The leading cause of death in patients with coronavirus disease 2019 (COVID-19), caused by the virus ‘severe acute respiratory syndrome coronavirus 2’ (SARS‑CoV‑2), is respiratory failure from acute respiratory distress syndrome.[1] Patients who required invasive mechanical ventilation had an 88% mortality rate in one study in New York, and a 53% mortality rate in one study in the UK.[2][3] While an alarming proportion of patients with respiratory failure are dying, for the those who recover there is an urgent need to consider, and subsequently manage, their longer-term care.[4] Patients who have survived the COVID‑19 infection continue to experience feelings of fatigue, shortness of breath and reduced exercise tolerance. There is currently limited information regarding the best route to full recovery for post-coronavirus infection patients. Care will likely be multidisciplinary in nature and include a respiratory review along with physiotherapy, nutritional advice, psychiatric support, and potentially other disciplinary involvement.Patients who survive COVID‑19 may suffer lasting lung damage. The related virus ‘severe acute respiratory syndrome coronavirus’ (SARS‑CoV), identified in 2003, left lasting lung injury in some patients.[5] Evidence that patients who have recovered from COVID-19 may suffer long-term lung damage has come from a study in Wuhan, China; where SARS‑CoV‑2 was first identified. [6] CT scans show damage ranging from dense clumps of hardened tissue blocking blood vessels within the alveoli to tissue lesions (a sign of chronic lung disease) around the alveoli. Of 70 patients discharged, 66 patients (94%) had residual disease on final CT scans. Some lung damage is likely to gradually heal or disappear. However, in some patients, lung abnormalities will harden into layers of scar tissue known as pulmonary fibrosis.
Pulmonary fibrosis in COVID-19
Clinical trials will be important to identify whether pulmonary fibrosis develops in COVID‑19 survivors in order to plan appropriate clinical care. At present, the long-term pulmonary consequences of COVID-19 have not been characterized and an appropriate prospective study is needed.[7] Given the huge numbers of individuals affected by COVID-19, even rare complications will have major health effects at the population level.
Respiratory Clinical Trial Designs
Clinical trial designs for respiratory trials post-SARS‑CoV‑2 infection are likely to face similar practical challenges to those for common respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) but also rarer pulmonary diseases, such as pulmonary fibrosis, cystic fibrosis and pulmonary hypertension.
For the patient population, disease intensity may vary between patients and, for individual patients, may vary with time (reducing, increasing or fluctuating), environmental factors, comorbidities, genetic factors and education concerning managing their disease. For patient recruitment to clinical trials, disease will need to be defined either by physiology or a symptom scale equivalent to those used for asthma, for example, the Global Initiative for Asthma (GINA) Severity Index. As with any clinical trial, the methods used to assess the outcomes may affect the willingness of patients to participate.
Respiratory outcomes are usually defined by clinical assessments including lung function tests and and imaging techniques (computed tomography [CT] and positron emission tomography [PET] scans) combined with patient‑reported outcomes (dyspnoea, exercise capacity, exacerbations, use of rescue medications, symptom scores, health‑related quality of life [QoL] and mortality). Lung function tests (spirometry) focus on forced expiratory volume in the one second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR), in addition to other endpoints. The spirometry needs to be performed per the American Thoracic Society (ATS)/European Respiratory Society (ERS) standards. The success (repeatability) of any assessment depends on user and operator competence and variability can be reduced by training both staff and patients in the techniques and equipment. The myriad of assessment questionnaires can be highly subjective and training can also help reduce variability here. Using the same, experienced staff for sequential assessments is obviously beneficial. It is universally recognized, and generally required for regulatory approval, that clinical trials need to be randomized, controlled and also blinded in order to reduce the potential influence on outcome measures and thereby robustly demonstrate efficacy. Interventions and devices are more difficult to blind in respiratory trials than medications but the more aspects of the trial that can be blinded from investigators, site staff, patients and the medical monitors means the least possible influence on outcome measures. As for clinical trials in most therapeutic areas, involvement of key opinion leaders during the design phase is key to ensure endpoints and analyses are not only fit‑for‑purpose, but class-leading.
Biomarkers of inflammation may be of interest to define disease phenotypes and as potential targets for biotherapies; specifically cytokines considering that a hyperactive immune response may also be responsible, at least in part, for possible long-term lung damage following SARS-CoV‑2 infection. Treatment-specific endpoints may be additionally assessed, such as the presence of anti‑drug antibodies (following biologic treatments) and specific gene expression (biomarkers). Biomarkers and scales need to be validated before they can be used as outcomes in clinical trials. Timeframes for respiratory clinical trials should allow for the assessment of the appropriate endpoints, considering both short‑term effects and long-term maintenance of improvements. It may be hoped that by carrying out interventional respiratory trials we can deliver appropriate clinical care following this devastating pandemic.
Quanticate has provided support for over 120 studies related to respiratory disorders over the last 5 years across all phases from Phase 1 to post-marketing safety updates. For these studies, we provided multiple services, including data management, statistical analysis and statistical reports (including data monitoring committee reports), programming, medical writing and project management services. We have completed trials for a wide range of respiratory indications including COPD, asthma, allergic rhinitis, bronchitis, pneumonia, pulmonary fibrosis, pulmonary tuberculosis, interstitial lung disease, cystic fibrosis and pulmonary arterial hypertension (PAH), and lifestyle factors such as smoking. Therapeutic interventions have included corticosteroids, bronchodilators, antibiotics, monoclonal antibodies, kinase inhibitors, as well as investigations into adaptive treatment regimen management. Our teams have been involved in clinical trials from the early stages of protocol design, through handling, analysis and reporting of endpoint data, and writing marketing applications.
References
[1] Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080116/
[2] Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020 Apr 22 [Epub ahead of print]. https://jamanetwork.com/journals/jama/fullarticle/2765184
[3] Docherty AB, Harrison EM, Green CA, et al; medRxiv. Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol. 2020 [internet publication]. https://www.medrxiv.org/content/10.1101/2020.04.23.20076042v1
[4] https://www.sciencemediacentre.org/expert-comment-on-treatment-and-recovery-post-covid-infection/
[5] https://www.nature.com/articles/s41413-020-0084-5
[6] https://pubs.rsna.org/doi/full/10.1148/radiol.2020200843
[7] https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30222-8/fulltext
