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.
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)
Drug: Ketotifen/Indomethacin
2 mg tablet, 75 mg SR tablet
Other Name: Array
Drug: Placebo
Matching placebo tablet
Inclusion Criteria:
1. Adult patients aged 18-75 years
2. 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.
3. 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:
1. Fever
2. nausea
3. vomiting
4. diarrhea
5. muscle aches
6. fatigue
7. headache
8. loss of smell or taste
9. others that are consistent with acute COVID-19 infection in the opinion of the
Investigator.
4. Able and willing to give written or oral informed consent
5. 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.
6. 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:
1. Clinical signs and symptoms for severe COVID-19, such as:
1. Need for hospitalization at the time of screening
2. Need for supplemental O2 at the time of screening
2. A person with any of the following laboratory values:
1. AST or ALT >/= 1000 U/L
2. Known serum creatinine > 1.6 mg/dL
3. 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)
4. Current usage (within the last 7 days prior to randomization) of any of the following
drugs:
1. anticoagulant drugs including, but not limited to, aspirin, warfarin, or
clopidogrel.
2. systemic corticosteroids or non-steroidal anti-inflammatory medications for any
indication
3. drugs that are known to block the functions of ketotifen, such as propranolol.
4. oral anti-diabetic agents
5. diflunisal or other drugs (or drugs at certain doses) that are contraindicated
for concurrent use with Indomethacin
5. Prior vaccination of at least one dose of vaccine for SARS-CoV-2
6. Has participated, is participating, or plans to participate in a clinical research
study evaluating any authorized, approved, or investigational drug SARS-CoV-2
7. Any other clinically significant acute illness within 7 days prior to first study drug
administration that would impact outcome assessment.
8. Patients with a history of any gastrointestinal bleeding requiring medical care.
9. Exposure to any new investigational agent within 30 days prior to the study drug
administration.
10. Clinically significant abnormal physical examination unrelated to COVID-19 infection
that would impact outcome assessment.
11. Females who are pregnant or breast feeding.
12. 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.
13. Any condition that would render the informed consent invalid, or limit the ability of
the patient to comply with the study requirements.
14. Inability to comply with completing the outcome assessment measure(s).
15. Any condition that, in the opinion of the investigator, would complicate or compromise
the study or well-being of the patient.
Dhulikhel Hospital
Kavre, Bagmati, Nepal
Global Clinical Research Pvt. Ltd.
Kathmandu, Nepal
Thomas A Dahl, Ph.D
617-818-2735
tadahl@sen-jam.com
Alexander T Limkakeng, MD, Principal Investigator
Duke University