Update 25 June 2020
There is currently no peer-reviewed evidence to support the use of any specific medication in any care setting for the prevention or treatment of COVID-19 of any disease severity.
Preliminary results from a number of recent, relatively small, trials and some larger observational studies with hydroxychloroquine and lopinavir/ritonavir (Kaletra) in hospital patients (some severely ill) show potential harm and unclear benefit.
This guidance applies only to patients managed as an inpatient in a physical hospital. Off-label experimental use of medicines to treat community-based patients with COVID-19 is not recommended.
Specific medical therapy should only be prescribed as part of a clinical trial. For all stages of COVID-19 illness, good supportive care is current best practice.
Access to medicines for exceptional individual patient use in hospital
While NSW Health is not endorsing any specific medical therapy for patients with COVID-19, some clinicians may nevertheless consider prescribing experimental or unproven off-label therapies outside a clinical trial for some deteriorating severely or critically ill patients.
Clinical decision making in these situations must align with the criteria for Off-Label Use of Medicines for “Exceptional/Individual Use” and “Conditional Use, with Evidence Development”, outlined in the Council of Australian Therapeutic Advisory Groups’ (CATAG) Guiding principles. Institutional governance is through the Individual Patient Use procedure, with shared decision making and informed consent involving the patient or carer, and entry of patient data into a registry for evidence development. Rigorous monitoring for adverse drug events and reporting of these is essential. Use of a registry will inform safer future use of treatments for COVID-19. Currently local sites are responsible for their own registry with collated information regarding IPUs reported through the usual process. A state-wide registry is being established to facilitate the collection of information on use and outcomes for all NSW patients with COVID-19 who are given experimental or unproven off-label medicine outside a clinical trial. Further information can be found on the NSW Therapeutic Advisory Group Inc. website.
If these criteria from the Guiding Principles are met, consensus amongst a panel of NSW Health Infectious Disease, Respiratory, Intensive Care, Immunology and Clinical Pharmacology experts on specific medications under investigation to inform such off-label use is that currently, for patients hospitalised with severe or critical COVID-19:
- Lopinavir/ritonavir: Data suggest that lopinavir/ritonavir can cause harm, with no proven clinical benefit to date and it should not be used outside a clinical trial setting.
- Lopinavir/ritonavir plus azithromycin: No proven clinical benefit of the combination and both drugs can cause cardiac toxicity. Should not be used outside a clinical trial setting.
- Hydroxychloroquine: Observational data suggest that hydroxychloroquine can cause harm including excess mortality, particularly if used at higher doses or with azithromycin or other drugs that prolong the QT interval. There is currently no evidence of clinical benefit in patients hospitalised with severe or critical COVID-19. Hydroxychloroquine should not be used outside a clinical trial setting.
- Oseltamivir: should only be prescribed if there is co-infection with influenza.
- Dexamethasone: a media release (16/6/2020) and preprint (23/6/20) of the results from the dexamethasone arm of the RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial in the UK reports that dexamethasone (6 mg daily oral or IV for 10 days) reduced deaths by one-third in ventilated patients, and by one fifth in other patients receiving supplemental oxygen, with no benefit among patients who did not require respiratory support. Pending a peer reviewed publication, there may be a role for low dose dexamethasone in hospitalised patients receiving oxygen or ventilator support.
- Immunomodulators: No RCT data are available. Evidence from case series in patients with severe or critical COVID-19 pneumonia suggests possible benefit from modulators of pro-inflammatory pathways (e.g. tocilizumab, anakinra). The safety of this approach is unclear.
- Remdesivir: Two RCTs of remdesivir versus placebo have been published, one terminated early owing to lack of patients, the other unblinded early. Preliminary results from the latter trial showed a shorter median recovery time with remdesivir (11 days [95% CI, 9–12] vs 15 days [95% CI, 13–19]). Neither showed any mortality benefit and viral loads were not measured. The safety profile for remdesivir is incompletely characterised in humans. Remdesivir, as an unregistered, investigational drug, is available through an expanded access program for patients aged ≥12 years old and >40 kg with an oxygen saturation of 94% or less while breathing ambient air or receiving oxygen support. The program is active in three hospitals (one in NSW, two in Victoria). The program’s structure is consistent with ‘conditional use with evidence generation’ for off-label drugs (see CATAG’s Guiding principles for the governance of Medicines Access Programs in Australian hospitals for further information. Remdesivir does not have regulatory approval in Australia but can be supplied in the context of clinical trials and compassionate use. Contact your hospital’s Director of Pharmacy for further information.
There are at least three clinical trials of specific medications for patients in hospital with COVID-19 with ethics approval in NSW, supported by NSW Health:
- REMAP-CAP is a randomised, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia recruiting ICU patients, investigating a wide range of antiviral and immunomodulatory therapies for COVID-19. Domains currently approved in NSW are antiviral therapy (no antiviral therapy, lopinavir/ritonavir, hydroxychloroquine, and the combination of hydroxychloroquine and lopinavir/ritonavir) and immune modulation therapy (no immune-modulating therapy, corticosteroids, interferon beta 1a, interleukin-1 receptor antagonist (anakinra) and tocilizumab). The hydroxychloroquine and corticosteroid arms are currently suspended, pending results of interim analyses. Antibody therapy, therapeutic anticoagulation and high dose vitamin C domains are not currently approved at NSW sites.
- Australasian COVID-19 Trial (ASCOT). A multi-centre, adaptive, randomised clinical trial to assess patients with SARS-CoV-2 infection (COVID-19) treated in hospital outside of ICU. Antiviral treatments are currently being investigated in NSW: no antiviral therapy, lopinavir/ritonavir, and the combination of hydroxychloroquine and lopinavir/ritonavir. The hydroxychloroquine-only arm of ASCOT has been terminated following report of its lack of efficacy in the RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial in the UK and termination of hydroxychloroquine-only arms in other large international trials; and,
- Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease (CLARITY) is a pragmatic prospective, open-label, randomised controlled trial investigating the effectiveness of angiotensin II receptor blockers (ARBs) on improving the outcomes of hospital- and home-based adults who have tested positive for COVID-19 disease.
There are other approved studies of therapies for prevention of COVID-19 as well as studies of other therapies for treatment, currently under ethics review and applications for funding.
This guidance will be updated regularly as new information becomes available.
- Management is summarised in Australia with the Living Guidelines.
- The recommended process to guide clinical decision making and governance of off-label use of medicines in Australia is described in the Council of Australian Therapeutic Advisory Groups (CATAG) Guiding principles.
- Resources regarding off-label experimental use of specific COVID-19 therapies in deteriorating or critically ill patients and clinical trials approved in NSW are available from NSW TAG, which does not endorse use outside a clinical trial setting.
- Worldwide clinical trials are listed at: Global Coronavirus COVID-19 Clinical Trial Tracker.
- Australia and NZ clinical trials are listed at: Australian New Zealand Clinical Trials Registry (ANZCTR) (search COVID studies).
Drug and Therapeutics Advisory Community of Practice.
Dr Nigel Lyons, Deputy Secretary, Health System Strategy and Planning, NSW Ministry of Health.
25 June 2020.
For use by
All Communities of Practice.