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Clinical results in hospitalized patients with COVID-19 1

The clinical evaluation of ACTEMRA in hospitalized COVID-19 patients was based on 4 clinical trials. These included one randomized, controlled, open-label, platform trial [Randomised Evaluation of COVID-19 Therapy (RECOVERY)] and 3 randomized, double-blind, placebo-controlled trials (EMPACTA, COVACTA, and REMDACTA).

RECOVERY (NCT04381936) was a large, randomized, controlled, open-label, multi-center platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia. All eligible patients received usual care and underwent an initial (main) randomization. Eligible patients for the trial had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments. Patients with clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L) qualified for a second randomization to receive either intravenous ACTEMRA or usual care alone.

Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 patients who were randomized, with 2022 patients in the ACTEMRA + usual care arm and 2094 patients in the usual care alone arm. The mean age of participants was 63.6 years (standard deviation [SD] 13.6 years). The majority of patients were male (67%) and White (76%). At baseline, 14% of patients required invasive mechanical ventilation, 41% of patients required non-invasive ventilation or high-flow oxygen, and 45% of patients required low flow oxygen; 82% of patients were reported to be receiving systemic corticosteroids.

The primary outcome was time to death through Day 28. The hazard ratio comparing the ACTEMRA + usual care arm to the usual care alone arm was 0.85 (95% CI: 0.76 to 0.94), a statistically significant result (p = 0.0028). The probabilities of dying by Day 28 were estimated to be 30.7% and 34.9% in the ACTEMRA and usual care arms, respectively. The risk difference was estimated to be -4.1% (95% CI: -7.0% to -1.3%), consistent with the primary analysis. The hazard ratio among the pre-specified subgroup of patients receiving systemic corticosteroids at baseline was 0.79 (95% CI: 0.70 to 0.89), and for the pre-specified subgroup not receiving systemic corticosteroids at baseline was 1.16 (95% CI: 0.91 to 1.48).

The median time to hospital discharge was 19 days in the ACTEMRA + usual care arm and >28 days in the usual care arm (hazard ratio [95% CI] = 1.22 [1.12 to 1.33]).

Among patients not requiring invasive mechanical ventilation at baseline, the proportion of patients who required mechanical ventilation or died by Day 28 was 35% (619/1754) in the ACTEMRA + usual care arm and 42% (754/1800) in the usual care alone arm (risk ratio [95% CI] = 0.84, [0.77 to 0.92]).

EMPACTA (NCT04372186) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of intravenous ACTEMRA in combination with standard of care (SoC) in hospitalized, non-ventilated adult patients with COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air. Patients were randomized at a 2:1 ratio to receive one infusion of either 8 mg/kg ACTEMRA, with a maximum dose of 800 mg, or placebo. If clinical signs or symptoms worsened or did not improve, one additional infusion of blinded treatment of ACTEMRA or placebo could be given, 8–24 hours after the initial infusion.

Of the 389 patients who were randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprised of patients who received any amount of study medication, grouped as randomized (249 in the ACTEMRA arm; 128 in the placebo arm). In the mITT population (n=377) at randomization, median age was 57 years (range 20-95); 59.2% of patients were male, 56.0% were of Hispanic or Latino ethnicity, 52.8% were White, 20.4% were American Indian/Alaska Native, 15.1% were Black/African American and 1.6% were Asian. At baseline, 35 (9.3%) patients were not on supplemental oxygen, 242 (64.2%) patients required low flow oxygen and 100 (26.5%) patients required high-flow oxygen. The median time from symptom onset was 8.0 days. At baseline, across treatment arms, 72.7% patients reported systemic corticosteroids use and 47.7% received remdesivir.

The primary efficacy endpoint was the cumulative proportion of patients who required mechanical ventilation or died by Day 28 estimated by the Kaplan-Meier method. For patients who received ACTEMRA, there was an observed improvement in the time to progression to mechanical ventilation or death compared to patients who received placebo (log-rank p value = 0.0360; HR [95% CI] = 0.56 [0.33 to 0.97]). The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12.0% (95% CI, 8.52% to 16.86%) in the ACTEMRA arm and 19.3% (95% CI, 13.34% to 27.36%) in the placebo arm.

The median time to hospital discharge or “ready for discharge” (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤ 2L supplemental oxygen) through Day 28 was 6.0 days in the ACTEMRA arm and 7.5 days in the placebo arm (HR [95% CI]=1.16 [0.91 to 1.48]).

Mortality at Day 28 was 10.4% in the ACTEMRA arm versus 8.6% in the placebo arm (weighted difference (ACTEMRA arm - placebo arm): 2.0% [95% CI, -5.2% to 7.8%]).

COVACTA (NCT04320615) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of intravenous ACTEMRA in combination with standard of care (SoC) in adult patients hospitalized with severe COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less. Patients were randomized at a 2:1 ratio to receive one infusion of either 8mg/kg ACTEMRA, with a maximum dose of 800 mg, or placebo. If clinical signs or symptoms worsened or did not improve, one additional infusion of blinded treatment of ACTEMRA or placebo could be given, 8–24 hours after the initial infusion.

Of the 452 patients who were randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprised of patients who received any amount of study medication, grouped as randomized (294 in the ACTEMRA arm; 144 in the placebo arm). For the overall mITT population (n=438) at randomization, median age was 62 years (range 22-96); 69.9% of patients were male, 32.2% were of Hispanic or Latino ethnicity, 57.5% were White, 15.1% were Black/African American and 8.7% were Asian. At baseline, 3.4% of patients were not on supplemental oxygen, 27.9% were on low flow oxygen, 30.4% were on non-invasive ventilation or high flow oxygen, and 38.4% were on invasive mechanical ventilation. The median time from symptom onset was 11.0 days. At baseline, across treatment arms, 22.4% patients reported systemic corticosteroids use and 5.7% received remdesivir.

The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale consisting of the following categories:

  1. Discharged (or “ready for discharge” as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤ 2L supplemental oxygen);
  2. Non–ICU hospital ward (or “ready for hospital ward”), not requiring supplemental oxygen;
  3. Non–ICU hospital ward (or “ready for hospital ward”), requiring supplemental oxygen;
  4. ICU or non–ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen;
  5. ICU, requiring intubation and mechanical ventilation;
  6. ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy);
  7. Death

There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the ACTEMRA arm to the placebo arm. 

The median time to hospital discharge or “ready for discharge” was 20 days in the ACTEMRA arm and 28 days in the placebo arm (HR=1.35 [95% CI, 1.02 to 1.79]).

Mortality at Day 28 was 19.7% in the ACTEMRA arm versus 19.4% in the placebo arm (weighted difference (ACTEMRA arm - placebo arm): 0.3% [95% CI, -7.6 to 8.2]). 

REMDACTA (NCT04409262) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study conducted to assess the efficacy and safety of intravenous ACTEMRA in combination with remdesivir (RDV) compared with matching placebo in combination with RDV in hospitalized patients with severe COVID-19 pneumonia. Eligible patients were at least 12 years of age with confirmed SARS-CoV-2 infection, including a positive polymerase chain reaction (PCR) and pneumonia confirmed by radiography, and required supplemental oxygen > 6 L/min to maintain SpO2 >93%. Patients were randomized at a 2:1 ratio to receive blinded treatment of either ACTEMRA + RDV or a matching placebo + RDV. Study treatment was given in combination with standard of care. Patients assigned to the ACTEMRA + RDV arm received one infusion of ACTEMRA 8 mg/kg, with a maximum dose of 800 mg, and patients assigned to the placebo + RDV arm received one infusion of placebo. For both arms, if clinical signs or symptoms worsened or did not improve one additional infusion of blinded treatment of ACTEMRA or placebo could be given, 8–24 hours after the initial infusion.

Of the 649 patients who were randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprised of all patients who received any amount of ACTEMRA/placebo, grouped as randomized (430 in the ACTEMRA + RDV arm; 210 in the placebo + RDV arm). For the overall mITT population (n=640) at randomization, median age was 60 years (range 20-93); 63.3% of patients were male, 51.6% were Hispanic or Latino ethnicity, 67.0% were White, 10.9% were Black/African American and 3.4% were Asian. At baseline, 6.6% were on low flow oxygen, 79.8% were on non-invasive ventilation or high flow oxygen, and 13.6% were on invasive mechanical ventilation. The median time from symptom onset was 8 days. At baseline, the majority of patients had received corticosteroids (84.2% across treatment arms).

The primary efficacy endpoint was time from randomization to hospital discharge or “ready for discharge” up to Day 28. There were no statistically significant differences observed between treatment arms with respect to time to hospital discharge or “ready for discharge” through Day 28 (HR 0.965 [95% CI: 0.78 to 1.19]) or time to mechanical ventilation or death through Day 28 (HR 0.980 [95% CI: 0.72 to 1.34]).

Mortality at Day 28 was 18.1% in the ACTEMRA + RDV arm versus 19.5% in the placebo + RDV arm (weighted difference [ACTEMRA arm - placebo arm]: -1.3% [95% CI, -7.8% to 5.2%]).

Mortality outcomes were assessed at Day 28 across all 4 trials. These data, expressed as risk differences comparing ACTEMRA to placebo or standard of care treatment alone, are summarized in Figure 1. Figure 1 in the EUA Fact Sheet for Healthcare Professionals.

Figure 1. Risk differences through Day 28 for EMPACTA, COVACTA, REMDACTA and RECOVERY

EMPACTA, COVACTA, and REMDACTA risk differences and 95% CIs were calculated as weighted differences using the Cochran-Mantel-Haenszel test stratified by study-specific stratification factors at randomization.

RECOVERY risk difference and 95% CI were estimated using the Kaplan-Meier approach.

CI=confidence interval; COVID-19=coronavirus disease 2019; CRP=C-reactive protein; HR=hazard ratio; PCR=polymerase chain reaction; SpO2=oxygen saturation.

AUTHORIZED USE

ACTEMRA is authorized for use under an Emergency Use Authorization (EUA) for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

ACTEMRA is not FDA-approved for this use.

ACTEMRA is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of ACTEMRA under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.

WARNINGS AND PRECAUTIONS

Serious Infections

In COVID-19 patients, ACTEMRA should not be administered if patients have any other concurrent active infection, including localized infection.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis).

The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients with chronic or recurrent infection, or who have a history of a serious or an opportunistic infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.

A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and closely monitor the patient.

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials for chronic indications, primarily as complications of diverticulitis, in patients treated with ACTEMRA. Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

Hepatotoxicity

Patients hospitalized with COVID-19 may have elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19.

During randomized, controlled studies, treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA chronically. In this setting, the time to onset for cases ranged from months to years after treatment initiation with ACTEMRA.

The decision to administer ACTEMRA should balance the potential benefit against the risks of acute treatment with ACTEMRA. ACTEMRA is not recommended in COVID-19 patients with elevated ALT or AST above 10 times the upper limit of the reference range. When ACTEMRA is used for treatment of COVID-19, ALT and AST should be monitored according to current standard clinical practice.

Laboratory Parameters

In randomized, controlled trials, patients receiving ACTEMRA had higher rates of neutropenia, thrombocytopenia, and elevations of ALT or AST.

ACTEMRA is not recommended in COVID-19 patients with an absolute neutrophil count (ANC) less than 1000 per mm3, platelet count below 50,000 per mm3, or ALT or AST above 10 times the upper limit of the reference range. Monitor ALT, AST, neutrophils, and platelet counts according to current standard clinical practice.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. These events have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA.

Demyelinating Disorders

The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in rheumatoid arthritis clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment

ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment.

Vaccinations

Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA.

No data are available on the effectiveness of vaccination in patients receiving ACTEMRA.

MOST COMMON ADVERSE REACTIONS

Most common adverse reactions (incidence ≥3%) are constipation, anxiety, diarrhea, insomnia, hypertension, and nausea.

DRUG INTERACTIONS

Inhibition of IL-6 may lead to increased metabolism of drugs that are CYP450 substrates. Caution should be exercised when co-administering ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable. The effect of ACTEMRA on CYP450 enzyme activity may persist for several weeks after stopping therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy. Healthcare providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

The limited available data with ACTEMRA in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

Lactation

No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

You or your designee must report all SERIOUS ADVERSE EVENTS or MEDICATION ERRORS potentially related to ACTEMRA (1) by submitting FDA Form 3500 online, (2) by downloading this form and then submitting by mail or fax, or (3) contacting the FDA at 1-800-FDA-1088 to request this form. Please also provide a copy of this form to Genentech at [email protected] or call 1-888-835-2555.

Please see additional information in Fact Sheet for Healthcare Providers Fact Sheet for Patients and Parents/Caregivers , and FDA Letter of Authorization .

Please see additional Important Safety Information in full Prescribing Information , including BOXED WARNING and other risks associated with chronic use of ACTEMRA.

As a healthcare practitioner, you must communicate to the patient and/or caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers  and provide them with a copy of this Fact Sheet prior to administration of ACTEMRA. However, if providing this information will delay the administration of ACTEMRA to a degree that would endanger the life of a patient, the information must be provided to the parent and/or caregiver as soon as feasible after ACTEMRA administration.