NIAID Began First Clinical Trial of Remdesivir in the U.S.

Recent strong warning messages from the World Health Organization (WHO) and U.S. health officials came in response to outbreaks of the coronavirus outside China, including in Iran, Japan, South Korea, and Italy, the global circumstances suggest it's likely that this virus will cause a pandemic. U.S. public health officials also said that it’s time for Americans to start preparing now for the possibility that more aggressive, disruptive measures might be needed to stop the spread of the new coronavirus in communities across the country. (1) (2) 

The Global Outbreak of COVID-19

The COVID-19（previously provisionally named 2019 novel coronavirus or 2019-nCoV）outbreak, which began in Wuhan, China, has spread in Asia, the Middle East, and Europe. As of February 26, the WHO has reported global 81109 confirmed cases  (871 new) of COVID-19 and 2718 deaths (52 new) in China, 2918 cases (459 new) of COVID-19 and 44 deaths (10 new) in 48 other countries (1) (3). To date, the U.S. has 60 confirmed cases of novel coronavirus, 14 confirmed cases of the virus in people who have traveled to China and an additional 40 residents were infected with the virus are among repatriated residents who were passengers of the Diamond Princess cruise ship, docked in Yakohama, Japan, according to the US Health and Human Services (HHS) and the Centers for Disease Control and Prevention (CDC). (2)(4)

People infected with COVID-19 will have mild symptoms (such as fever, cough and shortness of breath) , some patients may become severe illness and death. The symptoms of COVID-19 may appear in as few as 2 days or as long as 14 days after exposure per CDC. (2)

Remdesivir, the First Clinical Trial in the United States

An Investigational New Drug Application (IND)  Remdesivir is developed by American drugmaker Gilead Sciences Inc.. The drug is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Remdesivir was previously tested in patients with Ebola virus disease and has shown promise in animal models for treating Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) (5), more importantly, one case of COVID-19 pneumonia in the USA is responding well to Remdesivir. (6)

Based on these data and coronavirus outbreak, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) began a phase 2 randomized controlled trial for the treatment of COVID-19 patients on February 21, 2020, which is the first clinical trial of Remdesivir in the United States. (7)

According to the NIAID/NIH and U.S. Coronavirus Task Force member Anthony S. Fauci, M.D., this clinical trial is to evaluate the safety and efficacy of the novel therapeutic antiviral Remdesivir in hospitalized adults diagnosed with coronavirus disease 2019 (COVID-19)  if an experimental treatment can benefit patients. Although "Remdesivir has been administered to some patients with COVID-19, we do not have solid data to indicate it can improve clinical outcomes. We urgently need a safe and effective treatment for COVID-19 according to Dr. Fauci.

The primary objective of the study is to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in patients hospitalized with COVID-19. The secondary objectives of the study are to 1) evaluate the clinical efficacy of different investigational therapeutics as compared to the control arm as assessed by clinical severity, hospitalization, and mortality, and 2) evaluate the safety of the intervention through 28 days of follow-up as compared to the control arm.

Clinical trials of Remdesivir are also ongoing in China. NIAID/NIH developed the current trial taking those designs into account and in accordance with consultations convened by the WHO on the development of a therapeutic trial for patients with COVID-19.

Eligibility Criteria of Clinical Trial

This study is a multicenter trial that will be conducted in up to 50 clinical sites  in the U.S. and worldwide. Patients who meet the following criteria may be enrolled in the trial:

1. Subject (or legally authorized representative) provides written informed consent before the initiation of any study procedures.

2. Understands and agrees to comply with planned study procedures.

3. Agrees to the collection of oropharyngeal (OP) swabs and venous blood per protocol.

4. Male or non-pregnant female adult >/=18 years of age at time of enrollment.

5. Has laboratory-confirmed novel coronavirus/COVID-19 (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR), or other commercial or public health assay in any specimen < 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

• Requiring mechanical ventilation and/or supplemental oxygen.

    7. 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).

Patient Assignments

Eligible study participants will be randomly assigned into two equal groups (n=197/each) receiving either 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir for the duration of the hospitalization up to a 10 days total course or 200 mg of Remdesivir placebo administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir placebo for the duration of the hospitalization up to a 10 days total course.

Daily Score Monitoring

Patients will be monitored and will be assigned daily scores based on a predefined scale of clinical outcomes that considers factors such as respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness. Participants also will be asked to provide blood samples and nose and throat swabs approximately every two days.

Drug Safety (Pharmacovigilance)

Drug safety, also known as Pharmacovigilance (PV) heavily focuses on adverse drug reactions, or ADRs, which are defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.

About safety of Remdesivir, an adverse event (AE) or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor during clinical trials, an assessment of the clinical status is as follows:

1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

These randomized, multicenter studies will enroll 394 patients (Ages 18 to 99, All sexes, Adult, Older Adult)  beginning from February 21, 2020 until April 1, 2023.

Author Biography

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

References:

1        https://www.who.int

2        https://www.cdc.gov

3        https://www.businessinsider.com

4        https://www.hhs.gov

5        Cell Research (2020) 0:1–3;

6        N Engl J Med (2020 Jan 31), 10.1056

7        https://clinicaltrials.gov

Date: 2-27-2020

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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