Comparison of Two Corticosteroid Regimens for Post COVID-19 Diffuse Lung Disease (COLDSTER)

Comparison of the Efficacy and Safety of Two Corticosteroid Regimens in the Treatment of Diffuse Lung Disease After Coronavirus Disease 2019 (COVID-19) Pneumonia

A proportion of patients with COVID-19 pneumonia have a prolonged course of illness. Some of these patients continue to have considerable respiratory symptoms or persistent hypoxemia. The CT abnormalities in these patients are often a combination of ground-glass opacities and patchy multifocal consolidation consistent with a pattern of OP. In several patients, these radiologic abnormalities persist. As with other forms of OP, patients with post-COVID OP or post COVID diffuse lung disease (PC-DLD) may benefit from treatment with oral glucocorticoids. The ideal dose of glucocorticoids for treating PC-DLD is unknown.

In this study, the investigatros aim to compare the efficacy and safety of a medium dose and a low dose of prednisolone (as the initial dose) for the treatment of post-COVID. diffuse lung disease.

Study Overview

• Status: Completed
• Conditions: Post COVID-19 Diffuse Lung Disease
• Intervention / Treatment: Drug: Medium dose prednisolone; Drug: Low dose prednisolone

Detailed Description

A proportion of patients with COVID-19 pneumonia (with or without ARDS) have a prolonged course of illness. Some of these patients continue to have considerable respiratory symptoms or persistent hypoxemia. The CT abnormalities in these patients are often a combination of ground-glass opacities and patchy multifocal consolidation consistent with a pattern of OP. In several patients, these radiologic abnormalities persist even after the symptoms of active COVID-19 have subsided and swabs from the upper respiratory tract for SARS-CoV-2 have turned negative. Such patients may be classified as having a secondary form of OP, namely post-infectious OP. Some of the patients also start developing signs of fibrosis.

As with other forms of OP, patients with post-COVID OP or post COVID diffuse lung disease (PC-DLD) may benefit from treatment with oral glucocorticoids.

Glucocorticoids may be a double-edged sword in this clinical situation. Steroids reduce inflammation associated with OP with a resultant resolution of symptoms, improvement in gas exchange (resulting in the resolution of hypoxemia), and potentially preventing the progression of early parenchymal abnormalities to irreversible fibrosis. However, they are associated with adverse effects such as hyperglycemia, delayed viral clearance, and increased susceptibility to infections. The ideal dose of glucocorticoids for treating PC-DLD is unknown. As PC-DLD is likely to get recognised early (much earlier than the average duration between onset of symptoms and diagnosis in other forms of OP, i.e., about 3-6 months), there is a possibility a lower intensity of glucocorticoids may be sufficient for treatment than the usual regimens, with the advantage of lesser adverse effects. A previous retrospective study that compared two regimens (higher dose intensity [DI] of glucocorticoids alone vs. glucocorticoids at a lower dose intensity along with clarithromycin), however, found that a complete radiologic response was higher in the prednisone alone (higher DI) group (81% vs. 63%) than in the combination group (with a lower DI of prednisone). Statistical significance was however not achieved (p=0.38), mainly due to the small sample size.

The investiagtors hypothesize that in PC-DLD a higher intensity (i.e., starting with a medium dose of prednisolone) will be more effective than a lower dose intensity (i.e., starting with a low dose of prednisolone) of glucocorticoids in effecting a radiologic response at six weeks.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Postgraduate Institute of Medical Education and Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosed to have COVID-19 by means of a real-time reverse transcription polymerase chain reaction (rRT-PCR) test performed on a respiratory (upper or lower respiratory) sample or the detection of COVID-19 antigen
• Having significant respiratory symptoms (cough and breathlessness) or persistent hypoxemia or oxygen desaturation on exercise and CT chest showing residual changes of post-COVID parenchymal involvement of any extent OR having CT chest showing residual changes of post-COVID parenchymal involvement >20% of the lung parenchyma on visual inspection of the scans between 3-8 weeks of the onset of symptoms of COVID-19
• Willing to participate in the study

Exclusion Criteria:

• Receiving ventilatory or respiratory support (invasive or non-invasive mechanical ventilation or high flow nasal cannula) or supplemental oxygen with FiO2>0.35
• Requiring intensive care due to acute COVID-19 pneumonia or its complications
• Having a known lung parenchymal lung disease before the onset of COVID-19
• Pregnant or lactating women
• Having absolute contraindication for prednisolone in a dose of 40 mg/day (this includes untreated glaucoma, uncontrolled diabetes mellitus, signs of an uncontrolled or untreated infection or sepsis, pulmonary mycosis, untreated severe psychiatric disorders)
• Unwilling to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Medium dose prednisolone; An initial dose of 40 mg/day will be administered for 1 week, followed by 30 mg/day for 1 week, 20 mg/day for 2 weeks, 10 mg/day for 2 weeks	Drug: Medium dose prednisolone; Same as arm description
Active Comparator: Low dose prednisolone; A dose of 10 mg/day of prednisolone will be administered for 6 weeks	Drug: Low dose prednisolone; Same as arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with a complete radiologic response	Complete response is defined as complete disappearance or ≥90% reduction in the lung parenchymal abnormalities on a high-resolution CT scan	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with a complete or good response radiologic response	Complete response is defined as complete disappearance or ≥90% reduction in the lung parenchymal abnormalities on a high-resolution CT scan. Good response is defined as ≥50% but less than 90% reduction in the lung parenchymal abnormalities on a high-resolution CT scan.	6 weeks
Proportion of subjects with a good composite response	Complete or good radiologic resolution along with no oxygen desturation on exercise testing and a normal spirometry	6 weeks
Forced vital capacity as a percentage of the predicted	Forced vital capacity will be measured using spirometry. The predicted value will be calculated based on standard reference equations.	6 weeks
Change in resting oxygen saturation	The change in resting oxygen saturation (measured by pulse oximetry) from the day of randomization to 6 weeks	6 weeks
Proportion of subjects with oxygen desaturation on exercise testing	Oxygen desaturation will be defined as a fall in oxygen saturation by 4% or more on exercise testing (by one-minute sit-to-stand test and six-minute walk test)	6 weeks
Change in dyspnea score on modified Medical Research Council scale	The change in dyspnea score assessed using the modified Medical Research Council from the day of randomization to 6 weeks.The scale has a minimum score of 0 and a maximum score of 4, higher values indicate worse outcomes	6 weeks
Severity of dyspnea on the Functional Assessment of Chronic Illness Therapy - Dyspnea-10 item scale	Severity of dyspnea assessed using the Functional Assessment of Chronic Illness Therapy - Dyspnea-10 item scale. The scale has two item banks of 10 items each for dyspnea and functional limitations. EAch item has a minimum score of 0 and maximum score of 3. Higher scores represent worse outcomes.	6 weeks
Change in respiratory health status using the King's Brief ILD questionnaire	Respiratory health status assessed using the King's Brief ILD questionnaire. The questionnaire has 15 items. The total score varies from 0 to 100, with higher scores representing better outcomes.	6 weeks
Change in health-related quality of life using the Short Form-36 questionnaire	Health-related quality of life assessed using Short Form-36 questionnaire. The questionnaire consists of 36 items covering 8 domains. Each domain score has a minimum value of 0 and maximum value of 100, with higher scores representing better outcomes	6 weeks
Proportion of subjects who develop adverse effects of prednisolone	The adverse effects of treatment (acne, weight gain, hyperglycemia, hypertension, abdominal pain, dyspepsia, Cushingoid facies, skin thinning and bruising, mood changes, muscular weakness and any other adverse effects related to prednisolone)	6 weeks

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research

Publications and helpful links

General Publications

• Dhooria S, Chaudhary S, Sehgal IS, Agarwal R, Arora S, Garg M, Prabhakar N, Puri GD, Bhalla A, Suri V, Yaddanapudi LN, Muthu V, Prasad KT, Aggarwal AN. High-dose versus low-dose prednisolone in symptomatic patients with post-COVID-19 diffuse parenchymal lung abnormalities: an open-label, randomised trial (the COLDSTER trial). Eur Respir J. 2022 Feb 17;59(2):2102930. doi: 10.1183/13993003.02930-2021. Print 2022 Feb.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): September 1, 2021
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: December 5, 2020
• First Submitted That Met QC Criteria: December 5, 2020
• First Posted (Actual): December 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 26, 2022
• Last Update Submitted That Met QC Criteria: April 25, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: interstitial lung disease; diffuse parenchymal lung disease; SARS-Co-V-2; organizing pneumonia; coronavirus disease-2019
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; COVID-19; Lung Diseases; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: INT/IEC/2020/SPL-1528

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No