A multi-centre open-label two-arm randomised superiority clinical trial of azithromycin versus usual care in ambulatory COVID-19: study protocol for the ATOMIC2 trial

Azithromycin (AZM) is an orally active synthetic macrolide antibiotic with a wide range of antibacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide, on the World Health Organization (WHO) list of essential medications, and manufactured to scale and therefore an ideal candidate molecule to be repurposed as a potential candidate therapy for pandemic COVID-19. Macrolides, particularly azithromycin, were used to treat 1/3 of severe cases of MERS-CoV [1], and azithromycin has been tried in COVID-19 infection [2] although RCT data for any coronavirus disease are lacking [3].

The current COVID-19 pandemic has galvanised an unprecedented response within the global research community. AZM has been rapidly identified by a number of researchers as of potential utility based on theoretical grounds [48] and on data from in vitro drug screening [12] of molecules which could be repositioned. This approach of repositioning existing drugs has the advantage of known safety profiles and that drugs can be rapidly produced at relatively low cost and so being quicker to deploy than a new molecule or vaccine. AZM in particular is already synthesised at scale globally by a number of manufacturers and so is particularly attractive for repurposing.

The SARS-CoV-2 pandemic is now the third novel coronavirus to emerge in the last two decades, each with pandemic potential, and the emergence of further novel coronaviruses is to be expected. Despite widespread use in SARS-CoV and MERS-CoV, no randomised data yet exist. Therefore, well-designed randomised trials are urgently required. If efficacy is proven in such studies, then there is urgency in discovering, communicating and translating these findings. Equally, if robust randomised trials find convincing evidence of no therapeutic benefit, then this is also essential information to disseminate. Azithromycin is an extremely useful drug for a wide variety of indications including treatment or prevention of a range of bacterial infections of the respiratory tract, ear, skin and soft tissue, genital tract, and eye [47], as well as having proven efficacy against mycobacteria and inflammatory lung conditions [29, 34, 35]. Unfortunately, AZM is particularly prone to induction of antimicrobial resistance, with high levels of resistance already occurring globally [49], making restriction of unnecessary use a clear priority.

Several other trials of AZM in COVID-19 have been initiated including two national studies in UK [50, 51]. However, given the strong rationale for investigating this molecule, multiple trials are needed. If one trial provides evidence of clinical efficacy in one particular population or clinical setting, then further studies will be needed to provide data on which other populations and settings and dose regimens are appropriate. These trials differ in several significant aspects. Firstly, they are studying different time points in the disease course: for instance, the PRINCIPLE trial is investigating people within the first 7 days of symptoms, the RECOVERY trial in late disease after hospitalisation with severe clinical features. Secondly, they are recruiting in different settings, the former in primary care, the latter in secondary care. Thirdly, they are using different dose regimens, the former just 3 days of therapy, the latter 5 days. Together, these studies are therefore likely to be assessing different properties of AZM: in early disease, PRINCIPLE will explore antiviral effects, in very late disease RECOVERY is likely to expose anti-bacterial activities against secondary infection, whilst ATOMIC2 is intermediate and predominantly assessing AZM’s anti-inflammatory effects.

ATOMIC2 is positioned between primary and secondary care populations with several unique features. Selection of a population who have presented to secondary care will focus recruitment on those with significant early symptoms and a high risk (20–30%) of readmission within the next 2 weeks, and yet, we believe, not too late in the disease process for suppression of pulmonary macrophage-derived inflammatory cytokines to have a potentially clinically meaningful beneficial effect.

Azithromycin is safe and well tolerated. Even in long-term administration (500 mg thrice weekly for 48 weeks), there was no increase in serious adverse events besides mild increase in diarrhoea [7]. The main adverse event of concern in this trial would be potential cardiovascular toxicity. Although macrolides have a class warning for potential cardiac QT prolongation, azithromycin does not show this effect under experimental conditions [52]. Only a few cases of QT prolongation have been reported for patients treated with the drug [53], mainly because azithromycin, unlike other macrolide antibiotics, does not interact with CYP3A4, despite a minor interaction with the anti-coagulant warfarin [54]. In the large AMAZES RCT, there was no increase in QTc prolongation, although this study excluded participants with QTc>480 ms [7]. Recently, a large study of Medicaid prescriptions reported an additional risk of cardiovascular death of 47 extra deaths/million compared with amoxicillin (relative risk (RR) for cardiovascular death 2.49 [55], and a meta-analysis of 20 million patients suggested a RR for cardiac death or ventricular tachycardia of 2.42 [56]. However, these effects are very small and subject to confounding and at odds with more recent studies: in a review of 185,000 Medicare patients, odds ratio for CV death was only 1.35, and after controlling for covariates decreased to 1.01 (0.95–1.08) [57], whilst a large Cochrane review of 183 trials found no evidence of an increase in cardiac disorders with macrolides (OR 0.87) [58]. Overall, the risk to a patient treated would be low compared with the considerable mortality of COVID-19, particularly if patients with QTc>480 ms were excluded.

Besides answering the question of clinical efficacy, this study will also provide valuable samples at baseline and at subsequent admission for both blood and nasal epithelial samples. Using proteomics, direct ex vivo functional T cell analyses and RNA studies, this will provide information both on potential biomarkers of response and also insight into the immune consequences of SARS-CoV-2 infection on the peripheral blood and airway epithelial cell transcriptome. Such insights into the pathogenic mechanisms of coronaviruses may prove valuable in directing research into future epidemics of this challenging family of emergent RNA viruses.

The trial commenced recruitment on 3 June 2020 according to protocol version 3.0 (7 May 2020), with adoption of protocol version 5.0 on 29 July 2020, with an anticipated completion date of December 2020.