Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE3
233 participants
INTERVENTIONAL
2020-04-07
2020-09-07
Brief Summary
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Detailed Description
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In silico screening of FDA licensed compound libraries against the SARS CoV 2 protease Plpro catalytic site was performed using solved crystal structures of the protein. Plpro (Papain-like protease) is an early acting protease responsible for initial processing of the SARS CoV2 polyprotein into active subunits. Plpro also has ubiquitinase activity, and is implicated in early infection phase inhibition of innate (interferon) immune responses which otherwise would suppress viral replication. A ranked list of licensed compounds with predicted binding activity in the Plpro catalytic site was computationally generated, and the Plpro catalytic site binding pose of each of the top compounds was examined and ranked by a team of pharmaceutical chemists. Package inserts or product monographs for the licensed compounds which generated high computational binding scores and passed inspection were then reviewed and used to rank compounds based on adverse events, warnings, drug interactions on-target mechanisms, pharmacokinetic and absorption, metabolism, excretion and toxicity (ADMET), protein binding and available therapeutic window considerations. Famotidine (Pepcid), a histamine H2 antagonist widely available over-the-counter, was repeatedly computationally scored among the highest of the compounds tested, and was associated with the most favorable pharmacokinetic and safety profile. A series of analogs of famotidine were generated using PubChem, and many of these scored even higher as potential candidates. This control compound set further confirmed the predicted binding of the molecular backbone chemotype at the Plpro protease/ubiquitinase site. Currently available as oral and IV products, famotidine has a very attractive proven safety, drug interaction, and therapeutic window profile. Samples of famotidine have been submitted at Southern Research and IITRI for in vitro testing in COVID-19 cultures. Unpublished anecdotal case studies suggest clinical benefits associated with administration of famotidine 40 mg PO TID in mild COVID-19 infection.
On 29 April 2020, the National Institute of Allergy and Infectious Diseases (NIAID) announced that Remdesivir was better than placebo in reducing time to recovery for people hospitalized with advanced COVID-19 and lung involvement. In an earlier study of adult patients admitted to a hospital for severe COVID-19, Remdesivir was not associated with statistically significant clinical benefits. In that study, Remdesivir was not associated with a difference in time to clinical improvement. Although not statistically significant, patients receiving Remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. Remdesivir was stopped early because of higher numbers of adverse events compared to placebo. Because of these studies the FDA stated on 1 May 2020, that it is "reasonable to believe" that known and potential benefits of Remdesivir outweigh its known and potential risks, in some specific populations hospitalized with severe COVID-19.
Given the refinement of standard of care to include Remdesivir and no longer hydroxychloroquine, we have edited the study protocol to reflect this new standard of care.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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SOC/Famotidine
Subjects in this study arm will receive a combination of Standard of Care (SOC) treatment and intravenous famotidine. Famotidine Injection, 10mg/mL mixed with Normal Saline is given intravenously at 120mg (30% of 400 mg oral dose). The total daily dose proposed is 360mg/day famotidine IV for a maximum of 14 days, or hospital discharge, whichever comes first. SOC will be administered as per the current clinical protocol for COVID-19.
SOC + Intravenous Famotidine
Standard of Care treatment plus IV famotidine
SOC/Placebo
Subjects in this arm will receive the current Standard of Care treatment for COVID-19; plus placebo infusion three times daily.
SOC + Placebo
Standard of Care treatment plus IV placebo
Interventions
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SOC + Intravenous Famotidine
Standard of Care treatment plus IV famotidine
SOC + Placebo
Standard of Care treatment plus IV placebo
Eligibility Criteria
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Inclusion Criteria
2. Understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult ≥18 years of age at time of enrollment.
4. Subject consents to randomization within 36 hours of hospital admission.
5. Has radiographic confirmed COVID-19 disease \< 72 hours prior to randomization.
6. Illness of any duration, and at least one of the following:
* Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
* Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air, OR
* Requiring mechanical ventilation and/or supplemental oxygen.
7. Subjects do not require laboratory confirmation of the corona virus SARS-CoV-2 to determine eligibility
8. Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study (acceptable methods will be determined by the site).
Exclusion Criteria
2. Recent history of or any in-hospital exposure to investigational medications targeting COVID-19, or concurrent participation in a clinical trial targeting COVID-19
3. ALT/AST \> 5 times the upper limit of normal.
4. Moderate renal insufficiency (creatinine clearance 30-50 mL/min) OR Stage 4 severe chronic kidney disease OR requiring dialysis (i.e. creatinine clearance \<30 mL/min)
5. History of or evidence of QT prolongation on ECG examination
6. History of psoriasis or porphyria
7. Absolute neutrophil count (ANC) is \< 2000 mm3
8. Pregnancy
9. History of hepatic disease, Hepatitis C infection, or alcoholism
10. History of G-6-PD (glucose-6-phosphate dehydrogenase) deficiency
11. Concomitant use of the following medications: atazanavir, dasatinib, neratinib, ozanimod, pazopanib, rilpivirine, siponimod, and/or tizanidine.
12. Anticipated transfer to another hospital which is not a study site within 72 hours.
13. Allergy to any study medication
14. Known to be immunocompromised by disease or treatment for existing disease
18 Years
ALL
No
Sponsors
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Northwell Health
OTHER
Responsible Party
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Joseph Conigliaro
Vice Chairperson, Medicine, General Internal Medicine
Principal Investigators
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Joseph Conigliaro, MD
Role: PRINCIPAL_INVESTIGATOR
Northwell Health
Locations
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Southside Hospital
Bay Shore, New York, United States
North Shore University Hospital
Manhasset, New York, United States
Northern Westchester Hospital
Mount Kisco, New York, United States
Lenox Hill Hospital
New York, New York, United States
Long Island Jewish Medical Center
Queens, New York, United States
Countries
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References
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Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6:16. doi: 10.1038/s41421-020-0156-0. eCollection 2020. No abstract available.
Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016 Jun;123(6):1386-94. doi: 10.1016/j.ophtha.2016.01.058. Epub 2016 Mar 16.
Amrane S, Tissot-Dupont H, Doudier B, Eldin C, Hocquart M, Mailhe M, Dudouet P, Ormieres E, Ailhaud L, Parola P, Lagier JC, Brouqui P, Zandotti C, Ninove L, Luciani L, Boschi C, La Scola B, Raoult D, Million M, Colson P, Gautret P. Rapid viral diagnosis and ambulatory management of suspected COVID-19 cases presenting at the infectious diseases referral hospital in Marseille, France, - January 31st to March 1st, 2020: A respiratory virus snapshot. Travel Med Infect Dis. 2020 Jul-Aug;36:101632. doi: 10.1016/j.tmaid.2020.101632. Epub 2020 Mar 20.
Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. 1993 Oct;23(2 Suppl 1):82-91. doi: 10.1016/s0049-0172(10)80012-5.
Yao Y, Tian Y, Zhou J, Ma X, Yang M, Wang S. Epidemiological characteristics of SARS-CoV-2 infections in Shaanxi, China by 8 February 2020. Eur Respir J. 2020 Apr 23;55(4):2000310. doi: 10.1183/13993003.00310-2020. Print 2020 Apr.
Wang L, Gao YH, Lou LL, Zhang GJ. The clinical dynamics of 18 cases of COVID-19 outside of Wuhan, China. Eur Respir J. 2020 Apr 23;55(4):2000398. doi: 10.1183/13993003.00398-2020. Print 2020 Apr.
Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, Labella A, Manson DK, Kubin C, Barr RG, Sobieszczyk ME, Schluger NW. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Jun 18;382(25):2411-2418. doi: 10.1056/NEJMoa2012410. Epub 2020 May 7.
Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, Ambati J. Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19. Med. 2020 Dec 18;1(1):114-127.e3. doi: 10.1016/j.medj.2020.06.001. Epub 2020 Jun 5.
Freedberg DE, Conigliaro J, Wang TC, Tracey KJ, Callahan MV, Abrams JA; Famotidine Research Group. Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Gastroenterology. 2020 Sep;159(3):1129-1131.e3. doi: 10.1053/j.gastro.2020.05.053. Epub 2020 May 22. No abstract available.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9. Epub 2020 Apr 29.
Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
Other Identifiers
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20-0268
Identifier Type: -
Identifier Source: org_study_id