UC San Diego Health has launched a Phase III clinical trial, part of a global effort, to assess whether a medication used to treat rheumatoid arthritis and other inflammatory disorders might also have therapeutic value for COVID-19 patients who have developed or at high risk of developing serious lung damage from SARS-CoV-2 infections.
Tocilizumab, marketed as Actemra, is an immunosuppressive drug used primarily to treat rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of the disease in children.
The monoclonal antibody-based therapy works by blocking cellular receptors for interleukin-6 (IL-6), a small protein or cytokine that plays an important role in triggering inflammation as an early immune response to disease.
In some patients with COVID-19, however, the immune response runs amok, overexpressing IL-6 and generating a “cytokine storm,” which can lead to potentially life-threatening damage to lungs and other organs.
Cytokine storms have been linked to a number of inflammatory diseases, from respiratory conditions caused by coronaviruses such as SARS and MERS to some forms of influenza to non-infectious diseases such as multiple sclerosis and pancreatitis.
Previous research has suggested elevated levels of IL-6 are associated with higher mortality in people with community-acquired pneumonia. In the early days of the novel coronavirus outbreak in Wuhan last year, Chinese physicians used tocilizumab to treat a small number of COVID-19 patients with serious lung damage, and reported promising results.
The Chinese National Health commission now includes tocilizumab in its guidelines for treating COVID-19-related pneumonia and other lung issues.
“There are no approved therapies for COVID-19, beyond symptomatic treatment,” said Atul Malhotra, MD, research chief of pulmonary, critical care and sleep medicine at UC San Diego Health.
“But there is increasing evidence that COVID-19 can dramatically impact patients in many different ways, not least by severely damaging inflamed lungs.
“The mechanism of tocilizumab suggests a way to dampen and halt that inflammatory response, which might reduce the need for more extreme medical interventions, such as mechanical ventilation, and greater risk of chronic injury and death.”
The randomized, double-blind, placebo-controlled interventional trial will enroll approximately 330 participants at nearly 70 sites across the world. For its arm of the trial, UC San Diego will recruit up to 20 participants.
Participants must be 18 years or older and hospitalized with diagnosed COVID-19 pneumonia and evidence of impaired gas exchange.
Participants will receive one intravenous infusion of either tocilizumab or the placebo, with a possible second infusion if clinical symptoms worsen or show improvement. Funding and resources for the trial are provided by the pharmaceutical company Genentech/Roche, which makes Actemra.
“The endpoints or questions we’re seeking to answer are these: Does tocilizumab improve the health and clinical status of treated COVID-19 patients,” said Malhotra.
“Does it reduce the mortality rate due to COVID-19 pneumonia?
Does it reduce the need for mechanical ventilation or need for patients to go into intensive care units?”
Estimated study completion date is September 30, 2020.
Tocilizumab (TCZ), a monoclonal antibody against interleukin‐6 (IL‐6), emerged as an alternative treatment for COVID‐19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID‐19 infected patients.
The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and IL‐6 before and after TCZ therapy and clinical outcome in the 15 COVID‐19 patients were retrospectively assessed. Totally 15 patients with COVID‐19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill.
The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation.
Serum IL‐6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL‐6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID‐19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL‐6, the repeated dose of the TCZ is recommended.
Study design and participants
The patients infected with COVID‐19, who were treated with TCZ from January 27 to 5 March 2020 at Zhongfaxincheng campus of Tongji Hospital in Wuhan, China, were recruited in this retrospective study. All patients were anonymous. The study was approved by the ethical committee of Huazhong University of Science and Technology.
Procedures
The data of demographics, comorbidities, treatments, laboratory results, and clinical outcomes of the patients were obtained from the medical records. Based on Diagnosis and Treatment of Pneumonia Infected by Novel Coronavirus issued by the National Health Commission of China, the COVID‐19 was classified into four types: mildly ill, moderately ill, seriously ill and critically ill.5
The serum levels of CRP and IL‐6 were observed before and after TCZ administration. CRP, an acute‐phase reactant reflecting the inflammatory activity, was defined as elevated when it was higher than 5.0 mg/L.2 The level of IL‐6 was defined as elevated when it was higher than 7.0 pg/mL.2
The patients whose laboratory data of CRP or IL‐6 is complete deficiency before or after TCZ administration were considered as study dropouts. The most recent CRP or IL‐6 values before TCZ administration was selected as the value of before TCZ therapy and the changes of the value after TCZ administration was observed for a week. The clinical outcome of the patients was evaluated within 1 week after TCZ therapy.
Statistical analysis
Statistical analysis was done with SPSS, version 23.0. Data are presented as median (min‐max) or as the number and percentage, as appropriate. The Wilcoxon signed‐rank test used to compare parameters whenever appropriate. A P‐value of less than .05 was considered statistically significant.
RESULTS
Fifteen patients (12 males and 3 females) with COVID‐19 were included in this study. The characteristics of patients, the use of TCZ and other anti‐inflammatory drugs are summarized in Table 1. The median age (min‐max) of the patients was 73 (62‐80) years.
Two (13.3%) patients were moderately ill, six (40.0%) patients were seriously ill, and seven (46.7%) patients were critically ill. Ten (66.7%) patients had one or more co‐morbidities, including cadiocerebrovascular diseases and endocrine system diseases. Eight (53.3%) patients received TCZ in combination with MP. Five (33.3%) patients received TCZ administration twice or more. The dose of TCZ used in patients was the range from 80 to 600 mg per time.Table 1. The characteristics of COVID‐19 patients treated with TCZ
| Case No. | Age | Sex | Clinical classification | Co‐morbidity | Therapy | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 0 | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | Day 7 | |||||
| 1 | 73 | M | Critically ill | Hypertension | TCZ 480 mg MP 40 mg | MP 40 mg | MP 40 mg | MP 40 mg | … | … | … | … |
| 2 | 62 | M | Critically ill | None | TCZ 600 mg MP 40 mg | MP 40 mg bid | MP 40 mg bid | MP 40 mg bid | … | … | … | … |
| 3 | 62 | M | Critically ill | Hypertension | TCZ 320 mg MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | … | … |
| 4 | 74 | M | Critically ill | Hypertension Stroke history | TCZ 480 mg | … | … | TCZ 480 mg | … | … | … | … |
| 5 | 72 | M | Critically ill | Hypertension | TCZ 100 mg | TCZ 240 mg | … | … | … | … | … | … |
| 6 | 73 | M | Critically ill | None | TCZ 80 mg | TCZ 160 mg | TCZ 80 mg | … | … | … | … | … |
| 7 | 65 | M | Critically ill | Hypertension Stroke history | TCZ 480 mgMP 40 mg | MP 40 mg bid | MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | MP 80 mg bid | … | … |
| 8 | 66 | F | Seriously ill | Stroke history | TCZ 480 mg MP 80 mg | MP 80 mg | MP 80 mg | MP 80 mg | … | … | … | … |
| 9 | 73 | M | Seriously ill | Hypertension Diabetes | TCZ 480 mg | … | TCZ 480 mg | … | … | … | … | … |
| 10 | 77 | M | Seriously ill | Hypertension Diabetes | TCZ 400 mg | … | … | … | … | … | … | … |
| 11 | 65 | F | Seriously ill | Hypertension Diabetes | TCZ 400 mg MP 40 mg | MP 40 mg bid | MP 40 mg bid | MP 40 mg bid | MP 40 mg | MP 40 mg | MP 40 mg | … |
| 12 | 77 | M | Seriously ill | Hypertension Diabetes | TCZ 400 mg | … | … | … | … | … | … | … |
| 13 | 75 | M | Moderately ill | None | TCZ 480 mg MP 40 mg | MP 40 mg bid | MP 40 mg bid | MP 40 mg bid | MP 40 mg bid | … | … | … |
| 14 | 77 | M | Moderately ill | None | TCZ 80 mg | TCZ 160 mg | TCZ 80 mg | … | … | … | … | … |
| 15 | 80 | F | Seriously ill | None | TCZ 240 mg MP 40 mg | MP 40 mg bid | MP 40 mg bid | MP 40 mg bid | … | … | MP 20 mg | MP 20 mg |
- Abbreviations: bid, twice a day; F, female; M, male; MP, methylprednisolone; TCZ, tocilizumab.
The laboratory findings of the 15 patients before, and in the first week after TCZ treatment are summarized in Table 2. The CRP levels were far above the normal range in all patients before the start of TCZ therapy, and were rapidly ameliorated after the TCZ treatment.
The value of CRP at the first time it was detected after TCZ therapy was significantly decreased compared with before TCZ therapy, which dropped from 126.9 (10.7‐257.9) to 11.2 (0.02‐113.7) mg/L (P < .01).
Although TCZ has benefits in relieving inflammatory activity, for the four critically ill patients who received only single dose of TCZ therapy, three of them (No. 1, 2, and 3) were still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range (nearly 20 times higher than normal) during the week‐long session. In the other 11 patients, CRP levels were in or near the normal range within 1 week.Table 2. The laboratory findings of COVID‐19 patients at before and after TCZ treatment
| Case No. | Before TCZ therapy | After TCZ therapy | Clinical outcomes | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Day1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | Day 7 | |||
| CRP, mg/L | |||||||||
| 1 | 199.9 | 113.7 | 76.7 | 50.7 | … | 51.8 | … | Death | Death |
| 2 | 257.9 | 53.1 | … | … | 19.9 | 12.8 | Death | … | Death |
| 3 | 175.8 | 92.7 | 21.7 | 15.9 | … | 17.9 | Death | … | Death |
| 4 | 177.6 | 38.0 | … | … | 2.8 | … | … | … | Clinical stabilization |
| 5 | 32.2 | … | … | … | 2.8 | … | … | 1.1 | Clinical stabilization |
| 6 | 253.1 | … | … | … | … | … | … | 5.0 | Clinical stabilization |
| 7 | 126.9 | 74.7 | 40.6 | 20.6 | 11.1 | 51.9 | 147.6 | 93.5 | Disease aggravation |
| 8 | 96.1 | … | 29.0 | 9.2 | … | 5.7 | … | … | Clinical stabilization |
| 9 | 91.0 | … | … | … | 11.2 | … | … | 3.4 | Clinical stabilization |
| 10 | 10.7 | <0.02 | … | … | … | … | 0.5 | … | Clinical stabilization |
| 11 | 97.7 | … | … | … | … | … | … | 1.3 | Clinical stabilization |
| 12 | 26.3 | … | … | … | … | … | … | 0.5 | Clinical improvement |
| 13 | 91.2 | … | … | … | … | … | 2.5 | … | Clinical stabilization |
| 14 | 160.2 | … | … | … | 10.7 | … | … | 2.1 | Clinical stabilization |
| 15 | 180.6 | … | 31.5 | 11.8 | 8.0 | … | … | 6.3 | Disease aggravation |
| IL‐6, pg/mL | |||||||||
| 1 | 16.4 | 71.0 | … | … | … | 5000.0 | 5000.0 | death | Death |
| 2 | 32.7 | … | 232.9 | … | 1602.0 | 2230.0 | death | … | Death |
| 3 | 73.6 | 419.5 | 960.2 | … | … | 5000.0 | death | … | Death |
| 4 | 392.0 | 935.5 | … | … | 396.8 | … | … | … | Clinical stabilization |
| 5 | 24.4 | … | 204.3 | … | 172.4 | … | … | 172.0 | Clinical stabilization |
| 6 | 31.9 | … | 483.8 | … | 269.4 | … | … | … | Clinical stabilization |
| 7 | 46.8 | 55.5 | 73.7 | 70.1 | 483.0 | 557.0 | 3225.0 | 3628.0 | Disease aggravation |
| 8 | 72.7 | … | 208.8 | 133.1 | … | … | … | … | Clinical stabilization |
| 9 | 76.7 | … | 197.9 | … | 129.4 | … | … | 119.1 | Clinical stabilization |
| 10 | 46.5 | 59.3 | … | … | … | … | 45.7 | … | Clinical stabilization |
| 11 | 21.4 | … | 429.9 | … | … | … | … | 197.0 | Clinical stabilization |
| 12 | 19.7 | … | … | 125.0 | … | … | … | 108.8 | Clinical improvement |
| 13 | 71.1 | 12.4 | … | … | … | … | 66.6 | … | Clinical stabilization |
| 14 | 627.1 | 905.6 | … | 416.2 | 243.9 | … | … | 249.0 | Clinical stabilization |
| 15 | 112.8 | 247.4 | 688.2 | 828.1 | 1707.0 | … | 1087.0 | 704.7 | Disease aggravation |
- Abbreviations: CRP, C‐reactive protein; IL‐6; interleukin‐6; TCZ, tocilizumab.
Elevated IL‐6 is the indication for TCZ use in COVID‐19. The levels of IL‐6 before TCZ administration ranged from 16.4 to 627.1 pg/mL (2 times to nearly 90 times higher than normal).
After starting TCZ therapy, serum IL‐6 level in 10 (66.7%) patients tended to spike shortly in first and then decreased. One patient (No. 13) demonstrated a persistent decrease of IL‐6 after TCZ administration combined with MP. The clinical classification of these patients is mainly moderately ill and seriously ill patients.
But in these four critically ill patients who failed the treatment (No. 1, 2, 3, and 7), a persistent and dramatic increase of IL‐6 was observed. Except for patients No. 1, 2, 3, and 7, patient No. 15 also had a clinical outcome of aggravation.
DISCUSSION
In this study, we evaluated the effect of TCZ therapy in COVID‐19 patients in real life. Our findings supported the effectiveness of TCZ in the prevention or treatment of cytokine storms induced by COVID‐19. In most patients, acute phase reactant levels were decreased and the patients were getting to a stable condition reflected by a later gradual decrease of IL‐6 after TCZ administration.
Corticosteroids such as MP are the conventional agents used to fight cytokine storms. However, in the treatment of corticosteroids, a high dose and a long‐time period were often required and follow with subsequent risk of side effects.
In an attempt to provide a corticosteroid‐sparing effect, TCZ was recommended in COVID‐19 patients to prevent or treat cytokine storms. The rationale for the use of the anti‐IL‐6 receptor antibody TCZ in COVID‐19 patients is based on our understanding of the role of IL‐6 in this disease and the experience with this drug in the treatment of cytokine release syndrome caused by chimeric antigen receptors redirect T cells.6
The present study suggested that a single dose of TCZ seems to fail to improve the disease activity in critically ill patients although it was used in combination with glucocorticoid. However, repeated doses (even repeated with a lower dose) of TCZ might improve the condition of critically ill patients.
Therefore, in addition to the safety advantage, a repeated dose of TCZ is more likely to be effective than glucocorticoid in the treatment of COVID‐19. Moreover, single dose of TCZ might be expected to benefit these seriously ill patients with about 10 times elevated IL‐6.
And the moderately ill patient with an extremely higher level of IL‐6, almost 90 times of normal, could also benefit from repetitive TCZ therapy. Nevertheless, it seems that repeat the dose at a frequency of daily, every other day, or every 3 days with a totally two to three doses would be sensible in these critically ill patients or patients with an extremely higher level of IL‐6.
Considering the long half‐life time of TCZ and the saturate properties of receptor binding, the dose of TCZ could be reduced when repeated use.
IL‐6 can be used to evaluate the severity of the infection and predict the prognosis.7 Dynamic observation of IL‐6 levels is also helpful in understanding the progression of COVID‐19 and the response to treatment.
IL‐6 level tends to further spiked and then decreased in most patients after starting TCZ therapy. Actually, IL‐6 is mainly eliminated via IL‐6R‐mediated clearance.8 Binding of TCZ to IL‐6R inhibits receptor‐mediated clearance of IL‐6, leading to its accumulation in serum.
This is the likely explanation for the spiked IL‐6 levels in TCZ‐treated COVID‐19 patients in this study. And a later gradual decrease of IL‐6 might partly benefit from the inhibition of inflammatory activity by TCZ that resulting in stabilization or improvement of clinical outcome.
Given the application of TCZ combined with PM in patient 13, we propose that PM might account for the persistent decrease of IL‐6 in this patient since stopping PM administration trend to lead an increase of IL‐6. It is the other possible risk factors, not an inflammatory activity, which may attribute to the aggravation of the patient No. 15.
Our result should be evaluated with caution although we reported a good response in patients with TCZ. The number of cases reported is still small and using laboratory parameters to define the disease activity is still challenging.
Furthermore, the treatment duration observed in our study may not be sufficient to make a final conclusion. Therefore, observation with a sufficient number of COVID‐19 patients is still needed to document the effectiveness of TCZ.
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Source:
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