Major Clinical Trial in Sub-Saharan Africa (ANTICOV) to Study Hydroxychloroquine & Other Repurposed Treatments Targeting Early Onset COVID-19

Major Clinical Trial in Sub-Saharan Africa (ANTICOV) to Study Hydroxychloroquine & Other Repurposed Treatments Targeting Early Onset COVID-19

An international network of research institutions and thirteen African nations have formed an alliance to conduct the largest COVID-19 clinical trial of its kind in Africa with an emphasis on investigating treatment options for mild and moderate cases at onset of infection as well as prevent increases in hospitalization that could stretch already challenged African health delivery systems. Now the ANTICOV consortium, consisting of 19 trial site organizations in 13 countries includes 26 recognized global research and development (R&D) organizations, led by the Drug for Neglected Diseases initiative (DNDi), spearheads the ANTICOV study. With an emphasis on existing repurposed therapies, only two actual drugs are named as of this writing, including Hydroxychloroquine. Interestingly, the study will occur only in Sub-Saharan populations precluding all other parts of the African continent. While the developed world focuses on vaccines and advanced novel therapies (and argues about hydroxychloroquine), a new and important study focuses in on this antimalarial drug as well as other candidates, including those targeting hepatitis C and parasite infections. With the involvement of Wellcome, the study team may also look at novel translational breakthroughs associated with this adaptive platform trial. Importantly, this study reintroduces Hydroxychloroquine as a possible repurposed therapy in early onset, mild-to-moderate COVID-19 cases, albeit in Sub-Saharan Africa.

TrialSite offers a brief summary of the COVID-19 situation in Africa and introduces the players, sites and involved in the ANTICOV study.

Africa: The COVID-19 Enigma

Africa, both the world’s second most populated continent (1.35b) and the largest in total area is in many ways an enigma in relation to the topic of COVID-19. Putting the COVID-19 situation in context, the United States remains the global epicenter of the disease with over 13 million cases and approaching 270,000 deaths associated with the pathogen since the onset of the pandemic nine months ago. The European continent, including the western region of Russia, totals over 16 million cases while the Asian continent also totals over 16 million cases while nearly 11 million cases are now reported in South America.  

Africa, with about 1.4 billion inhabitants  totals  just 2.1 million cases, by far the lowest of any major continent.  Moreover the COVID-19 clusters in Africa occur either in Arabic-North Africa, the eastern Horn of Africa or South Africa.    Sub-Saharan Africa records incredibly low COVFD-19 infection and death rates that have perplexed global experts. Yet this is exactly where the ATICOV study will occur.

A recent study reported in the BBC summarized, “The case-fatality ratio (CFR) for COVID-19 in Africa is lower than the global CFR, suggesting the outcomes have been less severe among African populations.” But why? The same BBC publication suggested the lack of COVID-19 spread could be the result of a combination of factors from the young age of the population, proactive community health to weather. After all the predictions were that, given crowding in bid cities such as Lagos, widespread poverty and challenged health systems that Africa would be devastated.

Quite the opposite has occurred as the wealthiest societies (except for in Asia) are heavily impacted while Africa, which accounts for 17% of the world’s human population represents only 3.5% of global deaths attributed to COVID-19. Some have described the gaps in many predications as “staggering.”

Some scholars have a more controversial but nonetheless intriguing rationale. For example, Claire Nieri Wamae suggests in “Mass Drug Administration and Worms Experience in Africa: Envisage Repurposing Ivermectin for SARS-COV-2” that “the large-scale annual mass drug administration for preventive chemotherapy of neglected tropical diseases may be contributing to keeping COVID-19 cases in check and below projections in Africa.”

Whatever the cause for this significant trend, it certainly should be a topic for intense public health study.

ANTICOV Study Rationale

Although, overall, African nations have thus far limited SARS-CoV-2 infection and death rates, leaders there aren’t taking anything for granted. Hence, Dr. John Knkengasong, Director of the Africa Centres for Disease Control and Prevention, commented recently, “There is a need for large clinical trials in Africa for COVID-19 to answer research questions that are specific to the African context.”

As mentioned previously, the ANTICOV study will occur only in Sub-Saharan nations that to date have very low rates of COVID-19 infection.

He continued, “African countries have mounted an impressive response so far to COVID-19 and now is the time to prepare for future waves of the disease. We welcome the ANTICOV trial led by African doctors because it will help answer one of our most pressing questions: With limited intensive care facilities in Africa, can we treat people for COVID-19 earlier and stop our hospitals from   being overwhelmed.”

What is an Adaptive platform clinical trial?

ANTICOV is an adaptive platform clinical trial meaning that the study team can modify or change study (e.g. add, continue, or stop) treatment arms based on the unfolding results. As it turns out, ANTICOV is much more than simply a platform for testing existing approved therapies for repurpose potential but also a dynamic program to possibly introduce experimental, early-stage research that could be efficacious for treatment of mild-to-moderate COVD-19.  These therapies are not disclosed in preliminary disclosures but the sponsors commit to a highly transparent study.  TrialSite most certainly will help the world know more about this truly important clinical trial.

What organization is leading this consortium?

Although positioned in their recent news release as a coordinator of the study, Drugs for Neglected Diseases initiative (DNDi) appears to be fully spearheading the ANTICOV clinical trial effort. An international not-for-profit research and development organization, they emphasize their focus on discovery, development, and delivery of treatments for neglected patients worldwide. More on this organization is included below. 

Why focus on treatments given imminent vaccine approvals?

The announcement of well performing vaccine candidates in both the West (Moderna, Pfizer/BioNTech and AstraZeneca), Russia (Sputnik V) and China (Sinopharm, Sinovac and CanSino Biologics) doesn’t immediately guarantee a conclusion to the pandemic anytime soon.

As DNDi highlights via their website, a number of factors justify comprehensive research into potential low cost, available treatments for early onset COVID-19. From difficulty accessing quality vaccine product due to the potential for vaccine nationalism to raw market forces (e.g. wealthier nations buying up supply), to the scientific consensus that a combination of vaccines, therapies and diagnostics are needed to fully overcome the pandemic, the ANTICOV organizers recognize the importance for economical, widely available treatment for onset, mild-to-moderate COVID-19 cases. In fact, TrialSite has been part of a growing movement of physicians in the United States emphasizing the importance of this topic—that is adequate focus on low cost and available therapies for early stage mild-to-moderate COVID-19.

Why focus a large study in low-and moderate-income countries?

DNDi explains in their Frequently Asked Questions that the vast majority of COVID-19 clinical trials now occur in wealthy societies such as the United States, Europe and East Asia. The healthcare infrastructure, pool of scientific and medical professional talent and health system conditions are all things being equal, markedly different than in Sub-Saharan Africa. 

For example, the access to critical infrastructure in case of a COVID-19 pandemic spike in this region of the world would be less than in the United States or Europe for example. That is access to ventilators and supplemental oxygen, for instance, is considerably limited. Hence, healthcare systems and hospitals in African seek ways to inhibit virus progression to preclude large demand for such advanced medical care infrastructure. 

Why organize a large study in Africa given the limited COVID-19 impact thus far?

The leadership of DNDi declares there is no room for complacency when it comes to COVID-19 vigilance. Just because there are limited cases today doesn’t mean that won’t change tomorrow. Most studies in wealthy nations have focused on vaccines and new drugs for severe COVID-19 cases. Given the constraints already mentioned in many African nations the importance of identifying repurposed drugs that can be used to treat mild to moderate, early onset COVID-19 cannot be emphasized enough.

What drugs are DNDi and the ANTICOV Consortium targeting for the ANTICOV trial?

According to the DNDi website (FAQ), drugs such as Hydroxychloroquine and lopinavir/ritonavir in mild to moderate cases will be explored. Of course, the former drug has been the center of controversy in the West (U.S. and Europe) and the latter hasn’t fared well in existing trials.

The sponsors declare that this adaptive trial includes the flexibility to add therapies based on accumulation of evidence for mild-to-moderate cases. Leveraging the accumulating knowledge derived from Access to COVID-19 Tools Accelerator (ACT-A) Therapeutics Partnership (co-convened by Unitaid and Wellcome Trust (Wellcome) on behalf of the COVID-19 Therapeutics Accelerator), the study team will consider a number of therapeutic targets currently used to treat malaria, hepatitis C, parasitic infections and select cancers. The study team is striving to add more study arms in weeks.

Interestingly, despite the accumulating evidence for the use of ivermectin, at least for research purposes, there is no mention of this drug already widely in use in Africa to address parasitic-based illness. However, ivermectin is an anti-parasitic drug and that category is identified as a potential class of drug used.

No other drugs are named by DNDi; however, they do highlight a close collaboration with Unitaid-led Access to COVID-19 Tools Accelerator (ACT-A) and its Therapeutic Partnership, convened by Wellcome on behalf of the COVID-19 Therapeutics Accelerator. Note this group is funded by the Bill & Melinda Gates Foundation, Wellcome Trust and Mastercard.

Doesn’t the use of Hydroxychloroquine conflict with the WHO SOLIDARITY Trial Findings?

No. As will be noted below, the ANTICOV study has been designed to align with, and even compliment, World Health Organization studies such as the SOLIDARITY Trial. But given the tensions involving the use of Hydroxychloroquine to treat COVID-19 in the developed world, the SOLIDARITY Trial dropped the use of this anti-malarial drug. However, in their FAQ, DNDi highlights that SOLIDARITY was focused on moderate-to-severe hospitalized cases with an emphasis on reducing the mortality rate. In this case, the sponsors will use Hydroxychloroquine, among other drugs yet to be named, to explore efficacy earlier in disease onset.

This may come as interesting news for many physicians in the United States and Europe that have called for use of Hydroxychloroquine, the drug emphasized by U.S. POTUS as a potentially important drug for early onset administration prior to hospitalization. It would appear that ANTICOV concurs as DNDi declares, “The ANTICOV study is tackling the problem earlier, looking at solutions that would prevent mild and moderate cases from becoming severe. Patients in the ANTICOV trial whose symptoms become severe will be referred to the SOLIDARITY trial if relevant and appropriate.”

Are the sponsors looking at novel drugs too?

Yes. Interestingly, the UK’s Wellcome is actively engaged with DNDi and its partners to “design and implement a translational platform for mild and moderate COVID-19 that aims to identify promising new chemical entities and transition successful candidates into clinical trials.” In fact, it would appear that ANTICOV’s adaptive nature opens it up for considerable introduction of translational research activity, possibly opening the study up to a number of what could be promising earlier stage therapeutics.

What is the study size?

The open-label, randomized comparative and ‘adaptive platform trial’ will offer a platform for sponsors (and collaborators) to investigate the safety and efficacy of treatments in 2,000 to 3,000 mild-to-moderate COVID-19 patients in Burkina Faso, Cameroon, Côte d’Ivoire, the Democratic Republic of Congo (DRC), Equatorial Guinea, Ethiopia, Ghana, Guinea, Kenya, Mali, Mozambique, Sudan, and Uganda. The study sponsors seek to identify early stage treatments that can inhibit and completely block the progression of COVID-19 to severe progression hence avoiding the death rates that have occurred in places like the United States.

Alignment with World Health Organization

DNDi reports that the ANTICOV study is aligned with the World Health Organization R&D Blueprint, representing an agenda involving continuous effective coordination and collaboration between scientists and global health professionals to accelerate research and development while introducing new standards and norms for ongoing advancement in the fight against COVID-19.

Who is funding the ANTICOV study?

∙         German Federal Ministry of Education and Research (BMBF) via KfW

∙         Unitaid (a global health agency as part of ACT-A)

∙         European & Developing Countries Clinical Trials Partnership (EDCTP)—contributed early funding via its second program supported by the EU

∙         Swedish government

∙         Starr International Foundation (Switzerland)

What parties formerly reviewed the study protocol?

African Vaccine Regulatory Forum (AVAREF)—established by WHO in 2006

DNDi Background

With a diverse global team employing 250 staff and consultants, DNDi is led by Executive Director Bernard Pécoul and is based in Geneva Switzerland, with offices in Brazil, the Democratic Republic of Congo, India, Japan, Kenya, Malaysia, South Africa, and an affiliate in America.

Formed back in 2003, DNDi develops new treatments for neglected diseases. The organization, injected with seed funding by Médecins Sans Frontieres, was originally set up and funded by both research and health institutions including organizations in Brazil (Oswaldo Cruz Foundation), India (Indian Council of Medical Research), Kenya (Kenya Medical Research Institute), Malaysia (Ministry of Health of Malaysia) and Pasteur Institute in France. The World Health Organization Special Program for Research and Training in Tropical Diseases (TDR) has served a research observer. 

Who are the members in the ANTICOV consortium?

The ANTICOV consortium is mobilizing a wide network of diverse partners with recognized experience in clinical research. The 26 members of the ANTICOV consortium are:

∙         Alliance for International Medical Action (ALIMA), France / Senegal

∙         Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), France

∙         Bahir Dar University, Ethiopia

∙         Barcelona Institute for Global Health (ISGlobal), Spain

∙         Bernhard-Nocht-Institut für Tropenmedizin (BNITM), Germany

∙         Centre Muraz, Institut National de Santé Publique, Burkina Faso

∙         Centre for Research in Therapeutic Sciences, Kenya

∙         Centro de Investigação em Saúde de Manhiça, Mozambique

∙         Centro de Investigação e Treino em Saúde da Polana Caniço (CISPOC), Instituto Nacional de Saúde, Mozambique

∙         Centre Pasteur du Cameroun (CPC), Cameroon

∙         Centre Pour Le Développement Des Vaccins, Ministry of Health, Mali

∙         Centre Suisse de Recherches Scientifiques (CSRS), Côte d’Ivoire

∙         Drugs for Neglected Diseases initiative (DNDi), Switzerland – (coordinating partner)

∙         Epicentre, France

∙         Foundation for Innovative New Diagnostics (FIND), Switzerland

∙         Ifakara Health Institute, Tanzania

∙         Infectious Diseases Data Observatory (IDDO), United Kingdom

∙         Institute of Endemic Diseases, University of Khartoum, Sudan

∙         Institute of Tropical Medicine, Antwerp (ITM), Belgium

∙         Institut National de Recherche Biomédicale (INRB), Democratic Republic of Congo

∙         The Kenya Medical Research Institute (KEMRI), Kenya

∙         Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Ghana

∙         Medicines for Malaria Venture (MMV), Switzerland

∙         Swiss Tropical and Public Health Institute (Swiss TPH), Switzerland

∙         Université de Bordeaux – Institut National de la Santé et de la Recherche Médicale (INSERM), France

∙         University of Gondar, Ethiopia

Responses

  1. It’s great to see this focus on practical solutions. While the approach is commendable the key is to include promising therapeutics supported by early evidence which are both safe and affordable. The one drug that most convincingly checks all these boxes is Ivermectin. I think that including lopinavir/ritonavir is a waste of their time and effort. If they are going to include HCQ it should be combined with Bromhexine for it’s synergistic TMPRSS2 inhibition. This combination has shown extremely potent antiviral properties against SARS-CoV-2 in multiple in vitro studies in human epithelial cells and not just VERO cells which lack TMPRSS2. HCQ+Bromhexine have also shown very promising results against Covid-19 in small RCTs.

    Other promising therapeutics that could be investigated are ciclesonide (ICS), ARBs, SSRIs, Nitazoxanide, Melatonin, aspirin, Colchicine, among others. I wish them success in their investigations and hopefully they will prevail where other much better funded agencies have failed i.e. the NIH.

  2. It is admittedly only in small letters… but ivermectin is seen here as the reason there are so few cases and deaths from SARs Covid-19.
    Eventually this study may well find that if everyone took 12 mg of ivermectin (and some zinc and doxycycline if they already have Covid-19) EARLY , then there would be very few cases to deal with… I think .