Ten thousand adults and children are being enrolled in a large clinical study across seven sites in four African countries to test the safety of the newly-registered anti-malarial drug Eurartesim, according to scientists at the Dodowa Health Research Centre (DHRC).
Under the drug trial, a subset of 1,000 adults and children, recruited into the study, would further be subjected to rigorous medical scrutiny, in what is known as a nested trial, by examining their blood samples, testing organs like the liver, kidney and heart functions after receiving doses of the drug, to ensure that the anti-malarial drug is properly evaluated for the safe treatment of uncomplicated malaria.
The Eurartesim drug trial is part of the 4-year INDEPTH Effectiveness and Safety Studies (I N E S S), which is currently gathering information and practical evidence in Ghana, Burkina Faso, Tanzania and Mozambique for policy decisions to be based on scientific assessment of the effectiveness and safety of new or alternative post-registered anti- malarial drugs in real life settings.
Eurartesim is a fixed-dose combination product composed of dihydroartemisinin and piperaquine phosphate (DHA-PQP) for the treatment of uncomplicated plasmodium falciparum malaria, and is already registered in Ghana.
It is an artemisinin-based combination therapy (ACT) produced by the Italian drug company, Sigma-Tau Group and Medicines for Malaria Venture (MMV) and has received approval from the European Medicines Agency (EMA). In Ghana, the Eurartesim trial is taking place in the Health and Demographic Surveillance Sites at the Dodowa, Kintampo and Navrongo health research centres.
During the initial phase of the INESS project, artesunate-amodiaquine(ASAQ) and artemether-lumefantrine (ALu) were evaluated in Ghana and Tanzania after administering the drugs on patients confirmed with malaria, who were then followed up.
Currently in Ghana, three anti-malarials have been approved as first-line drugs for treating malaria and these are artesunate-amodiaquine, artesunate-lumefantrine and dihydroartemisinin-piperaquine, which, under the brand name Eurartesim, is now being tested in the INESS project.
However, unlike previous studies on ASAQ and ALu, the Eurartesim study has two arms of investigations. The first is the general study, where the study participants in this group would just be followed after taking the drug to gather safety information on them while the second is the nested group, involving the intensive examination of the study participants, in what closely looks like trials undertaken in a phase 3 clinical study of a drug.
Mr Richard Afedi Nagai, Eurartesim Study Coordinator at the DHRC of the Shai-Osudoku district of the Greater Accra region, said the study begins with the recruitment process at the health facilities' Out-Patient Department centres, when a patient walks in for treatment.
He said the patient would have to be a confirmed case of malaria either through the use of rapid diagnostic tests (RDTs) or microscopy.
After obtaining an informed consent facilitated by field workers and signed, the patient goes through screening to see if the person is still eligible.
Dr Margaret Gyapong, Director of the DHRC, said the recruitment for all the sites in the four countries was on a competitive basis, and that regardless of how many study participants are recruited by each of the sites, once the number hits the 10,000 mark required, enrolment would end across the sites.
At the nerve centre of the Eurartesim study is the laboratory, which is largely supporting the entire trial as up-to-date laboratory facilities and electrocardiogram (ECG) machines are needed to gather accurate data to evaluate how the drug performs when administered. The Shai-Osudoku District hospital in Dodowa has been designated as the only health facility equipped to specifically handle the nested study.
he other five facilities, scattered in the two districts of Shai-Osudoku and Ningo-Prampram, where the data on Eurartesim is being generated, would be involved in just the general study due to the lack of some standard laboratory equipment. All the health facilities would however use laboratory facilities and RDTs to for malaria Dr Alexander Adjei, Dodowa site Principal Investigator (PI) and Study Clinician at the Shai-Osudoku Hospital, said in an interview that as part of the study, “1,000 participants across the four countries would be closely followed for adverse drug reactions through laboratory and ECG investigation.”
The remaining 9,000 participants would be contacted on certain specific days after administering the drug to document drug completion and adverse events.
“The drug would be administered with water far away from meals, at least, three hours before or three hours after meals, to prevent the effect of the piperaquine component of the drug on the QT interval of the heart. Eurartesim could cause a life-threatening abnormality of the heart rhythm and rapid heart-beat if administered with high fat/calorie meal, hence those recruited would be advised on the three-hour rule for food and drug intake interval,” the Site PI said to clarify how the drug would be administered.
He said patients recruited in the nested group would have the “functioning of their hearts examined on the first day before taking the drug using the ECG machines and these investigations would be repeated on the third and seventh day as well. Additionally, a small amount of blood would be drawn on three different occasions to check the functioning of the participants' kidneys, liver, and presence of malaria parasites and levels of the Eurartesim drug in their blood.”
Dr Adjei explained that those enrolled in the general component would be followed and safety data collected after they take the drug to monitor drug reactions without going through the rigorous requirements in the nested investigations, just like what happens in real life situation.
“However, all study participants in both study groups would be followed for 28 days after which the patient's involvement in the study would be completed for the generation of a conclusive data.”
Dr Adjei said there were various international meetings to assess the capacities of the sites to undertake the project and to deliberate on the study protocol, regulatory requirements and standard operation procedures to carry out the study.
Among those who took part in these meetings were the INESS Principal Investigator, Prof. Fred Binka, representatives of the drug manufacturers, representatives of MMV and the site principal investigators from all the seven sites in the four countries. There are three sites in Ghana conducting the trial, one in Tanzania, two in Burkina Faso and one in Mozambique.
On matters of those qualified to take part in the study, the doctor said those with no predisposing cardiac condition for irregular heart rhythm would be admitted into the study while those to be excluded are lactating mothers, pregnant women, persons with known allergies to a component of the drug and children below six months or weighing less than 5kg.
Mrs Abigail Hammond, a nursing officer at the Shai-Osudoku district hospital said they were part of the study because they had to be on hand to help with the recruitment, screening, checking vital statistics for the eligibility of patients and administering the drug directly. Patients will be observed for some time after they receive the drug to see how they react, before they will be discharged.
Documents available indicate that there are some minor side effects of the drug and the most common ones among adults are seen in between one to 10 patients out of a 100 and these include anaemia, headache, prolongation or an alteration of the electrical activity of the heart, weakness and fever. In children, these are influenza, cough and fever.
This phase four trial of the Eurartesim drug and post- marketing phase of drug development seeks to examine the risks and benefits of new drugs in different segments of the population. Also, a phase four study, might be initiated to assess such issues as the longer-term effects of drug exposure.
A post-marketing surveillance is important because even the most well-designed phase three study might not uncover every problem that could later be discovered when a product becomes widely-used in the community.
The phase one, two and three clinical trials are carried out under controlled conditions on few patients to establish the initial safety and efficacy of such new products or drugs. However, a newly registered product might be more widely used by groups that might not have been well studied in the clinical trials and there might be reports of adverse drug reactions.