Clinical Data
The efficacy and safety of baricitinib were assessed in two phase 3, randomized, double-blind, placebo-controlled clinical trials1:
- ACTT-2, which evaluated the combination of baricitinib 4 mg and remdesivir compared to placebo and remdesivir.
- COV-BARRIER, which evaluated baricitinib 4 mg compared to placebo. Patients could remain on background therapy, as defined per local guidelines.
NIAID Ordinal Scale (used in ACTT-2 and COV-BARRIER)
SELECT IMPORTANT SAFETY INFORMATION RELATED TO SERIOUS INFECTIONS AND THROMBOSIS
Serious Infections: There is limited information regarding use of baricitinib in patients with COVID-19 and concomitant active serious infections.
Serious infections have occurred in patients receiving baricitinib. Avoid the use of baricitinib with known active tuberculosis. Consider if the potential benefits outweigh the potential risks of baricitinib treatment in patients with active serious infections other than COVID-19 or chronic/recurrent infections.
Thrombosis: In hospitalized patients with COVID-19, prophylaxis for venous thromboembolism is recommended unless contraindicated. If clinical features of deep vein thrombosis or pulmonary embolism occur, patients should be evaluated promptly and treated appropriately.
COV-BARRIER Data Overview
Study Design
COV-BARRIER was a randomized, double-blind, placebo-controlled clinical trial of hospitalized adults with confirmed SARS-CoV-2 infection that compared treatment with baricitinib 4 mg once daily (n=764) with placebo (n=761). Baricitinib was administered for 14 days or until hospital discharge whichever came first. Patients could remain on background standard of care, as defined per local guidelines, including antimalarials, antivirals, corticosteroids, and/or azithromycin. The most frequently used therapies were1:
- corticosteroids (79% of patients, mostly dexamethasone)
- remdesivir (19% of patients)
Patients had to have laboratory-confirmed SARS-CoV-2 infection, at least one instance of elevation in at least one inflammatory marker (CRP, D-dimer, LDH, ferritin), and at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2 ≤94% on room air, evidence of active COVID infection (with clinical symptoms including any of the following: fever, vomiting, diarrhea, dry cough, tachypnea defined as respiratory rate >24 breaths/min) or requirement for supplemental oxygen. Patients requiring invasive mechanical ventilation or ECMO at baseline were enrolled in a substudy of COV-BARRIER that is ongoing. This subset of patients was not included in present efficacy and safety results.1
The primary endpoint was the proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation within the first 28 days of the study. Patients who required non-invasive ventilation/high-flow oxygen at baseline needed to worsen by at least 1 point on an 8-point ordinal scale to progress.1
A key secondary endpoint was all-cause mortality by Day 28.1
Patient Characteristics for COV-BARRIER
aIncludes participants from Mexico and Latin America.
bIncludes Germany, Italy, Spain, and the United Kingdom.
cIncludes Argentina, Brazil, India, Japan, Korea (Republic of), Mexico, and Russian Federation.
SELECT IMPORTANT SAFETY INFORMATION RELATED TO ABNORMAL LABORATORY VALUES
There is limited information regarding use of baricitinib in patients with COVID-19 and any of the following clinical findings: absolute neutrophil count (ANC) <1000 cells/mm3, absolute lymphocyte count (ALC) <200 cells/mm3, and hemoglobin <8 g/dL.
Evaluate estimated glomerular filtration rate (eGFR), liver enzymes, and complete blood count at baseline and thereafter according to local patient management practice. Monitor closely when treating patients with abnormal baseline and post-baseline laboratory values. Follow dose adjustments as recommended in the Fact Sheet for Healthcare Providers for patients with abnormal renal, hematological and hepatic laboratory values. Manage patients according to routine clinical guidelines.
SELECT IMPORTANT SAFETY INFORMATION RELATED TO VACCINATIONS
Avoid use of live vaccines with baricitinib.
ACTT-2 Data Overview
ACTT-2 Study Design
The Adaptive COVID-19 Treatment Trial 2 (ACTT-2) study was a randomized, double-blind, placebo-controlled clinical trial of hospitalized adults with confirmed SARS-CoV-2 infection that compared treatment with baricitinib and remdesivir (combination group; n=515) to treatment with placebo and remdesivir (placebo group; n=518). Patients had to have laboratory-confirmed SARS-CoV-2 infection*, as well as at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2 ≤94% on room air, a requirement for supplemental oxygen, or a requirement for mechanical ventilation or ECMO.1,6,7
There was no limit to the duration of symptoms prior to enrollment.7
*Laboratory-confirmed SARS-CoV-2 infection was determined by RT-PCR assay.7
Patients treated with the combination received the following regimen1,6
- Baricitinib 4 mg once daily (orally) for 14 days or until hospital discharge, whichever was first
- Remdesivir 200 mg on Day 1 and 100 mg once daily (via intravenous infusion) on subsequent days for a total treatment duration of 10 days or until hospital discharge, whichever was first
In ACTT-2, all patients received standard supportive care at the trial site hospital. If a hospital had a written policy for COVID-19 treatments, patients could receive those treatments. In the absence of a written policy, other experimental treatment and off-label use of marketed medications intended as specific treatment for COVID-19 were prohibited. This included corticosteroids, which were permitted only for standard indications such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute respiratory distress syndrome.6
There were 223 patients who received corticosteroids for clinical indications during the trial.6
The primary endpoint, for the intent to treat population, was time to recovery within 29 days after randomization.
Recovery was defined as1,6,7:
- Being discharged from the hospital without limitations on activities,
- Being discharged from the hospital with limitations on activities and/or requiring home oxygen, or
- Hospitalized but not requiring supplemental oxygen and no longer requiring medical care
The key secondary endpoint was clinical status on Day 15, as assessed on an 8-point ordinal scale (OS).1,6,7
Patient Characteristics for ACTT-2
aRace and ethnic group were reported by the patients. With respect to “other” race, the categories that were used when data on race were reported included American Indian or Alaska Native and Native Hawaiian or other Pacific Islander.
bPercentages are based on the number of subjects with data available for the individual comorbidity.
SELECT IMPORTANT SAFETY INFORMATION RELATED TO HYPERSENSITIVITY
If a serious hypersensitivity occurs, discontinue baricitinib while evaluating the potential causes of the reaction.
Safety
In placebo-controlled COVID-19 clinical trials, ACTT-2 and COV-BARRIER, for up to 29 days, 1257 patients received at least one dose of baricitinib 4 mg once daily, and 1261 patients received placebo, for up to 14 days or hospital discharge, whichever occurred first.1
Comparisons of Adverse Events in the Safety Population1a,b
aAbbreviations: TEAE = treatment emergent adverse event; AE=adverse event; DCAE= AE leading to discontinuation of study drug (including death due to AE); N = number of patients in the Safety Population; n = number of patients reporting at least 1 event; SAE = serious adverse event.
bPatients are counted once for each category regardless of the number of events.
cIncludes patients who died from any cause.
dIncludes positively adjudicated pulmonary embolism and deep vein thrombosis.
Of the known adverse drug reactions of baricitinib in clinical trials of other indications, the Adverse Reactions table summarizes the observed frequencies of adverse reactions occurring in ≥1% of patients during the first 29 days of studies ACTT-2 and COV-BARRIER.
Adverse Reactions Occurring in ≥1% in the Safety Population1
aAs assessed by measured values within the clinical trial database. Frequencies are based on shifts from pre-treatment to post-treatment (with number at risk as the denominator), except for ALT and AST for which frequencies are based on observed elevation during treatment.
bCreatine phosphokinase frequencies presented in the table were available for a single trial in patients with COVID-19 (COV-BARRIER) and do not represent integrated data.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.
References: 1. Baricitinib. Fact Sheet for Healthcare Providers. Lilly USA, LLC; 2021. 2. Data on File. Lilly USA, LLC. DOF-BC-US-0003. 3. Data on file. Lilly USA, LLC. DOF-BC-US-0006. 4. Data on file. Lilly USA, LLC. DOF-BC-US-0007. 5. Data on file. Lilly USA, LLC. DOF-BC-US-0001. 6. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2020. doi: 10.1056/NEJMoa2031994. 7. Kalil AC, Patterson TK, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. Suppl. N Engl J Med. 2020. doi: 10.1056/NEJMoa2031994.