Ketotifen and Indomethacin Combination Treatment Clinical Trial for COVID-19

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is a recently emerged coronavirus that has resulted in an ongoing global pandemic. Fever and cough are most commonly experienced at disease presentation and complications involving the vascular system also occur as potential manifestations of severe disease. In human autopsy studies, infiltration of mononuclear cells in the lung tissue concurrent with edema and hemorrhage are frequently noted5. Other than lung epithelial cells, infection is also observed in endothelial cells, possibly augmenting endothelial activation and vascular permeability6. It is believed that lung pathology during COVID-19 is immune-mediated and compounded by the infiltration of monocytes, neutrophils and subsets of T cells7. Interestingly, perturbations in the numbers of granulocytes in the blood, such as neutrophils and eosinophils have also been shown to be associated with severe disease1, 8, 9.

Mast cells (MCs) are long-lived granulated immune cells that are present in both connective and mucosal tissues10. Our data in animal models support that MCs are strongly activated during infection by SARS-CoV-2 virus. Animal studies suggested that drugs in the class of MC "stabilizers" can effectively limit vascular leakage in mouse models of viral infection, such as caused by dengue virus (DENV).

Ketotifen is an oral drug currently used to prevent asthma. It is used to treat irritation and reduce vascular leakage, such as in the eye. It is a MC stabilizing agent that prevents degranulation of MCs, as well as the production of additional mediators that are not contained within MC granules, including leukotrienes and platelet activating factor 32. Indomethacin is an inhibitor of cyclooxygenase (COX) 1 and 2 receptors and, therefore, its primary mechanism of action is through inhibition of prostaglandin synthesis. It is used to treat inflammatory disorders and pain including rheumatoid arthritis, tendinitis, gout, and nephrogenic diabetes insipidus due to its antipyretic and analgesic properties.

This is a randomized, double blind, placebo-controlled, clinical study of ketotifen and indomethacin in adults 18 to 75 years of age, who meet at least two symptoms indicating COVID-19 infection, and who test positive for COVID-19 infection by a PCR based assay or rapid detection assay. Patients meeting all inclusion and exclusion criteria will be enrolled. Eligible patients who present at or are referred to trial sites will undergo screening. Trained research staff will obtain informed consent from participants. Patients meeting all inclusion and exclusion criteria and who agree to participate will be enrolled for the duration of the study.The study will be conducted as an outpatient study. One hundred and fifty (150) patients will be randomized 2:1 to ketotifen/indomethacin or placebo.

The primary objectives is as follows:

To evaluate the safety ketotifen and indomethacin, in combination, in COVID-19 patients.

Hypothesis: This drug combination will be safe in COVID-19 patients, with no increase in adverse events, and no increased severity of COVID-19 disease. (clinical endpoint)

To investigate the effectiveness of ketotifen and indomethacin for improving clinical measures of respiratory function and/or resolution of COVID-19 symptoms.

Hypothesis: Combination treatment of COVID-19 patients with ketotifen and indomethacin will improve patient measures of shortness of breath and/or promote the resolution of COVID-19 respiratory symptoms, shortening the duration of those symptoms. (clinical endpoint)