Ad-hoc COVID-19 Clinical Pharmacology Task Group: Statement on dexamethasone

Clinical Pharmacology Task Group (CPTG) meeting date: June 26, 2020

On this page

• Policy question
• Recommendations
• Background
  • Clinical evidence of efficacy to date
  • Clinical evidence of safety to date
  • Authorization/licensure status in Canada
• Considerations
• Acknowledgements

Policy question

The Public Health Agency of Canada (PHAC) asked the ad-hoc COVID-19 Clinical Pharmacology Task Group (CPTG) for advice on whether known and potential benefits of dexamethasone outweigh known and potential risks in the treatment of hospitalized COVID-19 patients receiving oxygen support.

Recommendations

The Clinical Pharmacology Task Group recommends that among hospitalized patients with COVID-19 who require supplemental oxygen or mechanical ventilation, dexamethasone 6 mg IV for 10 days (or until discharge, if earlier) or equivalent glucocorticoid dose should be strongly considered. This guidance is not meant to replace clinical judgment or specialist consultation.

This guidance will be updated as peer-reviewed evidence emerges, particularly regarding risks and benefits in older age groups, for those with different clinical presentations, and for different demographic subgroups such as sex and age.

This statement was approved by the Clinical Pharmacology Task Group on July 12, 2020.

Background

As of June 24, 2020, 14 clinical trials were registered worldwide to investigate dexamethasone as a treatment for COVID-19; none of these had treatment sites in Canada^{Footnote 1}. The largest study to date is the UK-based RECOVERY trial, a large randomized controlled trial testing different investigational COVID-19 therapies in hospitalized patients, including low-dose dexamethasone treatment.  

Numerous observational/retrospective studies have reported mixed clinical outcomes associated with corticosteroid treatment of COVID-19 patients. However, this may be due to the stage of disease at time of treatment.

When given during early stage COVID-19 disease, which is associated with logarithmic replication of SARS-CoV-2, anti-inflammatory properties of corticosteroids may dampen the antiviral response. This is supported by evidence of delayed viral clearance when treating SARS-CoV-2 infection^{Footnote 2} as well as SARS-CoV-1 infection^{Footnote 3}. Corticosteroid administration during later-stage COVID-19 infection, which can be characterized by increased oxygen requirement/ICU admittance, may be beneficial in counteracting the dysregulated immune response associated with COVID-19 induced cytokine storm syndrome/acute respiratory distress syndrome (ARDS). This is supported by observational data that showed lower rates of mortality in COVID-19 patients with ARDS who received methylprednisolone^{Footnote 4}.

Use of corticosteroids in ARDS (all causes) is controversial^{Footnote 5Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10Footnote 11}.

Clinical evidence of efficacy to date

On June 22, 2020, Horby et al. released a preliminary report of clinical findings from the dexamethasone treatment arm of the RECOVERY trial on a pre-print website without peer review, one arm of many investigational treatment arms from the RECOVERY trial, a large randomized controlled multi-centre trial conducted at 176 NHS hospitals in the UK (n=2,104 randomized to dexamethasone; n=4,321 patients randomized to receive standard of care)^{Footnote 12}.

• Inclusion criteria: Hospitalized patients with confirmed or clinically suspected COVID-19 (no specified disease severity, age, or other demographic/clinical factor; age was restricted to over 18 years of age until May 9, 2020 when a protocol modification removed the restriction). Pregnant and breastfeeding women were eligible.
• Baseline characteristics: The majority of patients were male (64%); mean age 66.1 years.
• Intervention: Treatment was standard of care plus low-dose dexamethasone (6mg once daily by oral or i.v. administration up to 10 days) or standard of care alone.
• Primary Outcome: The authors reported a significant reduction in the primary outcome of 28-day mortality for patients on 6 mg daily treatment of dexamethasone (454/2104 (21.6%) compared to those receiving standard of care alone (1065/4321; 24.5%; RR 0.83 (0.74-0.92); p<0.001) with available data (4.8% of patients had not completed 28 day follow-up).
• Secondary outcomes (not adjusted for multiplicity):
  • Significantly more patients in the dexamethasone group were discharged from hospital by day 28 (1360/2104 (64.6%)) than those treated with standard of care alone (2639/4321 (61.1%); RR 1.11 (1.04-1.19); p=0.002).
  •  For those patients not receiving invasive mechanical ventilation at time of randomization, patients randomized to the dexamethasone treatment arm had significantly less risk of requiring invasive mechanical ventilation or death (425/1780; 23.9%) vs. those receiving standard of care alone (939/3638 [25.8%]; RR 0.91 [0.82-1.00]) or invasive mechanical ventilation alone (921/1780 [5.2%] - dexamethasone arm, compared to 258/3638 [7.1%] -  standard of care arm; RR 0.76 [0.61-0.96]).
• The following subgroup analyses were reported but were not prespecified in the trial registry and do not appear to be adjusted for multiple testing (and therefore there is an elevated risk of finding statistical significance when it does not exist):
  • Subgroup analyses: Oxygen requirement. The impact of dexamethasone on reducing mortality was greatest for patients receiving invasive mechanical ventilation, where 28-day mortality was reduced by 35% (29% for those randomized to dexamethasone vs. 40.7% for those receiving standard of care alone, RR 0.65 [95% CI 0.51-0.82]). Twenty-eight-day mortality of patients receiving oxygen without invasive mechanical ventilation was reduced by 20% in response to dexamethasone treatment (21.5% dexamethasone vs. 25% usual care, RR 0.80 [95% CI 0.70-0.92]). There was no reported evidence of clinical benefit of dexamethasone, and while not significant, there was a numerical increase in 28-day mortality rate (17% dexamethasone vs. 13.2% usual care), among patients not receiving respiratory support (rate ratio 1.22 [95% CI 0.93 to 1.61]).
  • Subgroup analyses: Age. Patients <70 years old had a numerically better clinical response to dexamethasone treatment compared to patients aged 70-80 years or 80 years and above, as observed by reduced incidence of mortality at 28-days. Of 1142 patients aged <70 years receiving dexamethasone, 124 died by day 28 (10.9%) compared to 413/2506 patients receiving standard of care (16.5%; [RR 0.64; 0.52-0.78]). For patients aged ≥70 <80, mortality rate at day 28 was 146/467 (31.3%) for those randomized to dexamethasone, compared to 262/860 for those receiving standard of care alone (30.5%). For patients aged ≥80, mortality rate at day 28 was 184/495 (37.2%) for those receiving dexamethasone compared to 390/955 for those receiving standard of care alone (40.8%).
  • Subgroup analyses: Days since symptom onset. Consistent with increased clinical benefit observed for those patients requiring additional oxygen support, dexamethasone treatment had a greater impact at reducing mortality for patients with >7 days since symptom onset at time of trial randomization. 28-day mortality for patients with >7 days since symptom onset: 201/1184 (17.0%; dexamethasone) vs. 581/2507 (23.2%; standard of care) (RR 0.68 [0.58-0.80]). 28-day mortality for patients with ≤7 days since symptom onset: 252/916 (27.5%; dexamethasone), vs. 478/1801 (26.5%; standard of care) (RR 1.01; 0.87-1.17).
  • The study did not perform subgroup analyses on whether the patients received treatment by oral or intravenous (i.v.) administration of dexamethasone. Unlike i.v. administered dexamethasone, oral dexamethasone is only 70-80% bioavailable. It is therefore unknown whether outcomes were affected by differing concentrations of drug according to route of administration.

Clinical evidence of safety to date

• In the preprint issued by Horby et al., there was no outcome associated with safety reporting^{Footnote 12}. The authors note the full peer-reviewed publication is anticipated shortly, and if any safety signals are reported, they will be reviewed by the CPTG in full.
• Notwithstanding the indication for COVID-19, dexamethasone administration has a well-defined safety profile. Short-term dexamethasone is associated with several adverse effects that critically-ill patients may already be pre-disposed to, including hyperglycemia, psychiatric adverse effects, hypertension, infections, edema, and gastrointestinal bleeding.  It is unclear if data on adverse effects were monitored and collected in a systematic manner, as this is not described in the protocol or preprint manuscript.

Authorization/licensure status in Canada

• Dexamethasone is currently approved in Canada for multiple indications.

Considerations

• Dexamethasone has a well-defined safety profile and is an approved drug in Canada for numerous indications.
• Current evidence demonstrates low-dose dexamethasone treatment has a clear benefit for severe hospitalized patients with COVID-19, with the greatest benefit observed for patients that require supplemental oxygen or mechanical ventilation, who are < 70 years old with time from symptom onset > 7 days.
• The benefit-risk profile for dexamethasone for the treatment of elderly (>70y old) COVID-19 patients requiring supplemental oxygen is still unknown, as safety information from the trial has not been published.
• There is growing evidence that COVID-19 may cause ketosis and ultimately trigger diabetes in some patients; however, research on this association and molecular mechanism is still ongoing^{Footnote 13Footnote 14Footnote 15Footnote 16}. Given glucocorticoid therapy for non-COVID-19 indications has been associated with new-onset hyperglycemia^{Footnote 17}, dexamethasone treatment for patients with COVID-19, especially in those with diabetes, may cause glycemic dysregulation.
• There is no current shortage of i.v. formulations of dexamethasone. However, oral formulations of dexamethasone have historically been in and out of short supply in Canada and are currently in Tier 3 shortage at the present time, with an undetermined timeline to return to historical levels. There is concern that injectable formulations will be used to offset the shortage of oral formulations for existing, approved indications. Hospitals have restricted allocations based on historical demand for ordering injectable formulations of dexamethasone to prevent a shortage.
• Well-established steroid equivalents to dexamethasone have defined safety profiles, are approved in Canada for numerous indications, and have historically been used to treat ARDS as well as sepsis from non-COVID-19 causes.

Acknowledgements

This statement was prepared by:  N Forbes, M Patel, M Rieder, and M Salvadori, on behalf of the Clinical Pharmacology Task Group (CPTG).

CPTG Members:  M Salvadori (Co-Chair), M Rieder (Co-chair), M Lordkipanidze, R Hall, M Piquette-Miller, A Collier and S Murthy.

CPTG gratefully acknowledges the contribution of:  N Abraham, A House, M Tunis, A Killikelly, Y Chung, J Courtemanche, A Coady, B Mitchelmore, E Chong, and R Goddard.

CPTG also gratefully acknowledges the contribution from the Canadian Agency for Drugs and Technologies in Health.