Hydroxychloroquine, an anti-malaria drug that works by regulating the immune system, has been in and out of the news since it was proposed as a potential treatment option for COVID-19. Now, a clinical trial has begun to determine whether hydroxychloroquine, along with the antibiotic azithromycin, can prevent hospitalization and death from the viral illness. The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and is being conducted by the NIAID-funded AIDS Clinical Trials Group (ACTG). Medication for the study is being donated by Teva Pharmaceuticals.
News: NIH begins clinical trial of hydroxychloroquine and azithromycin to treat COVID-19 https://t.co/ttFCuOMio3
— NIH (@NIH) May 14, 2020
The Clinical Trial: A5395
The name given to the clinical trial is ‘A5395’, or the ‘Phase 2b trial’. It aims to compare the effectiveness of hydroxychloroquine (HCQ) administration, coupled with azithromycin (Azithro) versus a placebo, in symptomatic adult outpatients of COVID-19. Eligibility criteria for the study includes individuals who are 18 years of age or older; have been tested positive for COVID-19 via a nasopharyngeal swab test within 96 hours prior to when the first dose of study treatment is expected; have experienced at least one symptom within 24 hours (cough, fever, shortness of breath); do not need hospitalization; have agreed not to participate in any other COVID-19 study. Pregnant and breastfeeding women and people living with HIV are also eligible to participate in the study.
The study design ensures minimal in-person contact between participants and research staff. Processes such as informed consent, screening, enrollment and follow-up may be conducted remotely or in-person. Every participant will be given a study kit with sufficient pills for the entire study treatment, along with a diary for mentioning when the pills are taken and for recording symptoms. Participants will be required to provide their medical histories, history of previous medications and contact information.
Participants will have a 50-50 chance of receiving either the drugs or a placebo, as follows: a) Hydroxychloroquine/Placebo – Two capsules (200 mg each) to be taken by mouth twice on the first day, followed by one capsule (200 mg) twice every day for 6 days, and b) Azithromycin/Placebo – Two capsules (250 mg each) to be taken by mouth once on the first day, followed by one capsule (250 mg) every day for 4 days. The treatment will last for 7 days, followed by 23 weeks of follow-up.
Study staff will communicate participants via phone on days 2, 4, 6, 9, 13, and 17, followed by 3 and 6 months, after they enroll in the trial. On every visit, participants will be questioned about their overall health, their symptoms and treatment will be reviewed, and any hospitalizations or serious visits to the emergency or a clinic will be recorded. Participants will be asked to return their symptom/medication diary via mail or by hand on Day 20.
At selected sites, participants will be given the option of either having their blood drawn, giving a nose-throat swab, or providing a self-collected nose swab at the start of the study, on Day 6 and on Day 20 (in-person visits). The Phase 2b trial is expected to enroll about 2,000 adults from across the US. Investigators anticipate that most of the participants will be 60 years or older, with a comorbidity such as cardiovascular disease or diabetes that is associated with serious COVID-19 complications.
The study team is headed by Protocol Chair Davey Smith, M.D., of the University of California, San Diego. David Wohl, M.D., of the University of North Carolina at Chapel Hill, and Kara W. Chew, M.D., and Eric S. Daar, M.D., both of the University of California, Los Angeles, serve as protocol vice-chairs. The clinical trial is estimated to enroll quickly due to the high incidence of COVID-19, and preliminary results are expected to be available later this year.
NIAID Director Anthony S. Fauci, M.D. made this statement: “We urgently need a safe and effective treatment for COVID-19. Repurposing existing drugs is an attractive option because these medications have undergone extensive testing, allowing them to move quickly into clinical trials and accelerating their potential approval for COVID-19 treatment. Although there is anecdotal evidence that hydroxychloroquine and azithromycin may benefit people with COVID-19, we need solid data from a large randomized, controlled clinical trial to determine whether this experimental treatment is safe and can improve clinical outcomes.”
The Curious Case of Hydroxychloroquine
On March 28, 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EAU) which allowed hydroxychloroquine and medical-grade chloroquine to be prescribed, as appropriate, by doctors to adolescents and adults hospitalized with COVID-19, in the absence or non-availability of a clinical trial.
@US_FDA grants emergency authorization (EAU) to malaria drugs hydroxychloroquine sulfate and chloroquine phosphate for use in certain hospitalized patients with COVID-19.#CoronaUpdate #Chloroquine#coronavirus #COVID19 #malaria#Emergency #pandemichttps://t.co/rGVzQxycHX
— GeneOnline (@GeneOnlineNews) March 30, 2020
The use of hydroxychloroquine is founded on early evidence of its efficacy in cell cultures and clinical trials. An in-vitro study established that the anti-malaria drug did have potential in treating COVID-19 by decreasing viral replication. Another study revealed that hydroxychloroquine could eradicate the virus from within the body within 6 days of treatment, either alone or along with the antibiotic azithromycin. US President Donald Trump has also flaunted the drug as a ‘miracle treatment’ and ‘game changer’ for COVID-19 on various occasions, causing shortages of the drug throughout the country. Prescriptions for hydroxychloroquine increased by 46 times its average sale after the President promoted it in on television.
However, certain research studies have stated contradictory results. A study revealed that veterans who were administered hydroxychloroquine for treating COVID-19 showed no overall benefits in symptoms when compared to those who were not given the drug. A man from Arizona dies after taking the drug to treat his conditions, and his wife was hospitalized after having serious complications. Health agencies hence advised people not to hoard the drug irresponsibly, and also to not use the drug, alone or in combination, as a treatment or preventive measure against COVID-19, since its efficacy has not been 100% verified.
Further skepticism regarding hydroxychloroquine arose when researchers discovered that the drug poses significant health risks for severely ill patients, such as cardiac arrest. A study published in the JAMA Network Open revealed that 16 patients given the drug in a high dose had died, whereas viral RNA was found in 77.6% of patients with COVID-19 and two patients suffered from heart arrhythmias.
In a drug safety communication aimed at health care providers, the FDA stated that it was “aware of reports of serious heart rhythm problems” in patients with COVID-19 that has been given hydroxychloroquine, or an older drug known as chloroquine. The agency further said that it seeked to “remind health care professionals and patients of the known risks associated with both hydroxychloroquine and chloroquine.”
FDA Commissioner Stephen Hahn said in a statement: “We understand that health care professionals are looking for every possible treatment option for their patients and we want to ensure we’re providing them with the appropriate information needed for them to make the best medical decisions. Health care professionals should closely screen and monitor the patients who doctors decide to give the drugs to mitigate potential risks”.
Hopes for a Positive Outcome
Currently, various clinical trials are underway to assess the efficacy of hydroxychloroquine as a potential treatment in adults hospitalized with COVID-19. The main objective of all these trials, including A5395 is to establish whether a combination of hydroxychloroquine and azithromycin can help prevent hospitalization and death, while also evaluating the safety and tolerability of the treatment in people infected with SARS-CoV-2.
ACTG Chair Judith Currier, M.D., of the University of California, Los Angeles, explains: “This study will provide key data to aid responses to the COVID-19 pandemic. We are pleased to be able to leverage ACTG’s existing infrastructure for HIV treatment clinical trials to quickly implement this important study.”
Hopes are that the outcomes will definitively reveal the efficacy of both drugs in treating COVID-19, and will finally provide some relief in these anxious pandemic times.