Skip to main content
Download PDF

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

Trials volume 21, Article number: 718 (2020) Cite this article

Abstract

Background

Azithromycin is an orally active synthetic macrolide antibiotic with a wide range of anti-bacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide and manufactured to scale and is a potential candidate therapy for pandemic coronavirus disease 2019 (COVID-19). Azithromycin was widely used to treat severe SARS-CoV and MERS-CoV, but to date, no randomised data are available in any coronavirus infections.

Other ongoing trials are exploring short courses of azithromycin either in early disease, within the first 7 days of symptoms, when azithromycin’s antiviral properties may be important, or late in disease when anti-bacterial properties may reduce the risk of secondary bacterial infection. However, the molecule’s anti-inflammatory properties, including suppression of pulmonary macrophage-derived pro-inflammatory cytokines such as interleukins-1β, -6, -8, and -18 and cytokines G-CSF and GM-CSF may provide a distinct therapeutic benefit if given in as a prolonged course during the period of progression from moderate to severe disease.

Methods

ATOMIC2 is a phase II/III, multi-centre, prospective, open-label, two-arm randomised superiority clinical trial of azithromycin versus standard care for adults presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation. We will enrol adults, ≥ 18 years of age assessed in acute hospitals in the UK with clinical diagnosis of COVID-19 infection where management on an ambulatory care pathway is deemed appropriate. Participants will be randomised in a 1:1 ratio to usual care or to azithromycin 500 mg orally daily for 14 days with telephone follow-up at days 14 and 28. The primary objective is to compare the proportion with either death or respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation. Secondary objectives include mortality/respiratory failure in those with a PCR-confirmed diagnosis; all-cause mortality; progression to pneumonia; progression to severe pneumonia; peak severity of illness and mechanistic analysis of blood and nasal biomarkers.

Discussion

This trial will determine the clinical utility of azithromycin in patients with moderately severe, clinically diagnosed COVID-19 and could be rapidly applicable worldwide.

Trial registration

ClinicalTrials.gov NCT04381962. Registered on 11 May 2020. EudraCT identifier 2020-001740-26. Opened for accrual on 29 May 2020.

Peer Review reports

Background

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].

Antiviral properties

Azithromycin has well-documented, broad antiviral properties in vitro. Numerous studies have shown it to be effective against respiratory viruses, including the picornavirus human rhinovirus (RV), where it enhances viral-induced type I and type III interferons and interferon-stimulated gene (ISG) expression and reduced RV replication and release [4,5,6]. Macrolides reduce RV replication in vitro by enhancing type I and III IFN and induce the antiviral ISGs viperin and MxA [6]. In vivo in a large, well-designed, RCT of 420 adults with severe asthma, long-term AZM strikingly reduced exacerbations by 40% over 1 year [7]. These effects occurred irrespective of inflammatory phenotype, and may be mediated by antiviral effects, as viruses trigger up to 80% of exacerbations in asthma [8, 9].

AZM has antiviral activity against SARS-CoV-2 in vitro, being shown to reduce viral replication in combination with hydroxychloroquine [10]. Azithromycin was also associated with a reduced viral load of non-SARS-CoV-2 alpha- and betacoronaviruses in children receiving AZM during a mass distribution programme [11]. In a separate drug screen of 1520 approved drugs, AZM was also a key hit with an EC50 of 2.1 μM [12]. Macrolides have also shown efficacy in vitro against a wide range of other viruses. These include the flavivirus Zika, where AZM was a key hit in a drug screen of 2177 compounds and markedly reduce viral proliferation and virus-induced cytopathic effects [13]. In Zika, AZM upregulates type 1 and type III interferon responses and the viral pathogen recognition receptors MDA5 and RIG-I and increases the levels of phosphorylated TBK1 and IRF3 [14]. There is also evidence of in vitro activity against enteroviruses [15], Ebola [16, 17] and SARS [18], with in vivo activity against influenza A, with reduction in IL-6, IL-8, IL-17, CXCL9, sTNF and CRP in a small open-label RCT [19].

Anti-inflammatory properties

It is likely that AZM’s anti-inflammatory properties—rather than antiviral—will be more important in the treatment of severe COVID-19 disease in secondary care. Antivirals are likely to have limited efficacy in severe disease as they are administered late in the disease, after viraemia has peaked [20,21,22]. In stark contrast to the early cytokine storm responsible for 50% of deaths from influenza A, most COVID-19-related deaths occur due to sudden, late respiratory decompensation, peaking at day 14 after the onset of symptoms [23]. By this time, viral loads are low, and it is during the adaptive immunity stage that a late increase of innate/acute phase inflammatory cytokines occurs, including IL-1β, IL-2, IL-6, IL-7, IL-8, GCSF, MCP, MIP1a and TNF [24], and is associated with poor outcome [24]. These dysregulated cytokines are associated with features of haemophagocytic lymphohistiocytosis [25] and interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes [26]. This points to a failure not of viral control, but of the ability to halt an over-exuberant inflammatory cascade. Therefore, the priority should be to target the off switch for these signalling cascades, which are characteristically steroid-resistant [22] and associated with pulmonary inflammation and extensive lung damage in SARS patients [27] and MERS-CoV [24, 28].

AZM’s anti-inflammatory properties include dose-dependent suppression of lymphocyte expression of perforin and of many of these cytokines, including IL-1β, IL-6 and TNF, IL-8(CXCL8), IL-18, G-CSF and GM-CSF [29,30,31,32] and other components of the IL-1β/IL-6-induced acute phase response such as serum amyloid protein A [30]. For these reasons, they have proven clinical efficacy in asthma, COPD, CF and obliterative bronchiolitis, post lung transplant obliterative bronchiolitis and diffuse pan bronchiolitis (DPB): a disease characterised by alveolar accumulation of foamy macrophages [29, 33]. In DPB, macrolide therapy has dramatically increased survival from 10–20% to 90% [29, 34, 35], attributed to AZM’s inhibition of dysregulated IL-1, IL-2, TNF and GM-CSF [36].

A key cell in the steroid-resistant ARDS which develops in COVID-19 are pro-inflammatory monocyte-derived macrophages [37], which are increased in severe disease, replacing alveolar macrophages [38]. Macrophage-derived cytokines tend to be resistant to corticosteroids. It is also a cell type markedly impaired by diabetes, a dominant risk factor for COVID-19-related death. An important property of macrolides is that they accumulate 100–1000-fold [29, 30] in lysosomes of phagocytes and are released in those sites when they die. Within the alveolar macrophage, AZM attenuates LPS-induced expression of pro-inflammatory cytokines through inhibition of AP-1 [39, 40]; it inhibits arachidonic acid release in LPS-stimulated macrophages [41], inhibits GM-CSF [30, 39, 42] and increases phagocytosis, likely by upregulation of CD206, the macrophage mannose receptor [43]. AZM attenuates type 1 response and shifts macrophage polarisation to a more immunosuppressive, tissue repair M2-phenotype [44,45,46]. Thus, AZM reduces M1 macrophage markers CCR7, CXCL11, IL-12p70 and enhanced IL-10 and CCL18.

Anti-bacterial properties

Whilst not the main rationale for its use in COVID-19, the broad antibacterial properties of AZM which is active against a range of gram-positive, gram-negative, anaerobic and atypical infections may reduce secondary infection which were found in 16% of COVID-19 deaths [23].

Justification for dose regimen

AZM is generally well-tolerated with a very good and well-documented safety record. It is associated with diarrhoea. Whilst there have been concerns about cardiovascular risk, huge epidemiological studies suggest these are very small effects (e.g. 47 extra deaths/million prescriptions) or perhaps have no effect when corrected for confounding. It is contraindicated in known hypersensitivity to the drug. It can be used in pregnancy. It should be used in caution in those receiving some other drugs including fluoroquinolones such as moxifloxacin and levofloxacin and in patients with ongoing proarrhythmic conditions.

Due to its long half-life, AZM accumulates over time, but to achieve a rapid effect, we will use 500 mg OD for 14 days, similar to the dose recommended in UK for treatment of Lyme disease [47]. This dose is selected to be known to be well-tolerated and of sufficient duration to cover the period during which progression from moderate to severe disease may occur and during which anti-inflammatory effects may be most beneficial.

Rationale for design

This trial is designed to determine whether azithromycin is effective in preventing progression to severe respiratory failure requiring ventilatory support or death in adult patients with clinically diagnosed COVID-19 infection being assessed in secondary care but initially managed on an ambulatory care pathway. This specific situation provides a therapeutic window of opportunity to avert development of more severe disease.

Methods

Objectives

Aim

The aim is to test the hypothesis that the use of azithromycin 500 mg once daily for 14 days is effective in preventing and/or reducing the severity of lower respiratory illness of COVID-19 disease at 28 days.

Primary objective

The primary objective is to compare the effect of azithromycin in participants with a clinical diagnosis of COVID-19 in reducing the proportion with either death or hospital admission with respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation.

Secondary objectives

The secondary objectives are to compare the effect of azithromycin in participants with a PCR-confirmed diagnosis of COVID-19 in reducing the proportion with either death or hospital admission with respiratory failure requiring invasive or non-invasive mechanical ventilatory support over 28 days from randomisation (for those who had a COVID-19 swab at randomisation), to compare differences in all-cause mortality, to compare differences in proportion progressing to pneumonia, to compare differences in proportion progressing to severe pneumonia and to compare differences in peak severity of illness.

Exploratory objectives

The exploratory objective is the mechanistic analysis of blood and nasal biomarkers if available.

Trial design

This is a phase II/III, multi-centre, prospective open-label two-arm randomised superiority clinical trial of standard care versus azithromycin with standard care alone for those presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation (Fig. 1). The study procedures are outlined in Table 1.

Fig. 1
figure 1

CONSORT (Consolidated Standards of Reporting Trials) flow diagram

Full size image
Table 1 SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Schedule of Events Timeline: enrolment, assessment of safety, assessment of efficacy and dispensing of the medicine
Full size table

Discussion

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.

Trial status

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.

Trial registration

ATOMIC2 was registered with ClinicalTrials.gov NCT04381962 on 11 May 2020, EudraCT identifier 2020-001740-26, and opened for accrual on 29 May 2020.

Full protocol

The full protocol (V3.0) is attached as an additional file, accessible from the Trials website (Additional file 1). V5.0 of the protocol was implemented on 16 July 2020 including significant chagnes to inclusion / exclusion criteria and is also attached (Additional file 2). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 3). Patient Information Sheet (Additional file 4) and Informed Consent Form (Additional file 5) are attached as additional files.

Availability of data and materials

The research team will have access to the final trial dataset which will be hosted by the Oxford Clinical Trial Research Unit.

Abbreviations

AZM:

Azithromycin

BTS:

British Thoracic Society

COVID-19:

Coronavirus disease 2019

CURB-65:

Confusion, urea > 7.0 mmol/L, respiratory rate ≥ 30 breaths/min, blood pressure < 90 systolic or ≤ 60 diastolic, age ≥ 65 years

EDTA:

Ethylenediaminetetraacetic acid

ePR:

Electronic patient record

IMV:

Invasive mechanical ventilation

MERS:

Middle East respiratory syndrome

NHS:

National Health Service (UK)

PCR:

Polymerase chain reaction

RNA:

Ribonucleic acid

RV:

Rhinovirus

SARS:

Severe acute respiratory syndrome

SPIRIT:

Standard Protocol Items: Recommendations for Interventional Trials

SSRI:

Selective serotonin reuptake inhibitor

SST:

Serum separator tube

QTc:

Corrected QT interval

References

  1. Arabi YM, Deeb AM, Al-Hameed F, Mandourah Y, Almekhlafi GA, Sindi AA, et al. Macrolides in critically ill patients with Middle East Respiratory Syndrome. Int J Infect Dis. 2019;81:184–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gautret P, Lagier J, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;20:105949. https://doi.org/10.1016/j.ijantimicag.2020.105949.

    Article  CAS  Google Scholar 

  3. Belhadi D, Peiffer-Smadja N, Yazdanpanah Y, Mentre F, Laouenan C. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19. medRxiv. 2020. https://doi.org/10.1101/2020.03.18.20038190.

  4. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010;36(3):646–54.

    CAS  PubMed  Google Scholar 

  5. Schogler A, Kopf BS, Edwards MR, Johnston SL, Casaulta C, Kieninger E, et al. Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells. Eur Respir J. 2015;45(2):428–39.

    CAS  PubMed  Google Scholar 

  6. Porter JD, Watson J, Roberts LR, Gill SK, Groves H, Dhariwal J, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium. J Antimicrob Chemother. 2016;71(10):2767–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659–68.

    CAS  PubMed  Google Scholar 

  8. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310(6989):1225–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Johnston SL, Pattemore PK, Sanderson G, Smith S, Campbell MJ, Josephs LK, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med. 1996;154(3 Pt 1):654–60.

    CAS  PubMed  Google Scholar 

  10. Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microb Pathog. 2020;145:104228.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Doan T, Hinterwirth A, Arzika AM, Worden L, Chen C, Zhong L, et al. Reduction of coronavirus burden with mass azithromycin distribution. Clin Infect Dis. 2020:ciaa606. https://doi.org/10.1093/cid/ciaa606.

  12. Touret F, Gilles M, Barral K, Nougairede A, Decroly E, de Lamballerie X, et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. bioRxiv. 2020. https://doi.org/10.1101/2020.04.03.023846.

  13. Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A. 2016;113(50):14408–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li C, Zu S, Deng YQ, Li D, Parvatiyar K, Quanquin N, et al. Azithromycin protects against Zika virus infection by upregulating virus-induced type I and III interferon responses. Antimicrob Agents Chemother. 2019. https://doi.org/10.1128/AAC.00394-19.

  15. Zeng S, Meng X, Huang Q, Lei N, Zeng L, Jiang X, et al. Spiramycin and azithromycin, safe for administration to children, exert antiviral activity against enterovirus A71 in vitro and in vivo. Int J Antimicrob Agents. 2019;53(4):362–9.

    CAS  PubMed  Google Scholar 

  16. Madrid PB, Panchal RG, Warren TK, Shurtleff AC, Endsley AN, Green CE, et al. Evaluation of Ebola virus inhibitors for drug repurposing. ACS Infect Dis. 2015;1(7):317–26.

    CAS  PubMed  Google Scholar 

  17. Kouznetsova J, Sun W, Martinez-Romero C, Tawa G, Shinn P, Chen CZ, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect. 2014;3(12):e84.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kawamura K, Ichikado K, Takaki M, Eguchi Y, Anan K, Suga M. Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center. Int J Antimicrob Agents. 2018;51(6):918–24.

    CAS  PubMed  Google Scholar 

  19. Lee N, Wong CK, Chan MCW, Yeung ESL, Tam WWS, Tsang OTY, et al. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial. Antivir Res. 2017;144:48–56.

    CAS  PubMed  Google Scholar 

  20. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;382(19):1787–99.

    PubMed  Google Scholar 

  21. Baden LR, Rubin EJ. COVID-19 - the search for effective therapy. N Engl J Med. 2020;382(19):1851–2.

    PubMed  Google Scholar 

  22. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020;64(5):e00399–20.

    PubMed  PubMed Central  Google Scholar 

  23. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–8.

    CAS  PubMed  Google Scholar 

  24. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004;136(1):95–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018;104:8–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Altenburg J, de Graaff CS, van der Werf TS, Boersma WG. Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms. Respiration. 2011;81(1):67–74.

    CAS  PubMed  Google Scholar 

  30. Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143(2):225–45.

    CAS  PubMed  Google Scholar 

  31. Marjanovic N, Bosnar M, Michielin F, Wille DR, Anic-Milic T, Culic O, et al. Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro. Pharmacol Res. 2011;63(5):389–97.

    CAS  PubMed  Google Scholar 

  32. Shinkai M, Foster GH, Rubin BK. Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2006;290(1):L75–85.

    CAS  PubMed  Google Scholar 

  33. Hui D, Yan F, Chen RH. The effects of azithromycin on patients with diffuse panbronchiolitis: a retrospective study of 29 cases. J Thorac Dis. 2013;5(5):613–7.

    PubMed  PubMed Central  Google Scholar 

  34. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1829–32.

    CAS  PubMed  Google Scholar 

  35. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58(3–4):145–9.

    CAS  PubMed  Google Scholar 

  36. Weng D, Wu Q, Chen XQ, Du YK, Chen T, Li H, et al. Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of mTOR pathway. Biomed Pharmacother. 2019;110:440–8.

    CAS  PubMed  Google Scholar 

  37. Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. 2020. https://doi.org/10.1101/2020.02.12.945576.

  38. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing. Nat Med. 2020. https://doi.org/10.1038/s41591-020-0901-9.

  39. Bosnar M, Cuzic S, Bosnjak B, Nujic K, Ergovic G, Marjanovic N, et al. Azithromycin inhibits macrophage interleukin-1beta production through inhibition of activator protein-1 in lipopolysaccharide-induced murine pulmonary neutrophilia. Int Immunopharmacol. 2011;11(4):424–34.

    CAS  PubMed  Google Scholar 

  40. Meyer M, Huaux F, Gavilanes X, van den Brule S, Lebecque P, Lo Re S, et al. Azithromycin reduces exaggerated cytokine production by M1 alveolar macrophages in cystic fibrosis. Am J Respir Cell Mol Biol. 2009;41(5):590–602.

    CAS  PubMed  Google Scholar 

  41. Banjanac M, Munic Kos V, Nujic K, Vrancic M, Belamaric D, Crnkovic S, et al. Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells. Pharmacol Res. 2012;66(4):357–62.

    CAS  PubMed  Google Scholar 

  42. Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. 1999;11(2):121–32.

    CAS  PubMed  Google Scholar 

  43. Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, Holmes M, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178(2):139–48.

    CAS  PubMed  Google Scholar 

  44. Murphy BS, Sundareshan V, Cory TJ, Hayes D Jr, Anstead MI, Feola DJ. Azithromycin alters macrophage phenotype. J Antimicrob Chemother. 2008;61(3):554–60.

    CAS  PubMed  Google Scholar 

  45. Yamauchi K, Shibata Y, Kimura T, Abe S, Inoue S, Osaka D, et al. Azithromycin suppresses interleukin-12p40 expression in lipopolysaccharide and interferon-gamma stimulated macrophages. Int J Biol Sci. 2009;5(7):667–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Legssyer R, Huaux F, Lebacq J, Delos M, Marbaix E, Lebecque P, et al. Azithromycin reduces spontaneous and induced inflammation in DeltaF508 cystic fibrosis mice. Respir Res. 2006;7:134.

    PubMed  PubMed Central  Google Scholar 

  47. BMJ Group / Pharmaceutical Press. The British National Formulary. London: 2020. https://bnf.nice.org.uk/drug/azithromycin.html. Accessed 21 Mar 2020.

  48. Nabirotchkin S, Peluffo AE, Bouaziz J, Cohen D. Focusing on the unfolded protein response and autophagy related pathways to reposition common approved drugs against COVID-19. Preprints. 2020. https://doi.org/10.20944/preprints202003.0302.v1.

  49. Serisier DJ. Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir Med. 2013;1(3):262–74.

    PubMed  Google Scholar 

  50. Horby PW. Randomised evaluation of COVID-19 therapy (RECOVERY) 2020. Available from https://ClinicalTrials.gov: NCT04381936. Accessed 2 July 2020.

  51. Butler C. Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) 2020. Available from https://clinicaltrials.gov/ct2/show/NCT04280705. Accessed 2 July 2020.

  52. Milberg P, Eckardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther. 2002;303(1):218–25.

    CAS  PubMed  Google Scholar 

  53. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol. 2007;18(3):243–6.

    PubMed  Google Scholar 

  54. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cheng YJ, Nie XY, Chen XM, Lin XX, Tang K, Zeng WT, et al. The role of macrolide antibiotics in increasing cardiovascular risk. J Am Coll Cardiol. 2015;66(20):2173–84.

    CAS  PubMed  Google Scholar 

  57. Polgreen LA, Riedle BN, Cavanaugh JE, Girotra S, London B, Schroeder MC, et al. Estimated cardiac risk associated with macrolides and fluoroquinolones decreases substantially when adjusting for patient characteristics and comorbidities. J Am Heart Assoc. 2018;7(9):e008074. https://doi.org/10.1161/JAHA.117.008074.

  58. Hansen MP, Scott AM, McCullough A, Thorning S, Aronson JK, Beller EM, et al. Adverse events in people taking macrolide antibiotics versus placebo for any indication. Cochrane Database Syst Rev. 2019;1:CD011825.

    PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for additional contributions to drafting of study documents and regulatory approvals from Elizabeth Hamilton, Samuel Mills and Ling Pei Ho. We are grateful to the Nankai University for provision of PCR testing kits.

Funding

This research is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), by the University of Oxford and by an unrestricted research grant from Pfizer Inc. TSCH is supported by a fellowship from the Wellcome Trust (211050/Z/18/z). This research is supported by the NIHR Applied Research Collaboration (ARC) West Midlands through funding to DSL. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders played no role in the study design.

Author information

Authors and Affiliations

  1. Respiratory Medicine Unit and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxfordshire, OX3 9DU, UK

    Timothy S. C. Hinks, Maisha Jabeen, Najib M Rahman, Ian D. Pavord & Mona Bafadhel

  2. Oxford Clinical Trials Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK

    Vicki S. Barber, Joanna Black, Susan J. Dutton & Duncan Richards

  3. University Hospital Llandough, Cardiff, CF64 2XX, UK

    James Melhorn

  4. Nuffield Department of Medicine, Oxford University, Oxford, UK

    Daniel Lasserson

  5. Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK

    Daniel Lasserson

Authors
  1. Timothy S. C. Hinks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vicki S. Barber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joanna Black
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan J. Dutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maisha Jabeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James Melhorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Najib M Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Duncan Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel Lasserson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ian D. Pavord
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mona Bafadhel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TSCH, VSB, JB, SJD, MJ, JM, NR, DR, DL, IDP and MB contributed to the conceptualisation and design of the protocol. SJD performed the power calculation. TSCH drafted this submission which was approved by all authors. The authors read and approved the final manuscript.

Authors’ information

TSCH is a Wellcome Trust Career Development Fellow and Honorary consultant with expertise in the immunological effects of azithromycin.

Corresponding author

Correspondence to Timothy S. C. Hinks.

Ethics declarations

Ethics approval and consent to participate

This study will be conducted as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit (OCTRU) at the University of Oxford. It will follow their Standard Operating Procedures ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. The final version of this study protocol was approved by the London – Brent Research Ethics Committee (20/HRA/2105) on 5 May 2020. The local ethics committees will be given access to original records and databases. The chief investigator (Timothy SC Hinks) certifies that this trial has received ethical approval from the London – Brent Research Ethics Committee. Written informed consent will be required prior to inclusion.

Consent for publication

“Not applicable”.

Competing interests

TSCH has received grants from Pfizer Inc., grants from University of Oxford, grants from the Wellcome Trust, grants from The Guardians of the Beit Fellowship and grants from the NIHR Oxford Biomedical Research Centre during the conduct of the study and personal fees from Astra Zeneca, personal fees from TEVA and personal fees from Peer Voice outside the submitted work.

MJ has received grants from the University of Oxford and NIHR Oxford Biomedical Research Centre.

DR has undertaken paid consultancy for GSK outside the submitted work.

IDP reports personal fees from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, GlaxoSmithKline, Genentech, Regeneron, Teva, Chiesi, Sanofi, Circassia and Knopp and grants from NIHR outside the submitted work.

MB reports grants from AZ and personal fees and non-financial support from AZ, Chiesi, GSK and others from AlbusHealth, outside the submitted work.

DL, JM, NJM, VSB, SJD and JB declare they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hinks, T.S.C., Barber, V.S., Black, J. et al. 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. Trials 21, 718 (2020). https://doi.org/10.1186/s13063-020-04593-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13063-020-04593-8

Keywords

Trials

ISSN: 1745-6215