Are there randomized trials supporting the use of Ruxolitinib in the treatment of severe coronavirus disease 2019 (COVID-19)?

Background

The National Institute of Health's COVID-19 Treatment Guidelines Panel recommends against the use of Janus kinase (JAK) inhibitors such as baricitinib, ruxolitinib, and tofacitinib for the treatment of COVID-19, except in a clinical trial. [1]

The Infectious Diseases Society of America COVID-19 Guidelines do not mention the use of ruxolitinib or other JAK inhibitors for COVID-19. [2]

The Centers for Disease Control and Prevention does not provide any specifics on the use of JAK inhibitors for COVID-19. [3]

A review article assessing the role of ruxolitinib in the inhibition of cytokine signaling and associated implications for COVID-19 stated that early clinical findings support expedited investigation of ruxolitinib in phase 3 clinical trials. Ruxolitinib at pharmacologically achievable doses may be able to mitigate the hyperinflammatory state observed in patients experiencing COVID-19–associated cytokine storm. [4]

A review assessed role of specific and non-specific immunomodulating agents, including neutralizing monoclonal antibodies, corticosteroids, and other molecules in the management of severe COVID-19, along with the impact of these agents on survival and clinical symptoms. The role and safety of a JAK inhibitor in the management of inflammatory cytokine storm caused by COVID-19 is questionable. The review included a study in which two patients had to discontinue ruxolitinib treatment. The patients developed cutaneous reactions with purpuras and a progressive decrease in hematocrit values, and one patient also developed thrombocytopenia and a deep-tissue infection. [5]

A review article assessing the potential efficacy of ruxolitinib in COVID-19 hypothesized that since ruxolitinib is well-tolerated and used in the elderly population, it is a powerful candidate to overcome the hyperimmune syndrome that arises in COVID-19 patients. Ruxolitinib reduced the expression of inflammatory biomarkers at both the gene and protein levels in different cells. The authors concluded that ruxolitinib has potential in the treatment of COVID-19 infection; however, adverse effects such as opportunistic infections must also be considered. [6]

An review assessing different treatment options for COVID-19 stated that there is possible use of ruxolitinib as an IL-6 inhibitor in the advanced stages of the infection. [7]

Relevant Prescribing Information

Ruxolitinib (brand name, Jakafi®) is a kinase inhibitor indicated for the treatment of intermediate or high-risk myelofibrosis, polycythemia vera in adults who have had an inadequate response to or
are intolerant of hydroxyurea, and steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Ruxolitinib tablets come in the following dosage forms: 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. Doses should be individualized based on safety and efficacy, and vary dependent on indication.

Warnings and precautions for ruxolitinib include thrombocytopenia, anemia, and neutropenia, risk of infection, symptom exacerbation following interruption or discontinuation, risk of non-melanoma skin cancer, and lipid elevations.

In myelofibrosis and polycythemia vera, common adverse events include hematologic reactions (>20%) and bruising, dizziness, and headache (>10%). In acute graft versus host disease, the most common hematologic adverse reactions are anemia, thrombocytopenia, and neutropenia (>50%). The most common nonhematologic adverse reactions are infections and edema (> 50%) .

The dose for ruxolitinib should be reduced or treatment should be avoided for patients with hepatic or renal impairment. [1]

Literature Review

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

Is there any evidence (randomized trials) supporting the use of Ruxolitinib in the treatment of severe coronavirus disease 2019 (COVID-19)?

Please see Table 1 for your response.

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Design

Prospective, multicenter, single-blind, randomized controlled phase II trial

N= 43

Objective

To evaluate the efficacy and safety of ruxolitinib for COVID-19 in hospitalized patients

Methods

Inclusion Criteria:	Exclusion Criteria:
1) Met diagnostic criteria for COVID-19 2) Older than 18 years of age and younger than 75 years of age 3) Severe cases * The diagnosis and the illness severity of COVID-19 were defined according to the Chinese management guideline for COVID-19.	1) Patients with concomitant malignant tumors 2) Patients with severe, uncontrolled cardiovascular and metabolic disease 3) Patients with psychiatric disorders 4) Patients in need of invasive mechanic ventilation at recruitment 5) Women of child-bearing age with positive pregnancy test results or those in the lactating period 6) Patients with active infections

Patients were randomly allocated into two groups: the treatment group, which received ruxolitinib 5 mg orally twice a day plus standard-of-care (SoC) treatment; and the control group which received placebo (100 mg vitamin C) twice a day with SoC treatment. The randomization process was masked to all treating physicians.

The SoC treatment included antiviral therapy, supplemental oxygen, noninvasive and invasive ventilation, corticosteroid, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.

The safety profile was monitored daily.

Non–contrast-enhanced chest cat-scan (CT) examinations were performed on day 1 (D₀) and followed up at day 14 (D₁₄) for signs of improvement or disease progression.

Study Groups/Patients

A total of 43 patients were randomized, with 21 patients receiving placebo and 20 patients receiving drug treatment. A total of two patients were excluded.

Outcome Measures

The primary efficacy end point was the time to clinical improvement, defined as the time from randomization (D₀) to an improvement of two points on a 7-category ordinal scale or live discharge from the hospital (D_end), and improvement rate of follow-up CT scans at D_14.

Other outcomes included time from randomization to discharge, duration of invasive mechanical ventilation, time from randomization to death, time to lymphocyte recovery, and virus clearance time.

The primary safety end point was the incidence of serious adverse events occurring up to 28 days.

Results

Characteristic	Control Group (n= 21)	Ruxolitinib Group (n= 20)	p-value
Time to clinical improvement (days)	15	12	0.147
Clinical Improvement (patients):
D₇	2	4	0.410
D₁₄	9	12	0.354
D₂₁	18	18	>0.999
CT scan-follow up at D₁₄:
Improvement	13	18	0.495
Stable	7	6	--
Progression	3	2	--
D28 Mortality	3	0	0.232
Clinical Deterioration
D₇	3	0	0.232
D₁₄	4	0	0.107
Time from randomization to discharge (days)	16	17	0.941
Duration of invasive mechanical ventilation (days)	5	0	--
Time from randomization to death (days)	15	0	--
Time to lymphocyte recovery (days)	8	5	0.033
Virus clearance time (days)	12	13	0.649

Safety:

For primary safety end points, a total of 16 patients (80%) in the ruxolitinib group and 15 patients (71.4%) in the control group reported adverse events from randomization to D_28.

All serious adverse events, including secondary infection, sepsis, shock, and acute heart failure, occurred only in the control group.

Adverse event/characteristic	Control group (n= 21)	Ruxotlitinib group (n= 20)
Hematological adverse events	12	13
Chemical laboratory abnormalities	7	10
Headache	0	1
Dizziness	1	2
Rash	1	2
Nausea	2	2
Decreased appetite	2	1
Hypertension	2	1
Secondary infection	2	0
Acute Heart Failure	2	0
Shock	2	0
Sepsis	1	0

Study Author Conclusions

No statistical difference was observed between the two groups. Ruxolitinib recipients had numerically faster clinical improvement. Significant chest computed tomography improvement, a faster recovery from lymphopenia, and favorable side-effect profile in the ruxolitinib group supports starting future trials of ruxolitinib in a larger population.

InpharmD Researcher Critique

Given the preliminary findings of clinical improvement , ruxolitinib may be beneficial for hospitalized COVID-19 patients if they have failed other treatment options and can tolerate the associated adverse effects. Larger scale randomized trials need to be performed for more conclusive results.

References:

Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020;146(1):137-146.e3. doi:10.1016/j.jaci.2020.05.019