The Principle study, led by Oxford University, will compare patients treated with anti-parasitic drug ivermectin against those receiving standard NHS care.
Ivermectin has become controversial after being used to treat Covid in some countries without large studies showing efficacy against the disease.
There is so far “little evidence… to demonstrate that it can speed up recovery from the illness or reduce hospital admission” in large-scale randomised studies, researchers said.
Professor Chris Butler, from Oxford University’s Nuffield Department of Primary Care Health Sciences, said the study will aim to produce “robust” evidence as to its efficacy.
He said: “Ivermectin is readily available globally, has been in wide use for many other infectious conditions so it’s a well-known medicine with a good safety profile, and because of the early promising results in some studies it is already being widely used to treat Covid-19 in several countries.
“By including ivermectin in a large-scale trial like Principle, we hope to generate robust evidence to determine how effective the treatment is against Covid-19, and whether there are benefits or harms associated with its use.”
Ivermectin is the seventh drug to be tested in a wider study of potential Covid treatments.
Over 65s, or those over 18 with certain underlying conditions or shortness of breath, can join the trial up to two weeks after symptoms or a positive test.
Participants will be given a three-day course of treatment and then followed-up for 28 days.
Dr Stephen Griffin Associate Professor at Leeds University School of Medicine, said the Principle trial should provide a “final answer” to questions over ivermectin.
He cautioned that while the drug has been shown to kill viruses in laboratory petri dishes, this has been in much higher doses than would normally be given to humans.
He said: “There are numerous studies and meta analyses supporting the use of ivermectin for Covid therapy, yet there are no supportive RCTs [randomised controlled trials] and many other small studies showing no benefit, including a recent paper in the Lancet."
A well-conducted RCT would be “welcome to resolve ongoing controversy”, he said, but questioned whether this was justified by current available data.