Finding out which medicines work and which ones do not work can be a tricky business – especially if you are under severe time pressure. The ideal is to compare different options in large randomised controlled trials (RCTs), preferably trials where neither the study participants or healthcare workers know who is getting which treatment.

Unfortunately, head-to-head comparisons of different treatments are not as common as one might hope. This is particularly true with drug-resistant tuberculosis (DR-TB), where two relatively new medicines of the same class, delamanid and pretomanid, have never been directly pitted against each other in a RCT. 

In the absence of clear RCT evidence, we end up having to make do with what we have. This is risky, since the evidence on a number of questions simply isn’t clear without the right RCTs. Instead, as is the case with DR-TB, we extrapolate from observational data and the few relevant RCTs we do have. In other words, without a direct comparison between delamanid and pretomanid, we instead make educated guesses about which one is safer and more effective. Ideally we will be able to avoid this kind of uncertainty with Covid-19.

How to approach Covid-19

While a Covid-19 vaccine is probably 12 to 18 months away, it is not impossible that we might find some effective drugs (ie not vaccines) before then. It is both imperative that we work quickly, but that we also make sure the evidence is solid. Trials that are too small, for example, might purely by chance create the impression that a drug is effective, when in fact it is not.

There is also a risk that, by conducting a number of small studies in different settings, we could end up with the kind of difficulties we have in DR-TB, where it is difficult to draw reliable conclusions given the differences in study settings, populations, and  methodology. This, of course, does not mean that small studies are not important. For one, they have the advantage of more rapidly reporting findings. The New England Journal of Medicine for example just published a study showing disappointing results when treating very sick Covid-19 patients with the HIV drug combination lopinavir/ritonavir. It is a study we can learn from and does not necessarily mean that the drug combination might not offer some benefit in other groups of people.

In addition to small, quick  trials, it is however important that we take steps to build an evidence-base that is as solid as possible. If one of the treatment options under consideration is clearly better than the rest, then we need to establish that as soon as possible and in as reliable a way as possible.

SOLIDARITY

This is why a just-announced trial called SOLIDARITY is exactly what is needed. SOLIDARITY is a World Health Organisation (WHO) co-ordinated RCT that will compare five treatment arms – that is to say it will generate high quality evidence on which of five treatment options are most safe and effective.

“We commend the researchers around the world who have come together to systemically evaluate experimental therapeutics,” WHO Director-General Dr Tedros Adhanom Ghebreyesus said in a briefing on Wednesday. He, however, went on to point out that “Multiple small trials with different methodologies may not give us the clear, strong evidence we need about which treatments help to save lives. WHO and its partners are therefore organizing a study in many countries in which some of these untested treatments are compared with each other. This large, international study is designed to generate the robust data we need, to show which treatments are the most effective.”

The five study arms are as follows:

• Standard of care (the current treatments being used, such as providing oxygen.)
• Remdesivir (an experimental  antiviral drug made by the pharmaceutical company Gilead)
• Lopinavir/ritonavir (A drug combination already used in South Africa to treat some people living with HIV)
• Lopinavir/ritonavir and interferon beta
• Chloroquine or hydroxychloroquine (an anti-malarial drug)

According to the WHO, SOLIDARITY is a multinational trial that will be conducted in at least 10 countries, including South Africa.

Spotlight has not yet seen the full study protocol and we do not know whether people living with HIV, pregnant women, and children will be included in the trial, nor do we know how many people will participate in the trial. We also do not yet know which hospitals in South Africa will participate in the trial and how severe people’s disease will have to be for them to be included in the study.

Either way, the WHO and everyone else involved with the trial should be commended for co-ordinating the trial so quickly and for taking this important step toward generating reliable evidence on which treatments do and do not work for Covid-19 – arguably one of the most important questions in the world today.

Note: We will publish a follow-up article with more details on the SOLIDARITY trial when we get more information. DM/MC

This article was produced by Spotlight – health journalism in the public interest.