Multi-site Adaptive Trials for COVID-19

December 10, 2020 updated by: Joseph Conigliaro, Northwell Health

A Multi-site, Randomized, Double-Blind, Comparative Trial of the Safety and Efficacy of Standard of Care (SOC) Plus Famotidine vs SOC Plus Placebo for the Treatment of COVID-19 in Hospitalized Adults

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

233

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Bay Shore, New York, United States, 11706
        • Southside Hospital
      • Manhasset, New York, United States, 11030
        • North Shore University Hospital
      • Mount Kisco, New York, United States, 10549
        • Northern Westchester Hospital
      • New York, New York, United States, 10075
        • Lenox Hill Hospital
      • Queens, New York, United States, 11040
        • Long Island Jewish Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 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.
Drug: SOC + Intravenous Famotidine
Standard of Care treatment plus IV famotidine
Placebo Comparator: SOC/Placebo
Subjects in this arm will receive the current Standard of Care treatment for COVID-19; plus placebo infusion three times daily.
Drug: SOC + Placebo
Standard of Care treatment plus IV placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 30 days post hospitalization
Mortality status
30 days post hospitalization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Virologic response to study treatment detected in blood
Time Frame: Day 30 relative to admission Day 0
Percent change in PCR copy number from first measurement
Day 30 relative to admission Day 0
Virologic clearance in nasal swab and/or lower respiratory secretions
Time Frame: Day 6 and Day 30
Presence or absence of SARS-CoV-2 Viral RNA in Nasopharyngeal swab or lower respiratory secretions
Day 6 and Day 30
Clinical Severity
Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30.
Measured by 7-point ordinal scale: from (1) death, to (7) not hospitalized, no limit on daily activities
Measured on study Days 3, 5, 8, 11, 15 and 30.
Clinical Severity
Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30.
Measured by National Early Warning Score (NEWS): vital sign based score from 0-20, higher score indicates higher degree of illness
Measured on study Days 3, 5, 8, 11, 15 and 30.
Clinical Severity
Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30.
Measured by duration of use of supplemental oxygen (if applicable)
Measured on study Days 3, 5, 8, 11, 15 and 30.
Clinical Severity
Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30.
Measured by duration of use of mechanical ventilation (if applicable)
Measured on study Days 3, 5, 8, 11, 15 and 30.
Clinical Severity
Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30.
Measured by duration of hospitalization
Measured on study Days 3, 5, 8, 11, 15 and 30.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of New Onset Lymphopenia
Time Frame: Through study completion, average of 30 days
Incidence of new onset lymphopenia during hospitalization measured by blood draw
Through study completion, average of 30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northwell Health

Investigators

  • Principal Investigator: Joseph Conigliaro, MD, Northwell Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 7, 2020

Primary Completion (Actual)

September 7, 2020

Study Completion (Actual)

September 7, 2020

Study Registration Dates

First Submitted

April 27, 2020

First Submitted That Met QC Criteria

April 29, 2020

First Posted (Actual)

April 30, 2020

Study Record Updates

Last Update Posted (Actual)

December 11, 2020

Last Update Submitted That Met QC Criteria

December 10, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20-0268

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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