrolytes relevant. Microbiological tests: o Blood and sputum culture and sensitivity as relevant Imaging: CXR on the day of randomization and as relevant. HRCT as relevant.

Official Title
-----------------
The Efficacy of Baricitinib Plus Remdesivir Compared to Dexamethasone Plus Remdesivir in Hospitalised COVID-19 Patients With Diabetes Mellitus

Conditions
-----------------
COVID-19 Pneumonia

Intervention / Treatment
-----------------
* Drug: Baricitinib
* Drug: Dexamethasone
* Drug: Remdesivir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Hospitalized diabetic adults with laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) in any respiratory specimen within 10 days prior to randomization or *Hospitalized diabetic adults with typical features of COVID-19 for 10 days prior to randomization, not yet tested for SARS-CoV-2 infection by PCR in any respiratory specimen. RT-PCR for SARS-CoV-2 will be performed within 48 hours of enrollment and excluded from the study if found to be negative. 8-point ordinal scale category 5 patients, but O2 requirement not more than 10L / min. The subject provides informed consent before initiating any study procedures and understands and agrees to comply with planned study procedures Exclusion Criteria: Patients with evidence (clinical, hematological, microbiological or imaging ) of sepsis or any acute/subacute coinfection at the time of enrollment. Patients who have already received any of the study drugs prior to randomization. Patients with severe renal and/or hepatic impairment (eGFR <30 mL/min [EPI-CKD formula] or serum ALT more than 5 times normal upper limit, serum bilirubin > 2 mg/dl). Patients with known COPD. Patients with absolute neutrophil count <700 cells/microliter, 0.7 x 103/microliter. Patients with absolute lymphocyte count <200 cells/microliter, 0.20 x 103/microliter. Patients who are allergic to any of the study drugs. Patients with chronic infections, such as tuberculosis (TB), HIV infection etc. Immunosuppressed patients, such as taking cytotoxic/immunomodulating drugs or systemic steroid.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remdesivir plus Baricitinib<br>200 mg of remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of remdesivir while hospitalized for up to a 5-day total course; 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course | Drug: Baricitinib<br>* 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course<br>* Other names: Janus kinase inhibitors;Drug: Remdesivir<br>* 200 mg of remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of remdesivir while hospitalized for up to a 5-day total course<br>* Other names: Anti-viral;|
| Active Comparator: Remdesivir plus Dexamethasone<br>200 mg of remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of remdesivir while hospitalized for up to a 5 -day total course; and 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course. | Drug: Dexamethasone<br>* and 6 mg* of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course<br>* Other names: Steroids;Drug: Remdesivir<br>* 200 mg of remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of remdesivir while hospitalized for up to a 5-day total course<br>* Other names: Anti-viral;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rescue treatment | The proportion of subjects not requiring rescue treatment. Rescue treatment will be given if there is a deterioration of the ordinal scale beyond category 5 (unable to maintain SpO2 ≥ 92% with 10 L/ min O2) at any time 24 hours after enrollment. 10 mg of dexamethasone will be administered on top of existing treatment in group 1 and escalate to in group 2 as an intravenous injection, 2 to 4 times daily for 3 to 5 days based on the patient's condition, then tapered. Patients who deteriorate beyond the ordinal scale category 5 within 24 hours of enrollment will be excluded from the study. | Day 2 through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or invasive mechanical ventilation | The proportion of subjects not meeting criteria for one of the following two ordinal scale categories at any time: 8) Death; 7) Hospitalized, on invasive mechanical ventilation | Day 2 through Day 29 | 
| C-reactive protein (CRP) | Change from baseline in C-reactive protein (CRP) | Day 1 through Day 29 | 
| lactate dehydrogenase (LDH) | Change from baseline in lactate dehydrogenase (LDH) | Day 1 through Day 29 | 
| Ferritin | Change from baseline in Ferritin | Day 1 through Day 29 | 
| Creatinine | Change from baseline in creatinine | Day 1 through Day 29 | 
| alanine aminotransferase (ALT) | Change from baseline in alanine aminotransferase (ALT) | Day 1 through Day 29 | 
| d-dimer concentration | Change from baseline in d-dimer concentration | Day 1 through Day 29 | 
| fasting blood glucose (FBS) | Change from baseline in fasting blood glucose (FBS) | Day 1 through Day 29 | 
| hemoglobin | Change from baseline in hemoglobin | Day 1 through Day 29 | 
| platelets | Change from baseline in platelets | Day 1 through Day 29 | 
| white blood cell count (WBC) | Change from baseline in white blood cell count (WBC) | Day 1 through Day 29 | 
| total lymphocyte count | Change from baseline in total lymphocyte count | Day 1 through Day 29 | 
| adverse events (AEs) | Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) | Day 1 through Day 29 | 
| serious adverse events (SAEs) | Cumulative incidence of serious adverse events (SAEs) An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening. | Day 1 through Day 29 | 
| invasive mechanical ventilation | Days of invasive mechanical ventilation (if applicable) | Day 2 through Day 29 | 
| non-invasive ventilation/high flow oxygen | Days of non-invasive ventilation/high flow oxygen (if applicable) | Day 2 through Day 29 | 
| supplemental oxygen | Days of supplemental oxygen | Day 1 through Day 29 | 
| Desirability of Outcome Ranking (DOOR) | Desirability of Outcome Ranking (DOOR) based on ordinal scale: 1) Recovered (category 1, 2 or 3 on ordinal scale); 2) Improved (> / = 1 category improvement of ordinal scale compared with baseline) & no serious adverse event (SAE); 3) Improved (> / = 1 category improvement of the ordinal scale compared with baseline) & SAE (related or unrelated); 4) No change in ordinal scale from baseline & no SAE; 5) No change in ordinal scale from baseline & SAE (related or unrelated); 6) Worsening (> / = 1 category worse in ordinal scale from baseline); 7) Death. | Day 15 through Day 29 | 
| Duration of hospitalization | Measured in days | Day 1 through Day 29 | 
| Incidence of discontinuation or temporary suspension of study product administration | For any reason | Day 1 through Day 10 | 
| Subject 14-day mortality | Date of death (if applicable). | Day 2 through Day 15 | 
| Subject 28-day mortality | Date of death (if applicable). | Day 2 through Day 29 | 
| Subject clinical status | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use | Days 3, 5, 8, 11, 15, 22, and 29 | 
| The proportion of subjects meeting criteria for each of the 8 ordinal scale categories | The ordinal scale categories are defined as: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use | Day 15 | 
| The proportion of subjects not meeting criteria for one of the three most severe ordinal scale categories at any time | The ordinal scale categories: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices. | Day 2 through Day 29 | 
| Time to an improvement of one category from baseline using an ordinal scale | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, but has a new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, the patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use. | Day 1 through Day 29 | 
| Time to recovery | Day of recovery is defined as the first day on which the subject satisfies one of the following three ordinal scale categories: 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use. | Day 1 through Day 29 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, baricitinib, remdesivir, dexamethasone, diabetes mellitus, hospitalized