Ketotifen and Indomethacin Combination Treatment Clinical Trial for COVID-19

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effectiveness of ketotifen and indomethacin taken together to improve symptoms related with COVID-19. Ketotifen and indomethacin are medications approved by the Food and Drug Administration (FDA) to treat diseases other than COVID-19. Their use in this study is investigational, meaning they have not been approved by the FDA to treat COVID-19.

Detailed Description
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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)

Official Title
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Ketotifen and Indomethacin Combination Treatment Clinical Trial for COVID-19 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Proof-of-Concept Clinical Trial to Evaluate the Efficacy of Ketotifen and Indomethacin for Mild and Moderate COVID-19 in Adults

Conditions
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COVID-19 Respiratory Infection

Intervention / Treatment
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* Drug: Ketotifen/Indomethacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients aged 18-75 years Has SARS-CoV-2-positive antigen or molecular diagnostic test (validated SARS-CoV-2 antigen, RT-PCR, or other molecular diagnostic assay from a sample collected no more than 7 days prior to enrollment. At least two signs or symptoms of disease consistent with acute COVID-19 infection. One of these two symptoms must include cough OR shortness of breath with onset within 7 days prior to randomization. Other symptoms that qualify include: Fever nausea vomiting diarrhea muscle aches fatigue headache loss of smell or taste others that are consistent with acute COVID-19 infection in the opinion of the Investigator. Able and willing to give written or oral informed consent Willing to be an outpatient from Study Day 1 to 14, to provide blood during patient visits on Study Days 1, 3, 5, and 10, return on Study Days 1, 3, 5, 7, 10, 14, and 21 for assessment. Willing to keep a diary of pain medication usage, side effects, and COVID-19 associated symptoms and answer a follow-up questionnaire on Study Day 84. Exclusion Criteria: Clinical signs and symptoms for severe COVID-19, such as: Need for hospitalization at the time of screening Need for supplemental O2 at the time of screening A person with any of the following laboratory values: AST or ALT >/= 1000 U/L Known serum creatinine > 1.6 mg/dL Prior use of any of the following treatments: COVID-19 convalescent plasma, monoclonal antibodies against SARS-CoV-2, IVIG (for COVID-19), or COVID-19 treatments (authorized, approved, or investigational) Current usage (within the last 7 days prior to randomization) of any of the following drugs: anticoagulant drugs including, but not limited to, aspirin, warfarin, or clopidogrel. systemic corticosteroids or non-steroidal anti-inflammatory medications for any indication drugs that are known to block the functions of ketotifen, such as propranolol. oral anti-diabetic agents diflunisal or other drugs (or drugs at certain doses) that are contraindicated for concurrent use with Indomethacin Prior vaccination of at least one dose of vaccine for SARS-CoV-2 Has participated, is participating, or plans to participate in a clinical research study evaluating any authorized, approved, or investigational drug SARS-CoV-2 Any other clinically significant acute illness within 7 days prior to first study drug administration that would impact outcome assessment. Patients with a history of any gastrointestinal bleeding requiring medical care. Exposure to any new investigational agent within 30 days prior to the study drug administration. Clinically significant abnormal physical examination unrelated to COVID-19 infection that would impact outcome assessment. Females who are pregnant or breast feeding. Current significant medical condition or illness including cardiac arrhythmias, cardiomyopathy or other cardiac disease, advanced renal disease, immunocompromised state including known HIV infection, or any other illness that the Investigator considers should exclude the patient, especially those that require continuation of other medications likely to have an interaction with the study drug. Patients with a history of allergy will not be excluded unless the allergy may be directed to the Study Drug, other NSAIDs, or other tablet ingredient. Any condition that would render the informed consent invalid, or limit the ability of the patient to comply with the study requirements. Inability to comply with completing the outcome assessment measure(s). Any condition that, in the opinion of the investigator, would complicate or compromise the study or well-being of the patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Drug<br>Ketotifen 2 mg administered in tablet form twice a day (every 12 hr). Indomethacin sustained-release (SR) 75 mg, twice a day (every 12 hr). Patients will be administered 28 doses in total of ketotifen/indomethacin combination. | Drug: Ketotifen/Indomethacin<br>* 2 mg tablet, 75 mg SR tablet<br>* Other names: Tivorbex;|
| Placebo Comparator: Placebo<br>Placebo pills matching in appearance to study drug twice a day for 28 doses total. | Drug: Placebo<br>* Matching placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Study Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of severe disease | Severe disease defined as hypoxia to room air pulse oximetry below 93% | 28 days | 
| Development of severe disease | Severe disease defined as hypoxia to room air pulse oximetry below 93% | 84 days | 
| Development of severe disease | Severe disease defined as hypoxia to room air pulse oximetry below 93% | 14 days | 
| Proportion and number of medically attended visits related to COVID-19 | Need for emergency department visit or hospitalization for symptoms of COVID-19 | 28 days | 
| Proportion and number of medically attended visits related to COVID-19 | Need for emergency department visit or hospitalization for symptoms of COVID-19 | 84 days | 
| Need for hospitalization | inpatient hospitalization | 28 days | 
| Need for hospitalization | inpatient hospitalization | 84 days | 
| Intensive care unit admission | Intensive care unit admission | 28 days | 
| Intensive care unit admission | Intensive care unit admission | 84 days | 
| Supplemental oxygen | Clinical care provider prescribing supplemental oxygen | 28 days | 
| Supplemental oxygen | Clinical care provider prescribing supplemental oxygen | 84 days | 
| Need for mechanical ventilation | Clinical care provider prescribing mechanical ventilation | 28 days | 
| Need for mechanical ventilation | Clinical care provider prescribing mechanical ventilation | 84 days | 
| severe functional disability (WHO ordinal scale) | WHO Ordinal Scale | 28 days | 
| severe functional disability (WHO ordinal scale) | WHO Ordinal Scale | 84 days | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 84 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 2 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 3 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 4 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 5 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 6 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 7 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 8 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 9 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 10 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 11 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 12 | 
| UCSD Shortness of Breath Questionnaire | 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. | Day 13 | 
| Serum chymase concentration | Serum chymase concentration | day 10 | 
| Serum chymase concentration | Serum chymase concentration | day 5 | 
| Serum chymase concentration | Serum chymase concentration | day 3 | 
| coagulation | Hematocrit, platelets, PT/PTT | day 3 | 
| coagulation | Hematocrit, platelets, PT/PTT | day 5 | 
| coagulation | Hematocrit, platelets, PT/PTT | day 10 | 
| Patient Global Improvement Score | A questionnaire that results in a numerical value that is the sum of the patients responses to questions on a likert scale | Day 14 | 
| Patient Global Improvement Score | A questionnaire that results in a numerical value that is the sum of the patients responses to questions on a likert scale | Day 84 | 
| Patient Global Improvement Score | A questionnaire that results in a numerical value that is the sum of the patients responses to questions on a likert scale | Day 28 | 
| Incidence of associated symptoms of COVID-19 | Incidence of symptoms associated with allergy, respiratory viral infection, and/or vascular pathology | Day 14 | 
| Incidence of associated symptoms of COVID-19 | Incidence of symptoms associated with allergy, respiratory viral infection, and/or vascular pathology | Day 28 | 
| Incidence of associated symptoms of COVID-19 | Incidence of symptoms associated with allergy, respiratory viral infection, and/or vascular pathology | Day 84 | 
| adverse effect profile | incidence of GI upset, ulcers, and renal function | Day 14 | 
| adverse effect profile | incidence of GI upset, ulcers, and renal function | Day 28 | 
| adverse effect profile | incidence of GI upset, ulcers, and renal function | Day 84 |