The overall objective of the study is to evaluate the clinical efficacy of COVID-19 treatments consisting of standard of care (SOC), vs SOC with high dose famotidine in patients hospitalized and meeting radiologic criteria for COVID-19 disease. SOC for the treatment for COVID-19 has evolved since the initial conceptualization of this protocol and early recruitment of patients. Initially SOC included hydroxychloroquine and has progressed to include Remdesivir. This protocol is amended to allow the SOC to reflect the prevailing treatment for COVID-19. We will compare clinical outcomes associated with SOC and the addition of high-dose intravascular famotidine. The trial is designed to enroll at least 471 COVID-19 patients hospitalized with moderate to severe disease into each of the two treatment arms, with a total enrollment target of at least 942 patients. This trial has been designed and powered to support up to three interim analyses that will enable prompt assessment of benefits and risks of the two treatment groups while maintaining the rigorous gold standard of a randomized double blind clinical trial structure. Trial design has been guided by practical consideration of the current clinical context involving rapidly escalating demands on hospital staff and resources, and incorporates a minimalist approach employing existing laboratory information management systems and a clinically relevant binary primary outcome of 30-day endpoint of death or survival.
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral
pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in these patients.
This novel coronavirus has been designated SARS-CoV-2, and the disease caused by this virus
has been designated COVID-19 and has infected hundreds of thousands of confirmed individuals
in more than 200 countries. Currently there are no approved therapeutic agents available for
coronaviruses. There is an urgent need for an effective treatment to treat symptomatic
patients but also to decrease the duration of virus transmission in the community. Among
candidate drugs to treat COVID-19, repurposing of FDA-approved drugs for use as antiviral
treatments is proposed because knowledge on safety profile, side effects, and drug
interactions are well known.
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.
Drug: SOC + Intravenous Famotidine
Standard of Care treatment plus IV famotidine
Drug: SOC + Placebo
Standard of Care treatment plus IV placebo
Inclusion Criteria:
1. Subject (or legally authorized representative) provides written informed consent prior
to initiation of any study procedures.
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:
1. Mild COVID-19 disease (minor clinical symptoms, imaging does not show signs of lung
inflammation)
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
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
Joseph Conigliaro, MD, Principal Investigator
Northwell Health