Early View Research letter Add-on inhaled budesonide in the treatment of hospitalised patients with COVID-19: a randomised clinical trial Alvar Agustí, Gaston De Stefano, Alberto Levi, Xavier Muñoz, Christian Romero-Mesones, Oriol Sibila, Alejandra Lopez-Giraldo, Vicente Plaza Moral, Elena Curto, Andrés L. Echazarreta, Silvana E. Márquez, Sergi Pascual-Guàrdia, Salud Santos, Alicia Marin, Luis Valdés, Fernando Saldarini, Clara Salgado, Georgina Casanovas, Sara Varea, José Ríos, Rosa Faner Please cite this article as: Agustí A, De Stefano G, Levi A, et al. Add-on inhaled budesonide in the treatment of hospitalised patients with COVID-19: a randomised clinical trial. Eur Respir J 2022; in press (https://doi.org/10.1183/13993003.03036-2021). This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Copyright ©The authors 2022. This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org January 20, 2022 Research letter ERJ-03036-2021 SECOND REVISION ADD-ON INHALED BUDESONIDE IN THE TREATMENT OF HOSPITALIZED PATIENTS WITH COVID-19: A RANDOMIZED CLINICAL TRIAL Alvar Agustí1-4, Gaston De Stefano5, Alberto Levi5, Xavier Muñoz4,6,7, Christian Romero-Mesones4,6, Oriol Sibila1-4, Alejandra Lopez-Giraldo2-4, Vicente Plaza Moral4,8-10, Elena Curto4,8-10, Andrés L. Echazarreta11, Silvana E. Márquez11, Sergi Pascual-Guàrdia4,12,13, Salud Santos2,4,14,15, Alicia Marin4,16, Luis Valdés17-19, Fernando Saldarini20, Clara Salgado21, Georgina Casanovas1,3, Sara Varea1,3, José Ríos1,3,7, Rosa Faner2-4 1. Hospital Clinic, Barcelona, Spain. 2. Universitat Barcelona, Spain. 3. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 4. CIBER Enfermedades Respiratorias, Spain. 5. Servicio de Neumotisiologia, Hospital Francisco Muñiz, Buenos Aires, Argentina 6. Servei Pneumologia H. Vall d’Hebron, Barcelona Spain. 7. Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona 8. Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau. Barcelona, Spain 9. Institut d’Investigació Biomédica Sant Pau (IIB Sant Pau). Barcelona, Spain 10. Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain 11. Servicio de Neumonología, Hospital San Juan de Dios de La Plata, Buenos Aires, Argentina 12. Servei de Pneumologia, Hospital del Mar - IMIM. Barcelona, Spain 13. Universitat Pompeu Fabra. Barcelona, Spain 14. Department of Pulmonary Medicine, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain 15. Institut d’Investigació Biomèdica de Bellvitge – IDIBELL, Spain 16. Hospital Universitari Germans Trias i Pujol, Badalona, Spain 17. Servicio de Neumología. Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain 18. Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain 19. Universidad de Santiago de Compostela, Spain 20. Sección de Neumotisiologia. Hospital Donación Francisco Santojanni, Buenos Aires, Argentina. 21. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno Correspondence: Alvar Agusti, Institut Respiratori, Hospital Clinic. C/Villarroel 170, 08036 Barcelona 08036, Spain. Tel.: +34 93 227 1701; e-mail: aagusti@clinic.cat Funding: TACTIC was an investigator-initiated trial supported by AstraZeneca. Main text word count: 1.164 words; 15 references; 1 Table; 0 Figures SARS-CoV-2 vaccines have been extremely effective to reduce the incidence of severe COVID19 [1-3], but effective and safe treatments of the acute infection are still limited [4, 5]. An uncontrolled pulmonary inflammatory response to SARS-CoV-2 is considered a key pathogenic mechanism of COVID19 progression [6], so systemic dexamethasone is recommended in severe cases [5, 7]. On the other hand, in very mild patients at home inhaled corticosteroids (ICS) may prevent disease progression [8-11]. Whether ICS prevent disease progression too in patients hospitalized because of COVID19 has not been explored before. Accordingly, we designed an investigator- initiated, open-label, randomized clinical trial (RCT) to explore the efficacy of adding inhaled budesonide to usual care to prevent disease progression in patients hospitalized because of COVID19 pneumonia. We also monitored carefully the safety of this intervention since there are concerns about the use of systemic corticosteroids in other viral (influenza) lung infections [12]. METHODS The “Inhaled Corticosteroid Treatment of COVID19 Patients With Pneumonia” (TACTIC) was a multicentre, international (Spain and Argentina), randomized (1:1), open label RCT (NCT04355637) whose primary objective was to investigate if the addition of inhaled budesonide (400g/12 h via Pulmicort Turbuhaler®) to usual care (as dynamically established by the institutional protocol of each participating centre during the course of the pandemic) prevents disease progression, defined by a composite outcome that included treatment with non-invasive ventilation of high flow oxygen devices (WHO stage 5), invasive ventilation (WHO stage 6) and/or death from any cause (WHO stage 7) [13] during the first 15 days after randomization. We studied males and females between 18-80 years of age hospitalized because of PCR confirmed SARS-CoV-2 infection, with radiological evidence (plain chest x-ray) of pneumonia, without any contraindication to the study drug, who provided informed consent. Exclusion criteria included previous treatment with inhaled or systemic steroids (e.g., dexamethasone) and/or other immunomodulator drugs (e.g., anti- interleukins), high flow-oxygen or mechanical ventilation, and pregnancy. This RCT was approved by the Institutional Review Boards of participating institutions and was supported by AstraZeneca, who generously provided the study medication for free and economic support for logistics costs but did not participate in the design of the study, data analysis and/or writing of the manuscript. The Clinical Trial Unit of Fundació Clinic per la Recerca Biomedica-Hospital Clinic (Barcelona, Spain) monitored the trial in coordination with Klixar (in participating centres in Argentina), centralized all investigational information, and assured the quality control of results. Based on available knowledge at the time of trial design (March 2020), we hypothesized that this would occur in 15% of patients randomized to the usual care arm and 5% of those included in the intervention arm. Then, for a two-sided type I error of 5% and power of 80% and 5% estimated losses during follow-up, with three prespecified interim analyses designed using the Rho family spending functions with rho = 7 and a recalculation of sample size at 75% of expected events, we estimated that 300 patients (150 per arm) would be needed to be randomized, (East v6.5 Cytel Inc., Cambridge, MA). Randomization (1:1) was made by a permuted-block method with a block size of multiple of 2 elements and was stratified by centre with an interactive web service. The primary endpoint of the study was estimated by comparing the proportion of patients with disease progression (defined as above) in both arms using a binomial regression model, adjusted for centre (grouped by country) as covariate [14, 15]. Time- to-event analyses was described by means of the Kaplan-Meier method and inferential analyses was made by means log-rank test. All analyses were carried out by the Medical Statistics Core Facility of IDIBAPS-Hospital Clinic Barcelona (Spain) and performed using SAS v9.4 (SAS Institute Inc Cary, NC, USA) RESULTS From April 21, 2020 until March 16 2021, we randomized 120 patients (Full Analysis Set (FAS)). Because the progressive and generalized use of dexamethasone to treat hospitalized patients with COVID-19 [5] limited greatly our capacity to continue recruiting patients who had not received it before randomization, the steering committee of the study decided to stop the study prematurely in April 2021. As shown in Table 1, both groups were comparable in terms of demographics and main clinical and radiological characteristics at randomization, albeit the proportion of patients without supplemental oxygen at entry was nominally higher in the usual care group (n=49 (79.0%) vs. n=40 (69.0%)). Disease progression occurred in 4 patients (6.62%; 95% CI 0.45% to 12.79%) in the usual care group and 2 patients (3.74%; 95%CI -1.23% to 8.72%] in the usual care + budesonide one, difference being non- significant (-2.88% [95%CI -10.48% to 4.72%], p=0.458). Of note, 13 patients (21%) in the usual care arm were treated with dexamethasone after randomization at the discretion of the attending physician, whereas only 6 patients (10.7%) in the intervention group were. Importantly, adverse events were similar in both groups and there were no treatment-related adverse events (Table 1). Two patients died during follow-up, both beyond day 30, 1 in the control group (due to liver cirrhosis) and 1 in the intervention group (due to COVID19) (log-rank p value = 0.9564). DISCUSSION This RCTs lacks statistical power because it had to be terminated prematurely. However, results suggest that the addition of inhaled budesonide to usual care in patients hospitalized because of COVID19 pneumonia is safe and showed an encouraging trend towards a reduction in disease progression. The fact that the proportion of patients not requiring oxygen supplementation at randomization was larger in the usual care group (hence, better pulmonary gas exchange at baseline), and that, despite this, a higher proportion of them received systemic dexamethasone at the discretion of the attending physician, provides additional indirect evidence of a beneficial clinical effect of inhaled budesonide to prevent disease progression. Finally, it is important to highlight that the use of an inhaled corticosteroid in these patients was safe. These results may open the door for larger RCT in the near future, now that a new pandemic wave seems to be emerging again in several countries around the world. Dexamethasone reduces mortality in patients requiring supplementary oxygen in hospital and is recommended by ERS guideline [5, 7], but is not recommended for patients not requiring supplementary oxygen, which accounted for 74% of our cohort. A safe treatment that could reduce disease progression in this patient group would still be desirable. In fact, three very recent reports have shown that the use of inhaled steroids can reduce disease progression in mostly asymptomatic COVID-19 patients treated at home [8-11]. The results of the current RCT extend these previous observations on the use of inhaled steroids in the community to patients hospitalized because of COVID-19 pneumonia. Future studies may also need to explore the efficacy and safety of higher doses of inhaled budesonide (800g/12h), as previously investigated in milder patients at home [8]. In conclusion, the results of this RCT suggest that the addition of inhaled budesonide (400g/12h) on top of usual care in patients hospitalized because of COVID-19 pneumonia is safe and may reduce the risk of disease progression. ACKNOWLEDGMENTS Authors thank all participants in the study for their willingness to contribute to medical research, and the Barcelona Respiratory Network (www.brn.cat) to facilitate collaborative research. We also acknowledge the support of the Clinical Trial Unit (L. Aparicio, JA Arnaiz), the Medical Statistics Core Facility (F. Torres, G. Domenech) of IDIBAPS-Hospital Clinic Barcelona in Spain, the members of the DSMB (Drs. B. Cosio, JM. Miro, F. Barbe, F. Torres) as well as Klixar in Argentina (F. Licastro), for their support during the conduct of the trial and analysis of results. Finally, we acknowledge the economic and logistic support of AstraZeneca (Dra. Ana Perez and Dr. Gonzalo de Miquel). REFERENCES 1. Thompson MG, Stenehjem E, Grannis S, Ball SW, Naleway AL, Ong TC, DeSilva MB, Natarajan K, Bozio CH, Lewis N, Dascomb K, Dixon BE, Birch RJ, Irving SA, Rao S, Kharbanda E, Han J, Reynolds S, Goddard K, Grisel N, Fadel WF, Levy ME, Ferdinands J, Fireman B, Arndorfer J, Valvi NR, Rowley EA, Patel P, Zerbo O, Griggs EP, Porter RM, Demarco M, Blanton L, Steffens A, Zhuang Y, Olson N, Barron M, Shifflett P, Schrag SJ, Verani JR, Fry A, Gaglani M, Azziz-Baumgartner E, Klein NP. Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings. N Engl J Med 2021. 2. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine 2020. 3. Thompson MG, Stenehjem E, Grannis S, Ball SW, Naleway AL, Ong TC, DeSilva MB, Natarajan K, Bozio CH, Lewis N, Dascomb K, Dixon BE, Birch RJ, Irving SA, Rao S, Kharbanda E, Han J, Reynolds S, Goddard K, Grisel N, Fadel WF, Levy ME, Ferdinands J, Fireman B, Arndorfer J, Valvi NR, Rowley EA, Patel P, Zerbo O, Griggs EP, Porter RM, Demarco M, Blanton L, Steffens A, Zhuang Y, Olson N, Barron M, Shifflett P, Schrag SJ, Verani JR, Fry A, Gaglani M, Azziz-Baumgartner E, Klein NP. Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings. New England Journal of Medicine 2021: 385(15): 1355-1371. 4. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh M-d, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC. Remdesivir for the Treatment of Covid-19 — Final Report. New England Journal of Medicine 2020: 383(19): 1813-1826. 5. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine 2020. 6. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant 2020: 39(5): 405-407. 7. Group TWREAfC-TW. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta- analysis. JAMA 2020. 8. Ramakrishnan S, Nicolau DV, Langford B, Mahdi M, Jeffers H, Mwasuku C, Krassowska K, Fox R, Binnian I, Glover V, Bright S, Butler C, Cane JL, Halner A, Matthews PC, Donnelly LE, Simpson JL, Baker JR, Fadai NT, Peterson S, Bengtsson T, Barnes PJ, Russell REK, Bafadhel M. Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial. The Lancet Respiratory Medicine 2021: (in press). 9. Yu L-M, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, Van Hecke O, Ogburn E, Evans PH, Thomas NPB, Patel MG, Richards D, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Shanyinde M, de Lusignan S, Andersson MI, Barnes PJ, Russell REK, Nicolau DV, Jr., Ramakrishnan S, Hobbs FDR, Butler CC, Yu L-M, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, van Hecke O, Ogburn E, Evans PH, Thomas NPB, Patel MG, Richards D, Berry N, Detry MA, Saunders CT, Fitzgerald M, Harris V, Shanyinde M, de Lusignan S, Andersson MI, Barnes PJ, Russell REK, Nicolau DV, Ramakrishnan S, Hobbs FDR, Butler CC. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. The Lancet 2021: 398(10303): 843-855. 10. Agusti A, Torres F, Faner R. Early treatment with inhaled budesonide to prevent clinical deterioration in patients with COVID-19. The Lancet Respiratory Medicine 2021: 9(7): 682-683. 11. Clemency BM, Varughese R, Gonzalez-Rojas Y, Morse CG, Phipatanakul W, Koster DJ, Blaiss MS. Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA Internal Medicine 2021. 12. Zhou Y, Fu X, Liu X, Huang C, Tian G, Ding C, Wu J, Lan L, Yang S. Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis. Sci Rep 2020: 10(1): 3044. 13. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine 2020: 382(19): 1787-1799. 14. Wacholder S. Binomial regression in GLIM: estimating risk ratios and risk differences. Am J Epidemiol 1986: 123(1): 174-184. 15. Greenland S. Model-based estimation of relative risks and other epidemiologic measures in studies of common outcomes and in case-control studies. Am J Epidemiol 2004: 160(4): 301-305. Table 1. Demographics and main clinical variables (n (%) or mean±SD) at randomization (FAS), concomitant medications received and adverse events (Safety population). Usual Care Usual Care + Budesonide Total N=62 N=58 N=120 Demographics (FAS) Age (years) 51.6 ± 13.8 50.6 ± 13.7 51.1 ± 13.7 Males 32 (51.6%) 24 (42.1%) 56 (47.1%) Body mass index (Kg/m2) 30.1 ± 6.5 28.6 ± 6.0 29.4 ± 6.3 Smoker status Current 3 (4.8%) 1 (1.8%) 4 (3.4%) Former 12 (19.4%) 10 (17.5%) 22 (18.5%) Never 47 (75.8%) 46 (80.7%) 93 (78.2%) Symptoms (FAS) Fever 53 (85.5%) 40 (70.2%) 93 (78.2%) Cough 40 (64.5%) 40 (70.2%) 80 (67.2%) Arthromyalgia 26 (41.9%) 26 (45.6%) 52 (43.7%) Anosmia 19 (30.6%) 19 (33.3%) 38 (31.9%) Ageusia 19 (30.6%) 17 (29.8%) 36 (30.3%) Diarrhoea 16 (25.8%) 21 (36.8%) 37 (31.1%) Chest x-ray findings (FAS) Bilateral pneumonia 48 (77.4%) 49 (86.0%) 97 (81.5%) Unilateral pneumonia 14 (22.6%) 8 (14.0%) 22 (18.5%) Oxygen requirements at admission (FAS) None 49 (79.0%) 40 (69.0%) 89 (74.2%) Low flow O2 13 (21.0%) 18 (31.0%) 31 (25.8%) Concomitant medications (Safety population) Enoxaparin 42 (67.7%) 32 (57.1%) 74 (62.7%) Dexamethasone 13 (21.0%) 6 (10.7%) 19 (16.1%) Methylprednisolone 1 (1.6%) 1 (1.8%) 2 (1.7%) Azithromycin 5 (8.1%) 6 (10.7%) 11 (9.3%) Chloroquine 4 (6.5%) 6 (10.7%) 10 (8.5%) Remdesivir 4 (6.5%) 6 (10.7%) 10 (8.5%) Lopinavir/Ritonavir 3 (4.8%) 4 (7.1%) 7 (5.9%) Tocilizumab 1 (1.6%) 0 (0.0%) 1 (0.8%) Adverse Events (Safety population) Any adverse event 21 (33.9%) 20 (35.7%) 41 (34.7%) Any severe adverse event 3 (4.8%) 2 (3.6%) 5 (4.2%) Any treatment-related adverse event 0 (0%) 0 (0%) 0 (0%) Any treatment-related severe adverse event 0 (0%) 0 (0%) 0 (0%) Mortality at day 30th follow-up 0 (0%) 0 (0%) 0 (0%) Mortality at day 90th follow-up 1 (1.6%) 1 (1.8%) 2 (1.7%)