Now that tocilizumab is so difficult to obtain (written on 9/2/21 and obviously subject to change), we need another therapy to help improve outcomes in patients with COVID-19 who are hospitalized and critically ill. Baricitinib has entered the chat. Wow, I am all full of stupid meme references these days. Baricitinib is a Janus kinase 1/2 inhibitor that has anti-inflammatory properties. COVID-19 is an inflammatory disease so, coupled with corticosteroids, this should improve patient outcomes. Key word is “it should”. But does baricitinib really improve outcomes in COVID-19 patients? Let’s find out. Original post on 9/2/21. Updated on 10/12/21 and then 2/4/22.

Spoiler Alert: Baricitinib decreases mortality in patients on HFNC and NIV

I am going to go ahead and say that, although this isn’t the magic pill we all hope and wish it is, it does decrease mortality with a number needed to treat of 20 with the use of corticosteroids in all hospitalized patients. The special sauces shines in patients who are “hospitalized, receiving non-invasive ventilation or high-flow oxygen” where the NNT drops to 8.3 in this patient population. In contrast, tocilizumab had a NNT of 25 for mortality in all-comers based on the RECOVERY trial. It’s a bit dishonest to compare NNT’s between studies but it at least provides some perspective. ADDENDUM: See the review of the second part of this study including patients who are on invasive mechanical ventilation and ECMO.

Baricitinib: Mechanism of Action in COVID

From a historical perspective, baricitinib has been used for other inflammatory illnesses such as severe atopic dermatitis and rheumatoid arthritis. It worked in these populations by inhibiting Janus kinase (JAK) enzymes. I had to look this up because I had never heard of these fellas. They are “intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway.” UpToDate helped me with that and the following sentence. “In response to extracellular cytokine or growth factor signaling, JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. Inhibition of JAKs prevents the activation of STATs and reduces serum IgG, IgM, IgA, and C-reactive protein.“

What COVID-19 population was baricitinib studied in?

It’s obvious that they used patients with COVID-19 who were hospitalized. They had to have pneumonia and at least one inflammatory marker (C-reactive protein, D-dimer, lactate dehydrogenase, or ferritin). The interesting part here is that they did not have a cutoff to use the therapy. Everyone who had an elevated marker just got it. They listed who they excluded but this included the usual suspects like renal failure, liver failure, and other biologics. For those wondering, they did not check procalcitonin levels in these patients.

What COVID patient population does Baricitinib help in?

Well, this is encouraging. Focusing on the mortality endpoint, which was a secondary endpoint (and that has it’s own limitations), if you take into account everyone who was enrolled into the study, then there’s an all-cause mortality benefit in all-comers. But let’s say that you’re running low on resources and have to triage who gets the medication and who doesn’t. The authors used the NIAID-OS score to rank severity. There was no benefit in patients who were on room air.

Can’t say I was surprised here given that there were less than 100 people in each arm of this group. There was no benefit in patients who were on run of the mill supplemental oxygen neither. These would be your patients who are on less than high-flow and NIV. Some would say that there’s a trend for benefit but that’s a discussion for another day. The group that had the greatest benefit was in those who were on high-flow nasal cannula and non-invasive ventilation (BPAP/CPAP).

I don’t know what to do with the fact that it seems that patients who got baricitinib without corticosteroids seemed to do better than those who did get corticosteroids. Is this a signal we need to be investigating further? Baricitinib monotherapy? It also seems that combined with remdesivir, baricitinib doesn’t really help.

One of the factors that makes me happy is that it seems to work in patients on a broad spectrum of disease duration. We all know that the sooner therapies can be initiated the better. The NNT in patients who receive baricitinib when their COVID disease duration is less than 7 days is 11.1. The patient shows up to the hospital after > 7 days of disease duration, this number increases to 25 which is definitely not as good.

Baricitinib helps COVID patients who are younger (<65) more than those who are older >65 with the older group showing a trend but no statistically significant improvement (p=0.072).

Will I be using Baricitinib in my practice for COVID-19 patients?

Yes, and in fact I have already been using it for several weeks since tocilizumab is now out of stock. Given how incredibly ill many of these patients with the delta variant get, the sooner it is initiated the better. Outside of the groups specified in the study as not being candidates for this therapy, liver failure, renal failure, secondary infection, etc., I will be providing this to my patients. This is not medical advice and you should read this article for yourself.

Baricitinib in ECMO and Mechanical Ventilation (UPDATED 10/14/21 & 2/4/22)

These new data we released on 10/12/21 on HERE. Disclaimer: it is also not yet peer-reviewed. As noted above, the first robust data series of using baricitinib in COVID-19 was in patients who were not on mechanical ventilation. Hat tip to the authors who call themselves the COV-BARRIER Study Group. They enrolled SICK patients, those on mechanical ventilation or ECMO. The referred to this study as an “addendum trial” which I found entertaining.

In this trial, the allowed patients who were receiving dexamethasone but not if they were receiving more than 20mg of dexamethasone per day. Another factor to consider is that the enrollment ended in April 2021 so the variants included in this trial do not include delta. Like the first trial, they gave 4mg via NGT daily for 14 days. If the kidneys were crappy, they gave 2mg per day. They enrolled a total of 101 patients split almost evenly between the two groups.

ADDENDUM: Here are the links to the peer-reviewed paper in Lancet Respiratory Medicine
Link to Article
Link to FULL FREE PDF

What were the outcomes?

Part of my thought that the inflammatory cascade would be too far gone to help these patients. The fact that this helps is a huge deal. How much does it help? Well, a good bit. The numbers listed below are for your reference. Please read the full paper as I don’t want to just copy/paste it for you all.

• Mortality (All-cause)
  • 39.2% in baricitinib vs. 58% in the control group
  • NNT 5.3
  • 46% relative risk reduction
  • 18.8% absolute risk reduction
• 60-day Mortality
  • 45.1% in baricitinib vs. 62% in the control group
  • NNT 5.9
  • 44% relative risk reduction
  • 16.9% absolute risk reduction
• Ventilator-free days
  • 8.1 vs 5.5 days (not statistically significant)
• Length of Stay
  • 23.7 vs. 26.1 days
• Adverse effects
  • No differences noted.

In my opinion, these data are sufficient to start utilizing this therapy in patients who are on mechanical ventilation. It’s crazy that they achieved such a treatment effect with such a small sample size. Usually to find a mortality benefit one needs a larger sample size.

Black Box Warning for Baricitinib.

I have to tip my hat to Ameen Pirasteh for sending me much of the baricitinib data several weeks ago as well as pointing out that there is now a black box warning for this medication. This is copied from the FDA PDF.

• Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving OLUMIANT. (5.1)
• If a serious infection develops, interrupt OLUMIANT until the infection is controlled. (5.1)
• Prior to starting OLUMIANT, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting OLUMIANT. (5.1)
• Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. (5.1)
• Lymphoma and other malignancies have been observed in patients treated with OLUMIANT. (5.2)
• Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred in patients treated with OLUMIANT. Patients with symptoms of thrombosis should be evaluated promptly. (5.3)

Citations of Baricitinib in COVID

Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, Piruzeli MLB, Goldman JD, Alatorre-Alexander J, de Cassia Pellegrini R, Estrada V, Som M, Cardoso A, Chakladar S, Crowe B, Reis P, Zhang X, Adams DH, Ely EW; COV-BARRIER Study Group. 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. Lancet Respir Med. 2021 Aug 31:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3. Epub ahead of print. Erratum in: Lancet Respir Med. 2021 Oct;9(10):e102. PMID: 34480861; PMCID: PMC8409066.
Link to Article
Link to FULL FREE PDF

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.
Link to Article
Link to FULL FREE PDF

Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomised, Placebo-Controlled TrialE. Wesley Ely, Athimalaipet V. Ramanan, Cynthia E. Kartman, Stephanie de Bono, RanLiao, Maria Lucia B. Piruzeli, Jason D. Goldman, José Francisco Kerr Saraiva, SujatroChakladar, Vincent C. MarconimedRxiv 2021.10.11.21263897; doi:https://doi.org/10.1101/2021.10.11.21263897
Link to Article
Link to FULL FREE PDF

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