Baricitinib

Definition of mild illness:

• Symptomatic (any acute COVID-19 related symptoms)
• AND respiratory rate <24/min
• WITHOUT pneumonia or hypoxia

Definition of moderate illness:

• Pneumonia (clinical or radiological)
• AND respiratory rate ≤30/min
• AND SpO2 ≥94% on room air

A conditional recommendation is one for which the desirable effects probably outweigh the undesirable effects (weak recommendation FOR an intervention) or undesirable effects probably outweigh the desirable effects (weak recommendation AGAINST an intervention) but appreciable uncertainty exists. This implies that not all will be best served by this recommendation and decisions can be made by the patient and caregiver based on patient values, resources and setting with a clear understanding of the ensuing harms and benefits.

Definition of moderate illness

• Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Definition of severe illness:

Pneumonia with ANY ONE of the following:

• respiratory rate >30/min
• severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Definition of critical illness:

• Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
  •  OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
  •  OR sepsis
  •  OR shock

Baricitinib is a Janus kinase (JAK) inhibitor which has been used in Rheumatoid arthritis for many years as an anti-inflammatory agent. In COVID-19 infection it has been used as an anti-inflammatory agent and has also been thought to have potential antiviral effects by interfering with viral entry (1).

Baricitinib was found to reduce mortality and progression to invasive mechanical ventilation in hypoxic moderate, severe and critical COVID-19 infection with the number needed to prevent one death being approximately 25 across all the severity groups. We also found that Baricitinib reduced the time to clinical recovery and length of hospital stay, with a slight decrease in the progression to non-invasive ventilation (NIV) as well.

The risk of adverse events and serious adverse events are uncertain, but appeared to be low in the short term. However, it is important to mention that the long-term effects were not assessed in either of the randomized controlled trials (RCTs) available. However, there is considerable clinical experience with use of this drug in other clinical conditions (such as rheumatoid arthritis), where it has a well-defined and acceptable safety profile. At present there appears to be no data for the use of this drug in the non-hospitalized, mild COVID-19 infection. The safety and efficacy of its concomitant use with other immunomodulators like Tocilizumab is also unavailable at the moment. With the present data available it is recommended that Baricitinib should NOT be given along with Tocilizumab as it may lead to severe immunosuppression.

Taking the evidence into account, the group recommends for a conditional use in hypoxic patients with moderate to critical COVID-19 infection, if there is a rapid progression of respiratory requirements despite use of steroids.

Date of latest search: 21st July 2021

Date of completion & presentation to Expert Working Group: 29th July 2021

Date of planned review: 29th January 2022

Evidence synthesis team: Karthik G, Annabelle Kaunds, Sujith Chandy,  Bhagteshwar Singh, Richard Kirubakaran and Priscilla Rupali.

The Anti-inflammatory Expert Working Group met on 29^th July 2021 to consider Baricitinib as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to Baricitinib.

A summary and then more detailed explanations of the Expert Working Group's judgements follow.

Problem

The COVID-19 pandemic in India with more than 30 million cases and over 0.39 million deaths has significantly impacted and stressed the health structure of the country. With a shortage of intensive care unit beds, oxygen and trained personnel the country is facing a major health crisis. Any intervention which is cheap, easily available and reduces mortality, progression to invasive ventilation and increases clinical recovery will be a major boon.

Desirable effects

The group agreed that the evidence suggests that Baricitinib has a clinically significant effect on mortality and progression to mechanical ventilation overall and across all severity sub groups especially the moderate and severe categories and also reduced time to clinical recovery and length of hospital stay. The group also noted that though the confidence intervals of the point estimates crossed the line of no difference the signal was towards a beneficial effect in the Baricitinib group.

Undesirable effects

The group noted that the pooled data suggested that patients did not experience major adverse events, and in fact serious adverse effects which may be related to either drug or disease were less in the Baricitinib group. Since it is an immunosuppressive drug, nosocomial infections may be higher in our population and not necessarily reflected in the trials which have been done in high income countries. Increased cases of Mucormycosis were noted in the second wave of the epidemic and immune-suppressants especially steroids were noted to be an important risk factor. Considering this fact caution should be exercised when prescribing Baricitinib. JAK inhibitors especially Baricitinib have been used in Rheumatoid arthritis for years. Though Herpes zoster has often been reported, other secondary infections are uncommon. There has been extensive experience in Rheumatoid arthritis where it has been used for years.

Certainty of evidence

Using GRADE methodology, the evidence synthesis team rated Certainty of evidence was found to be moderate for desirable effects like mortality, need for NIV and mechanical ventilation, low for time to recovery and serious adverse events, very low for adverse events in non-severe patients. Similarly, certainty of evidence was moderate for severe to critical COVID patients across the critical outcome of mortality and important outcome of clinical recovery. The group agreed with these judgements and rated the overall certainty of evidence as moderate.

Values

The EWG felt that all the outcomes including those of admission to hospital, mortality and progression to mechanical ventilation were expressed variably in the studies. However, there is no important uncertainty or variability on how people would value the main outcomes.

Balance of effects

The expert working group felt that the balance of effects probably favored the intervention for across all severity subgroups. The trials that were evaluated both showed Baricitinib was beneficial. Though the study -Khalil et al was older it did reveal that when compared to steroids it fared as well as steroids if not better. However, it did not reflect the practice today where all hypoxic patients are automatically given steroids as standard of care. The subsequent study Marconi et al showed that  Baricitinib was given in 70% of cases suggesting that Baricitinib was given in addition to steroids. However, it is a slower acting drug and possibly needs to be given earlier in the disease when rapid worsening is expected.

Resources required

The group felt that this is a very cheap drug (generic versions are available) and costs only Rs 420 for 14 days. The group discussed and concluded that this was an efficacious drug proven beneficial and as compared to other monoclonal antibodies available in the market with anti-inflammatory activity, it was much cheaper and would result is large savings. The group includes clinicians in different types of Indian hospitals who have a good idea of drug and hospitalization costs.

Certainty of evidence of required resources

The group felt that the cost of the drug varied, with generic options varying cost from Rs 420 – Rs 22,000 for 14 days. No studies reporting this were reviewed by the group but the clinicians in the group were aware of the cost and hence felt that there was high certainty of evidence for required resources to implement this intervention.

Cost effectiveness

The group discussed that even though there is mortality reduction according to the evidence in moderate and sever subgroups, there is no evidence of benefit in critical category of patients because Marconi excluded ventilated patients. The group acknowledged the benefit and felt it should be used in hypoxic patients where steroids are used and there is evidence of systemic inflammation. So, the group favored the intervention for moderate and severe categories and was a cost-effective alternative.

Equity

At this point in time this intervention would probably increase equity as the costs are low and there is reduction in mortality and progression to invasive mechanical ventilation.

Acceptability

The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policy-makers, patients and clinicians) as it is an oral drug that is probably quite safe. Taking evidence and cost into account a well informed clinician would be very likely to use it.

Feasibility

This is a feasible intervention if found efficacious as it is easy to deliver and available easily over the counter in the country.

The recommendations are based on 2 large multi-center placebo controlled randomized trials done across several countries (including centers in India). It has been shown to reduce mortality and reduce time to recovery in patients with moderate to severe COVID (ordinal scores of 5 and 6), especially patients requiring high flow oxygen or non-invasive ventilation. The result was not so marked in those who were mechanically ventilated (ordinal scale 7). Given the availability of generic Baricitinib in India and the low cost of the generic drug, it seems to be a very feasible and cost-effective intervention in India (and also in other low to middle income countries). The overall evidence favors its use when combined with Remdesivir or steroids at 4mg once daily dose for 14 days or till discharge/death for moderate to severe COVID.  There seems to be an additive effect when the drug is added to either of these agents. Baricitinib has been in use for rheumatoid arthritis for several years and therefore, many clinicians are familiar with the drug. The side effects of Baricitinib are easily manageable and the 2 large randomized trials in COVID have not raised any new safety concerns. Also, administration of the drug is only till hospital discharge or till 14 days (whichever is earlier) and hence the duration of therapy is short. Major increase in infections does not seem to have been a problem in the trials.  However, in the Indian setting where infections are inherently more common one would have to wait and see for a delayed increase/reactivation of problems like TB and fungal diseases.  Given the potential of the drug to have a steroid - sparing effect in the treatment of moderate to severe COVID, the drug may be of particular importance in diabetics and in patients with pre-existing or co-existing fungal or bacterial infections. When needed, steroids may be added to patients receiving Baricitinib. Currently, (when needed) we would consider giving steroids in the same dose as in the RECOVERY trial. However, it remains to be studied whether a lower dose of steroids would be sufficient in such situations.

Its action is indirect by modifying cytokine release and therefore effects are likely to take a few days. In more severe disease when rapid response is necessary it is probably prudent to consider a parenteral preparation like Tocilizumab.

Since the drug acts at the level of JAKs, it seems likely that the drug will remain effective against the delta and the delta-plus variants. However, this is something which has not been formally evaluated and we will need to wait further data to make any conclusive statements on the efficacy of Baricitinib against the variants of concern.

The group carefully considered a potential subgroup effect across patients with different levels of oxygen and ventilation requirement (i.e. measures of severity), early administration and utility of Baricitinib.

Non-severe patients: Studies included patients with no oxygen requirements which could be extrapolated to a non-severe group; however, there was no mortality benefit noted and the overall certainty of evidence was found to be very low. Hence at this point Baricitinib is not recommended for this group of patients.

Severe patients: Baricitinib benefits hypoxic patients with moderate and severe illness. Moderate certainty of evidence was found in critical outcomes of reduction of mortality and progression to invasive mechanical ventilation. One study excluded those who were invasively ventilated and hence evidence is less certain in this group. However, there is a clear signal towards benefit and hence it is likely that it will work in this group of patients. The NNT was 16 in severe to critical group and 40 in the moderate group.

Baricitinib appears to be an attractive intervention owing to the incremental benefit it provides over steroids in COVID-19 patients with hypoxia with no increase in side effects. Hence it is likely to be used upfront along with steroids in these patients. While the available trials do not signal serious adverse effects and some of the patients were from India, there is a need to monitor safety with regards to secondary infections especially when patients in our setting may have received steroids prior to hospitalization or may get higher doses than recommended. Previous literature from longer term use has reported Varicella Zoster as a secondary infection, however with this dose and duration, it seems unlikely that the incidence would remain the same. The risk of mucormycosis needs to be particularly monitored. The risk of infections in patients who are later transitioned from Baricitinib to tocilizumab needs to be additionally evaluated. Another side effect that warrants monitoring is the risk of thromboembolism (FDA alert). The group will also review new efficacy data about the drug from RCTs worldwide as well as observational data in the Indian setting to update its recommendation.

The use of Baricitinib based on currently available evidence is limited to hypoxic patients who are moderate or severely ill. Areas of equipoise include

1.  Correct timing of initiation of Baricitinib (based on oxygen requirement of inflammatory markers) after initiation of steroids

2.  Long term adverse effects, when given with steroids in the Indian setting.

3.  Further studies should also focus on its indication relative to Tocilizumab

4.  Could Baricitinib replace steroids in patients in whom they are relatively contraindicated e.g., uncontrolled diabetics or diabetic ketoacidosis?

5.  How could we utilize biomarkers to optimize Baricitinib use?

1. Arthur Y Kim, Rajesh T Gandhi. Baricitinib. COVID-19 management in hospitalized adults. In: UpToDate, Martin S Hirsch (Ed), UpToDate, Waltham, MA. (Accessed on 26 August, 2021.)
2. Kalil AC, Patterson TF, Mehta AK et al for ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021;384(9):795. Epub 2020 Dec 11.
3. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial [published online ahead of print, 2021 Aug 31] [published correction appears in Lancet Respir Med. 2021 Sep 8;:]. Lancet Respir Med. 2021;S2213-2600(21)00331-3. doi:10.1016/S2213-2600(21)00331-3

Covid Management Guidelines India Group – Anti-inflammatory and Antibody working Group – Baricitinib. Covid Guidelines India; Published online on September 17th, 2021; URL: https://indiacovidguidelines.org/baricitinib/ (accessed ).