Study evaluating BA of Atoguanil against Malarone in healthy adults
Research type
Research Study
Full title
A randomised, open label 2-period crossover study to evaluate the relative bioavailability of Atoguanil compared to Malarone® in healthy adult participants in the fed state
IRAS ID
295503
Contact name
Ulrike Lorch
Contact email
Sponsor organisation
Medicines for Malaria Venture
Eudract number
2021-003422-69
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 2 months, 30 days
Research summary
Summary of Research
We are conducting a clinical trial with the already licensed medication Malarone® (a fixed combination of atovaquone (ATV) and proguanil (PG)) and the investigational medication Atoguanil (a complex of ATV and PG free base) that has shown approximately 2-fold higher ATV oral bioavailability compared to Malarone®, in rabbits.As recommended by WHO, Seasonal Malaria Chemoprevention (SMC) is given to children to prevent/treat malaria, in high risk areas in Africa. Resistance is growing against the current medications used, so new combinations are required. Malarone® is a suitable candidate but is not economically viable. Atoguanil is expected to be as efficacious as Malarone® but is potentially more economically viable due to the reduction in ATV dose.
The main aim of the trial is to establish whether the pharmacokinetic profile of both ATV and PG from Atoguanil is similar to that of Malarone® and whether exposure of ATV from Atoguanil indicates that at least a 2-fold reduction in ATV dose compared with Malarone® is feasible. Further aims include determining the safety/tolerability of Atoguanil and further documenting the safety/tolerability of Malarone®.
This trial is an open label, randomised, 2-period, 2-treatment balanced crossover design. In Period 1, 16 participants will be randomised to one of two treatments in a 1:1 ratio, and to the alternative treatment in Period 2.
• Treatment 1: one single dose of Atoguanil (ATV 500mg + PG 348mg), as 4 tablets.
• Treatment 2: one single dose of Malarone® (ATV 1000mg + PG 400mg), as 4 tablets.In each period, participants will be admitted on Day -1, dosed on Day 1, and discharged on Day 4. There will be outpatient visits on Days 8, 15, and 22 after each period.
We will assess safety parameters including physical examination, vital signs, laboratory evaluations, electrocardiograms, and monitoring of adverse events.
Summary of Results
Malaria is an infectious disease that causes a number of symptoms, including fever and headache, and in severe cases, can progress to coma and death. It is caused by a parasite from the Plasmodium family that is transmitted to people via the bite of a certain type of mosquito (Anopheles mosquito).Malarone® is used for the treatment and prophylaxis of malaria, and Atoguanil is formulated in a way that aims to make it as effective as Malarone®, but at lower dose. Atoguanil breaks down into atovaquone (ATV) and proguanil (PG), which are the same components of Malarone®. PG is broken down further in the body into another compound known as cycloguanil (CG). This is the first time Atoguanil was given to humans.
The main aim of this clinical trial was to assess how much of Atoguanil and Malarone® enters the blood stream and how long they remain in the body by measuring levels of their breakdown products, ATV, PG and CG (i.e., pharmacokinetics). This after a single oral dose of Atoguanil as compared to a single oral dose of Malarone® is given to healthy participants under fed conditions.
This will enable the planning of larger clinical trials to assess if Atoguanil is a more affordable alternative to Malarone® for prevention of malaria.
Another aim was to assess the safety and tolerability of Atoguanil and Malarone®.
This trial was conducted in a specialised early phase Clinical Pharmacology Unit with onsite resuscitation equipment and medication, in addition to access to an acute hospital with Critical Care facilities, thus ensuring direct access to equipment and staff for resuscitating and stabilising participants in acute medical conditions and emergencies. The trial was conducted by an experienced PI and well trained medical and technical staff with ample experience in the conduct of early phase clinical trials.
The trial was designed to closely monitor, treat and communicate potential expected adverse reactions (to the drug) as well as potential unexpected adverse events (side effects)Male and female participants of any race and aged between 18 and 55 years, considered healthy for their age, were invited to participate in the trial. 16 participants were enrolled into the study having met all the inclusion criteria and none of the exclusion criteria of the protocol.
Every participant in this trial received a single dose of Atoguanil and a single dose of Malarone®, with a minimum 24-day washout period between each dose.
• Eight participants (Treatment group 1) received Atoguanil in Period 1 and Malarone® in Period 2.
• Eight participants (Treatment group 2) receive Malarone® in Period 1 and Atoguanil in Period 2.The gender composition of the 2 Treatment groups was uneven although overall the same number of males as females took part.
• Treatment group 1: males (5); females (3)
• Treatment group 2: females (5) and males (3)The study took approximately 11 weeks for each participant to complete.
During the course of the study, no participant suffered any adverse event of special interest or serious adverse events, and all participants completed the study.
No concerns were observed with laboratory, electrocardiogram or vital sign recordings and all changes were both transient and reported to be non-clinically significant. Overall, the safety profile for Atoguanil was both acceptable and comparable to that of Malarone® during the trial.
The relative bioavailability (amount of drug measured in the blood versus another drug) of Atovaquone in Atoguanil compared to Malarone®, when both drugs were administered in the fed state was as follows:
• When measuring the highest concentration of the drug in the blood = 93.6%
• When measuring for the extent of exposure to the drug = 77.8%.
To demonstrate equivalence between Atoguanil compared to Malarone®, the range the results should be is between 80% - 125%, and for the highest concentration of the drug in the blood, this was achieved. As the dose of Atovaquone in Atoguanil was half that which was administered in the reference treatment, Malarone®, these data indicate that there is an improvement in bioavailability of Atovaquone in the Atoguanil tablet.
It is still to be determined if these results will lead to further study of Atoguanil as a more affordable alternative to Malarone® for prevention of malaria.After completion of the study and analysis of safety and pharmacogenetic data, it was decided not to analyse blood samples for any genetic variations between participants that may have impacted the way medicines are processed in the body.
REC name
London - London Bridge Research Ethics Committee
REC reference
21/LO/0488
Date of REC Opinion
1 Oct 2021
REC opinion
Favourable Opinion