LAY SUMMARY
Formal title: Comparing drug-regimens for clearing parasites in Phase IIb trial designs prior to PCR monitoring for Plasmodium falciparum infection

Lay Title: A study to compare how three different anti-malarial drug regimens can clear parasites from the blood.

What is the background?
Malaria is a leading cause of illness and deaths in Africa. A malaria vaccine is therefore still a high priority for malaria control in Kenya as well as other African countries.
We want vaccines to protect children, but for reasons of safety prefer to test them in adults first.  Adults in Kenya and other African countries are usually immune to malaria.  This immunity prevents them from becoming unwell, but even though healthy adults do not become unwell they nevertheless have low levels of malaria parasites in their blood.

In order to find out if new malaria vaccines are working, scientists can use the following design after recruiting adults as trial participants; a) treating the trial participants with anti-malarials so as to clear any parasites that may be present in blood, b) administering the experimental vaccine, then c) following the trial participants with repeated blood tests to look for low-level malaria infections.  If the vaccine is working well it should be able to prevent new malaria infections.

This study aims at determining the best anti-malarial drug regimen that will be used in these trials to clear parasites before carrying out tests to check if a vaccine is preventing one from acquiring new infections. We will therefore not administer any vaccine in this trial, since we are only interested in the correct choice of drug at this stage.  

In this study, we shall divide the participants into three groups and compare the groups so as to find out which anti-malarial regimen clears all malaria parasites in the blood fastest and doesn’t have many side-effects. The anti-malarial drugs that we will use in this trial have already been approved for use. People will be divided into the groups using a system based on chance without any preference, such that everyone has the same chance of being in either group. We hope to include 90 healthy adults (men and women) with 30 in each malaria treatment group.

What questions are we trying to answer?

We wish to compare the ability of 3 different anti-malarial treatments to clear malaria parasites in the blood without persisting in the body after completion of treatment. We also wish to assess the side effects associated with the various anti-malarial treatments so as to find the one with the least side effects.

Where is the study taking place, how many people does it involve, and how are they selected?  

The study will be done in Kilifi district and will involve 90 healthy adult male and female volunteers aged between 18 and 50 years.
 

What does the study involve for those who are in it?  
Following attainment of all the necessary approvals (Scientific, Ethical and Regulatory), community engagement process will begin with contact with the district health management team then other local administrative and community leaders within the catchment area. Public meetings will then be arranged in the study villages to inform the communities of the planned study then individuals will be invited to the informed consent process.

Those willing to take part will have a health check to ensure they can take part in the study which will also include a 15ml venous blood sample. Those recruited into the study will be divided into 3 groups and will receive anti-malrial treatment as follows strating from day 0(day of enrollment); 1) Atovaquone/proguanil + Artesunate (3 days) 2) Artesunate (7 days) or 3) S/P + Artesunate + Primaquine. The clinic attendances will range from 27 to 30 depending on whether one will be on a 3 day or 7 day anti-malarial course clinic attendances will be a total of 25 blood sampling occasions. After enrollment, blood samples will be taken as follows; 3 times a week for 4 weeks, followed by twice weekly for 3 weeks and finally once weekly for 6 weeks. All these blood samples will be 1ml in volume except on day 44 and day 90 when a 5ml blood sample will be drawn.

There shall be a field worker home visit in the course of the study to assess bed net usage. Pregnant and lactating women will be excluded from this trial. A pregnancy test will be done during screening, on the day of enrollment (day 0) and on day 7. This is because some anti-malarial drugs are not safe during pregnancy. It is however safe to become pregnant after the completion of the anti-malarial treatment.

What are the benefits and risks of the study for those involved?  
No direct payments will be gained from participating in this study.
Participants will receive medical care for acute illness from the day of the first dose of vaccine until the completion of the study at no cost. This study will involve taking time off work and travel costs for participants. Participants will however be compensated for their time spent off their routine work to be in this study, for each clinic visit at a level commensurate with the lost wages as well as travel costs.
 
As with any other medication, some side effects may be seen with this malaria medication. These include nausea and vomiting, abdominal pain, headache and loss of appetite. One of the anti-malarials in this trial is known to decrease the amount of blood in the body for those whose liver is not able to break it down. However, we shall test all volunteers prior to administering the anti-malarial drugs and will not administer this anti-malarial to anyone whose liver is not able to break it down as well as not enrol anyone with abnormal liver function.
There may be some pain and bruising associated with blood drawing which will resolve after a few days. There is a small risk of infection. This risk is minimized by use of pre packaged sterile equipment and trained staff.
 How will the study benefit society?
This study is justified by the high incidence of malaria mortality and morbidity in Kenya and the rest of sub-Saharan Africa. While other malaria control measures are in place, they are still not able to eliminate malaria. A vaccine may provide that last effort to malaria control.  Anti-malarial drugs may be used in various malaria vaccine trials to clear parasites before assessing if one is acquiring new infections after vaccination.

When does the study start and finish?
This study is planned to start early in the 3rd quarter of 2013 and will run for 6 months.

 

Malaria transmission has been on the decline in some parts of Africa in association with scaling up of malaria control measures such as bed-nets and anti-malarials. However, transmission still persists and it appears that additional control measures including vaccination are required. The leading malaria vaccine candidate in development is RTS,S which has efficacy against clinical malaria measured at 30-50% in the field. This partial protection might be enhanced by combination with other components. The other vaccination approach that has produced repeatable efficacy in humans is the use of viral vectors to induce T cell responses.

The field trials required to test malaria vaccines require large sample sizes and are laborious and time-consuming. Previous studies have relied on blood films to diagnose infection, but Polymerase Chain Reaction (PCR) based technology is considerably more sensitive, and therefore may reduce the sample size and period of monitoring required.   The first such trial was conducted in the Gambia. Adult subjects were recruited, treated with curative anti-malarials, and then followed up by daily finger-prick blood testing to identify the first episode of PCR-measured parasitaemia. Subjects given anti-malarial vaccine were compared with control subjects, and were less frequently parasitaemic as measured by PCR.

We have recently repeated a similar trial design in Kenya (SSC no.2116) PPB/ECCT/11/12/02. Although the statistical analysis has remained blinded to vaccine allocation since data cleaning is incomplete, our examination of blinded data without reference to vaccination status gives cause for concern for two reasons; a) there are a substantial number of positives remaining after anti-malarials (i.e. atovaquone/proguanil and artesunate) were given (17%, compared with 60% prior to giving anti-malarials), and there are very few positive PCR results after drug clearance, and the majority are at low levels.

We therefore propose a phase IIb trial design study that aims at determining the best anti-malarial drug regimen that will be used in future malaria vaccine trials to clear parasites before carrying out tests to check if a malaria vaccine is preventing one from acquiring new infections. We will therefore not administer any vaccine in this trial, since we are only interested in the correct choice of drug at this stage. 90 healthy adults (both male and female) will be recruited for this purpose in Kilifi district.