Is tocilizumab effective for preventing intubation or death in hospitalized patients with Corona Virus Disease 2019 (COVID-19)?

Background

The National Institute of Health COVID-19 treatment guidelines recommend against the use of immunomodulators for the treatment of COVID-19, except in a clinical trial. [1]

Among patients who have been admitted to the hospital with COVID-19, the Infectious Diseases Society of America guideline panel suggests against the routine use of tocilizumab. [2]

A review article assessing tocilizumab in COVID-19 acute respiratory distress syndrome (ARDS) found that one- or two-times administration of intravenous and subcutaneous tocilizumab may be considered to be safe in patients with severe COVID-19. Researchers concluded that given the limited data, further randomized trials needed to take place to confirm the role of tocilizumab in COVID-19. [3]

A review article assessing potential therapeutic targets in COVID-19 stated that tocilizumab may be effective in the cytokine storm phase of COVID-19. [4]

A review article assessing current therapeutic agents for COVID-19 stated that tocilizumab may be used as adjunct therapy to blunt the cytokine storm seen in progressing COVID-19 disease. [5]

A review article assessing the cytokine storm seen in COVID-19 stated that clinical data showed improved hypoxgenmia, CT opacity, and symptoms after treatment with tocilizumab, suggesting that tocilizumab could be an efficient therapeutic agent for treatment of the cytokine storm associated with COVID-19. [6]

A meta-analysis assessing the efficacy of tocilizumab for the treatment of severe COVID-19 included studies comparing the clinical efficacy of tocilizumab and its competitors that explicitly reported at least all-cause mortality, intensive care unit (ICU) admission, and/or requirement for mechanical ventilation (MV). Researchers concluded that there is no suggestion that tocilizumab would provide any additional benefit for patients with severe COVID-19. [7]

Relevant Prescribing Information

ACTEMRA® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA).

Tocilizumab can come as an intravenous (IV) or subcutaneous (SC) injection and can be used alone or in combination with methotrexate.

The recommended IV dosage for adults with RA is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

The recommended SC dosage for adults with RA is 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response, if the patient weighs less than 100 kg. If the patient is at or above 100 kg, the dose is 162 mg administered subcutaneously every week.

It is recommended that tocilizumab not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or who have ALT or AST above 1.5 times the
upper limit of normal. Doses exceeding 800 mg per infusion are not recommended in RA patients.

Tocilizumab has a warning for serious infection and it should not be administered during an active infection. Other warnings include gastrointestinal perforation, changes in neutrophils, platelets, lipids, and liver function tests, and hypersensitivity reactions including anaphylaxis.
Live vaccines should be avoided with tocilizumab.

Most common adverse reactions (>5%) include upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, and injection site reactions.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is tocilizumab effective for preventing intubation or death in hospitalized patients with Corona Virus Disease (COVID-19)?

Please see Table 1 for your response.

Study Name

Efficacy of Tocilizumab in Patients Hospitalized with COVID-19

Design

Randomized, double-blind, placebo-controlled trial

N= 243

Objective

To assess if early intervention with interleukin-6 receptor blockade might limit COVID-19 progression to hypoxemic respiratory failure or death, reduce the risk of clinical worsening, and decrease the duration of supplemental oxygen use

Methods

Eligibility criteria included patients aged 19-85 years old with confirmed SARS-CoV-2 infection. Patients had to have at least two of the following signs: body temperature > 38C within 72 hours before enrollment, pulmonary infiltrates, or a need for supplemental oxygen to maintain an oxygen saturation greater than 92%. One of the following laboratory criteria had to be fulfilled: a C-reactive protein level higher than 50 mg per liter, a ferritin level higher than 500 ng per milliliter, a d-dimer level higher than 1000 ng per milliliter, or a lactate dehydrogenase level higher than 250 U per liter.

Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of 8 mg/kg of body weight of tocilizumab intravenously (not to exceed 800 mg), or placebo.

Concomitant therapy included antiviral therapy, hydroxychloroquine, glucocorticoids, and remdesivir.

Study Groups/Patients

Tocilizumab group: n= 161

Placebo group: n= 81

Outcome Measures

The primary outcome was intubation (or death, for patients who died before intubation) after administration of tocilizumab or placebo, assessed in a time-to-event analysis.

Secondary outcomes included clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving supplemental oxygen at baseline.

Results

A total of 27 patients (11.2%) were intubated within 28 days or died before intubation. At day 28, 17 patients (10.6%) in the tocilizumab group and 10 patients (12.5%) in the placebo group had been intubated or had died.

Outcome	Number of patients with event within 28 days	Percentage of patients with event (95% Confidence Interval)		Hazard ratio (95% Confidence Interval)	Log-rank P-value
		Day 14	Day 28
*Measures of Worsening*
Primary Outcome: mechanical ventilation or death
Tocilizumab	17	9.9 (6.2–15.7)	10.6 (6.7–16.6)	0.83 (0.38–1.81)	0.64
Placebo	10	10.0 (5.1–18.9)	12.5 (6.9–22.0)
Secondary Outcome: clinical worsening on ordinal scale
Tocilizumab	31	18.0 (12.9-24.9)	19.3 (14.0–26.2)	1.11 (0.59–2.10)	0.73
Placebo	14	14.9 (8.7–24.7)	17.4 (10.7–27.7)
*Measures of Improvement*
Secondary Outcome: discontinuation of supplemental oxygen among patients receiving it at baseline
Tertiary	114	75.4 (67.9–82.2)	82.6 (75.9–88.4)	0.94 (0.67–1.30)	0.69
Placebo	56	78.8 (68.3–87.7)	84.9 (75.2–92.2)

Safety:

There were 36 serious adverse events in the tocilizumab group, occurring in a total of 28 patients. Of these 36 serious adverse events, 25 were considered by the investigators to be unrelated to tocilizumab, and 11 were considered to be possibly related.

Significant adverse effects:

Side effect:	Tocilizumab	Placebo	p-value
Neutropenia	22	1	p= 0.002
Serious infection	13	14	p= 0.03

Study Author Conclusions

Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19. There was no efficacy of interleukin-6 receptor blockade for the treatment of hospitalized patients with COVID-19.

InpharmD Researcher Critique

This trial was double-blinded and took place amongst multiple hospital systems, allowing for a large sample size and limiting bias. Furthermore, the trial population was ethnically diverse including 109 total patients being Hispanic or Latino, implying that these results could be applied to a diverse audience.

The results from the ACTT-1 trial became available during the course of this study. Thus, some patients were treated with remdesivir as concomitant therapy and others were not. This affected general approaches to management and strategies to delay intubation in certain patients.

References:

Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D'Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Epub ahead of print. PMID: 33085857.