Clinical trial NCT04970719: Baricitinib in Hospitalized Covid-19 Patients With Diabetes Mellitus
Official title: The Efficacy of Baricitinib Plus Remdesivir Compared to Dexamethasone Plus Remdesivir in Hospitalised COVID-19 Patients With Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: COVID-19 Pneumonia
Keywords: COVID-19
baricitinib
remdesivir
dexamethasone
diabetes mellitus
hospitalized
Lead sponsor: Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders
Sponsor class: OTHER
First posted: 2021-07-21
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

  1. 8-point Ordinal scale activities and no new or increased oxygen use.
  2. 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.

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.

Primary outcomes:
measure: Rescue treatment
timeFrame: Day 2 through Day 29
Secondary outcomes:
measure: Death or invasive mechanical ventilation
timeFrame: Day 2 through Day 29
measure: C-reactive protein (CRP)
timeFrame: Day 1 through Day 29
measure: lactate dehydrogenase (LDH)
timeFrame: Day 1 through Day 29
measure: Ferritin
timeFrame: Day 1 through Day 29
measure: Creatinine
timeFrame: Day 1 through Day 29
measure: alanine aminotransferase (ALT)
timeFrame: Day 1 through Day 29
measure: d-dimer concentration
timeFrame: Day 1 through Day 29
measure: fasting blood glucose (FBS)
timeFrame: Day 1 through Day 29
measure: hemoglobin
timeFrame: Day 1 through Day 29
measure: platelets
timeFrame: Day 1 through Day 29
measure: white blood cell count (WBC)
timeFrame: Day 1 through Day 29
measure: total lymphocyte count
timeFrame: Day 1 through Day 29
measure: adverse events (AEs)
timeFrame: Day 1 through Day 29
measure: serious adverse events (SAEs)
timeFrame: Day 1 through Day 29
measure: invasive mechanical ventilation
timeFrame: Day 2 through Day 29
measure: non-invasive ventilation/high flow oxygen
timeFrame: Day 2 through Day 29
measure: supplemental oxygen
timeFrame: Day 1 through Day 29
measure: Desirability of Outcome Ranking (DOOR)
timeFrame: Day 15 through Day 29
measure: Duration of hospitalization
timeFrame: Day 1 through Day 29
measure: Incidence of discontinuation or temporary suspension of study product administration
timeFrame: Day 1 through Day 10
measure: Subject 14-day mortality
timeFrame: Day 2 through Day 15
measure: Subject 28-day mortality
timeFrame: Day 2 through Day 29
measure: Subject clinical status
timeFrame: Days 3, 5, 8, 11, 15, 22, and 29
measure: The proportion of subjects meeting criteria for each of the 8 ordinal scale categories
timeFrame: Day 15
measure: The proportion of subjects not meeting criteria for one of the three most severe ordinal scale categories at any time
timeFrame: Day 2 through Day 29
measure: Time to an improvement of one category from baseline using an ordinal scale
timeFrame: Day 1 through Day 29
measure: Time to recovery
timeFrame: Day 1 through Day 29
Other outcomes:
Locations:
city: Comilla
country: Bangladesh
facility: Debidwar Upazila Health Complex
city: Dhaka
country: Bangladesh
facility: BIRDEM General Hospital
city: Dhaka
country: Bangladesh
facility: Mugda Medical College and Hospital
city: Dhaka
country: Bangladesh
facility: Kurmitola General Hospital
city: Kurigram
country: Bangladesh
facility: Kurigram Adhunik Sadar Hospital
city: Rajshahi
country: Bangladesh
facility: Rajshahi Medical College & Hospital
city: Rangpur
country: Bangladesh
facility: Dedicated Corona Isolation Hospital (DCIH)
Study officials:
affiliation: Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders
name: Wasim MM Haque, FCPS
role: PRINCIPAL_INVESTIGATOR
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