Efficacy, safety and population pharmacokinetics of artesunate-mefloquine combination for the treatment of uncomplicated falciparum malaria in African children versus artemether-lumefantrine
| ISRCTN | ISRCTN17472707 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17472707 |
| Secondary identifying numbers | DNDi-ASMQ-AF09 |
- Submission date
- 27/07/2010
- Registration date
- 26/08/2010
- Last edited
- 28/03/2017
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
We are conducting a study on a new malaria combination drug called artesunate-mefloquine. This drug will be used by sick children who are able to take the drug orally. Available information about this drug, which comes mostly from the use of this drug in East Asia and Southern American countries, indicates that the artesunate-mefloquine combination is better and safe for children. However, we need to understand more about the safety of this combination drug in the African continent, where this information is rare. It is for this reason that this study is conducted.
Who can participate?
Children aged between 6 and 59 months, either sex, with uncomplicated falciparum malaria.
What does the study involve?
Patients will be divided into two groups to ensure that each participant has an equal chance of being in either group (like a lottery). Half of the children will be given the trial drug artesunate-mefloquine (ASMQ) and the other half will be given a combination drug with a known efficacy (i.e. artemether-lumefantrine, AL) in order to be able to compare the results of the current malaria drug and the new drug. At the first visit your child will be seen by a doctor and a small amount of blood (less than a teaspoon) will be drawn from her/his hand to verify if the child has malaria parasites and to check the health status. This initial investigation will help us to know if your will be able to participate or not. Following this stage, your child will receive treatment based on the assigned group as described above. Blood from a finger prick to follow the malaria parasites will be taken every eight hours until the malaria parasites are not seen. Your child will be admitted in the ward not less than 3 days until she/he receive the last dose of malaria drug. A blood sample will be taken once again from the finger at days 1, 2, 3, 7, 14, 21, 28, 35, 42,49, 56 and 63 when the child will be brought for follow up. The doctor will see and examine your child during all these 12 visits. An extra blood sample will be taken during the investigation of your child on days 7, 28 and 63 and any other sample will be taken only if it is needed for the childs treatment. Also, on day 0 (i.e. before the first dose) and day 7, a sample will be taken from every child to test the amount of drug in the childs body, as well as the last day if the child has recurrence of parasitemia. A total of 100 children (50 in each group, ASMQ and AL) will be selected out of the 940 for follow up of drug levels in the childs body. For the 50 children in ASMQ group, four additional samples will be taken on day 0 (after the first dose), day 2 (after the third dose), day 3, and either on day 28, 35, 42, 49, 56 or 63. For the 50 patients in the AL group, two additional samples will be taken on day 3 and either on day 28, 35, 42, 49, 56 or 63. You may stay with your child during the treatment, follow-up and in all stages. The child will be in the study for a total of nine weeks. In case of recurrent parasitaemia during the efficacy follow-up period (63 days), your child will be treated with the investigational product of the other arm. For example, if your child has received Coartem he would receive ASMQ, and vice versa, and follow-up of 63 days will recommence after the day of failure in order to supervise the progression. Three visits will be performed during this follow-up: at 7, 28 and 63 days. The following assessments will be done during these three visits and any other day if you return spontaneously: blood from a finger prick to follow the malaria parasites and recording of eventual adverse effects and concomitant medications.
What are the possible benefits and risks of participating?
If you agree for your child to participate in this study, you may have the following benefits: the child will be watched closely for a period of more than six weeks and in case of any sickness during that period, she/he will be given treatment without any cost. Also, participating in this study could help to understand if the combination drug artesunate-mefloquine is better and safe for African children and this will facilitate availability of this drug in African countries where children are dying of malaria.Incentives will not be provided to persuade people to participate in this study; however, to value your time and recognize your participation in this study; we will pay the treatment costs for your child in this hospital during the study period. Moreover, you will be paid for travel costs during the follow-up days. During the time you are admitted in the ward, you will be provided with food from the hospital cafeteria and at discharge you will be given an insecticide-treated bed net. When participating in this study, there is a possibility of discomfort to your child during examination and frequent blood sampling. Also in participating in this investigation there is a possibility of increased nausea and vomiting. We will try to reduce the possibility of discomfort, and in case of any problem your child will be provided with appropriate medical care without any cost. The sponsor will have an insurance policy which will be in place prior to the start of the trial.
Where is the study run from?
1. Centre National de recherche et de Formation sur le paludisme (CNRFP), Burkina Faso.
2. NIMR, Dar Es Salaam, Tanzania.
3. NIMR Korogwe, Korogwe, Tanzania.
4. Ifakara Health Institute, Bagamoyo, Tanzania.
5. KEMRI, Nairobi, Kenya.
When is the study starting and how long is it expected to run for?
October 2010 to October 2013
Who is funding the study?
Drugs for Neglected Diseases initiative (DNDi) (Switzerland)
Who is the main contact?
Dr Sodiomon Bienvenu Sirima
Centre National de recherche et de Formation sur le paludisme (CNRFP), Burkina Faso
Contact information
Scientific
Centre National de recherche et de Formation sur le paludisme (CNRFP)
Ouagadougou
2208
Burkina Faso
Study information
| Study design | Open-label prospective randomised controlled non-inferiority multicentre clinical trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Efficacy, safety and population pharmacokinetics of artesunate-mefloquine combination for the treatment of uncomplicated falciparum malaria in African children versus artemether-lumefantrine: an open label prospective randomised controlled clinical trial |
| Study hypothesis | 1. To evaluate efficacy of artesunate-mefloquine fixed-dose combination in children with uncomplicated falciparum malaria, by determining the proportion of patients achieving a negative parasitemia without recrudescence by 63 days 2. To measure the parasite reduction ratio on Day 1, 2 and 3 3. To compare the proportion of patients with parasitaemia on Day 2 and 3 4. To compare the proportion of patients with fever on Day 2 and 3 5. To compare the gametocyte carriage at Day 2 and 3, and Day 28, 42 and 63 6. To evaluate cure rate at 28 and 42 days 7. To evaluate the population pharmacokinetics of artesunate-mefloquine and lumefantrine in under-5 children 8. To evaluate the incidence and severity of adverse events 9. To evaluate the incidence of serious adverse events and adverse events leading to treatment discontinuation 10. To analyse the time description of time course and vomiting frequency |
| Ethics approval(s) | 1. Burkina Faso: Ministry of Health approved on 07/07/2010 2. Tanzanian ERB approval on 12/07/2010, 15/05/2012 3. Tanzania Food and Drugs Authority (TFDA) approval on 24/02/2011, 02/05/2012 4. Kenyan ERB approval on 22/02/2011 5. Kenyan ECCT/PPB (Expert Committee on Clinical trials- Pharmacy and Poisons Boards) approval on 04/03/2011 |
| Condition | Malaria |
| Intervention | All patients recruited into the study will be given full, supervised treatment with either: 1. Artesunate-mefloquine (ASMQ) co-formulation (25/55 mg), administered orally for 3 consecutive days according to the following dosing schedule: 1.1. 6 to 11 months a single tablet once daily 1.2. 12 to 59 months of age, 2 tablets once daily 2. Artemether-lumefantrine (AM-LM) (Coartem® dispersible, Novartis Pharma), 6 doses at 0, 8, 24, 36, 48 and 60 hours will be administered orally to patients. Doses will be as follows: 2.1. 5 to less than 15 kg body weight (BW): 1 tablet at inclusion, again 8 hours later and then twice daily on each of the following 2 days (total course comprises 6 tablets) 2.2. 15 to less than 25 kg BW: 2 tablets at inclusion, again 8 hours later and then twice daily on each of the following 2 days (total course comprises 12 tablets) Total duration: 3 days of treatment and 60 follow-up days. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Artesunate-mefloquine, artemether-lumefantrine |
| Primary outcome measure | Cure rate as determined by polymer chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on Day 63. Treatment success or failures will be classified according to WHO Guidelines 2003. |
| Secondary outcome measures | 1. Safety, measured on day 0, 1, 2, 3, 4, 7, 14, 21, 28, 35, 42, 49, 56, 63: 1.1. Frequency of adverse events by intervention 1.2. Detailed description of time course and vomiting frequency 1.3. Frequency of serious adverse events and adverse events leading to treatment discontinuation by intervention 2. Pharmacokinetics: population pharmacokinetic parameters for artesunate (AS), its main metabolite, dihydroartemisinin (DHA), mefloquine (MQ) and lumefantrine in a sub-set of 50 randomly selected patients. Drug levels for MQ and lumefantrine will be obtained for all patients on day 0 and day 7 and correlated with clinical response. Measured on day 0, 2, 3, 7, 28, 35, 42, 49, 56, 63. Furthermore, for all patients with recurrence of parasitemia, a blood sample will be collected on the day of failure, in order to know the drug level at that specific time point. |
| Overall study start date | 01/10/2010 |
| Overall study end date | 01/10/2013 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 6 Months |
| Upper age limit | 59 Months |
| Sex | Both |
| Target number of participants | 940 |
| Participant inclusion criteria | 1. Aged between 6 to 59 months, either sex 2. Presence of acute uncomplicated P. falciparum mono-infection confirmed by: 2.1. Axillary temperature greater than 37.5°C, and 2.2. Positive microscopy of P. falciparum with parasite density between 2,000 and 200,000 asexual parasites/µl 3. Written informed consent from parent/guardian |
| Participant exclusion criteria | 1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 2. Weight less than 5 kg 3. Inability to tolerate oral medication (presence of any of the following danger signs: unable to drink or breastfeed, severe vomiting, recent history of convulsions, lethargic or unconscious state, unable to sit or stand up) 4. Mixed Plasmodium infection 5. Presence of febrile conditions caused by diseases other than malaria 6. Known history of hypersensitivity, allergic or serious adverse reactions to mefloquine, quinine, quinidine, artesunate or other artemisinins 7. History of use of any anti-malarial agent within 2 weeks prior to start of the study (except mefloquine and piperaquine within 4 weeks) 8. Prior participation in a therapeutic trial within 3 months |
| Recruitment start date | 01/10/2010 |
| Recruitment end date | 01/10/2013 |
Locations
Countries of recruitment
- Burkina Faso
- Kenya
- Tanzania
Study participating centres
2208
Burkina Faso
PO Box 3436
Kalenga Street
Plot 582 Upanga
Dar Es Salaam
-
Tanzania
PO Box 20778 00200
Nairobi
-
Kenya
Korogwe
-
Tanzania
ASMQ Clinical Trial
PO Box 74
Bagamoyo
-
Tanzania
Sponsor information
Research organisation
15 chemin Louis Dunant
Geneva
1202
Switzerland
| Website | http://www.dndi.org |
|---|---|
"ROR" |
https://ror.org/022mz6y25 |
Funders
Funder type
Research organisation
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/10/2016 | Yes | No |
Editorial Notes
28/03/2017: Internal review.
21/07/2016: Publication reference added.
15/08/2013: The overall trial end date was changed from 31/12/2012 to 01/10/2013.
12/06/2012: The overall trial end date was changed from 31/12/2011 to 31/12/2012.
