Efficacy and Safety of Artemether + Lumefantrine and Dihydroartemisinin + Piperaquine for the Treatment of Uncomplicated Malaria in Guinea-Bissau.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 346
- 试验地点
- 1
- 主要终点
- Adequate clinical and parasitological response rate
研究概览
简要总结
Plasmodium falciparum causes malaria and approximately 665 000 deaths each year. chloroquine and sulphadoxine-pyrimethamine resistant P. falciparum are widespread. An artemisinin derivative combined with lumefantrine, amodiaquine or piperaquine is therefore recommended for the treatment of malaria in Africa. However, artemisinin resistance appears to be developing and resistance/tolerance to amodiaquine and lumefantrine exists. We are presently conducting a study in Guinea-Bissau. Preliminary data indicates that the effectiveness and availability of artemether-lumefantrine (AL), the 1st line drug, is poor. Consequently there is a need for another treatment option. Dihydroartemisinin-piperaquine (DP) has been shown to be efficacious and well tolerated in several African countries and is therefore such an option. A clinical trial comparing the safety and efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine is therefore needed.
Parents to children seeking Bandim Health Centre (CSB) with symptoms compatible with malaria will be informed of the study. If accepting and the child fulfil the inclusion criteria, the child will be randomised to treatment with either AL or DP. The treatment will be given supervised at the health centre in the morning and the evening on day 0, day 1, and day 2.
At each visit and in the morning on day 3, the child will be examined, the mother asked for any symptoms and signs of side-effects, the temperature measured. Furthermore, a blood sample will be taken for examination of malaria parasites. On day 0 samples for measurement of antimalarial drugs and for genotyping of the parasites will be taken on filterpaper. In a subgroup of 50 children a blood sample for in vitro culturing and for analysis of the number of leucocytes will also be taken.
After having finished the treatment the children will be followed on day 7 and then once a week until day 42. At each visit the condition of the child will be examined and a bloodsample taken for examination of parasites in the blood. Furthermore, a filterpaper bloodsample will be collected for measurement of the drug concentration of if the child has recrudescence for genotyping of the parasites. On day 0, 3 and 42 the haemoglobin level will be examined.
The result of the two treatments will be evaluated by comparing the number of children with recurrent parasitaemia, both corrected and uncorrected (recrudescence vs. reinfections). This will be presented as adequate clinical and parasitological response rates PCR-corrected and PCR-uncorrected. Furthermore, the chance in haemoglobin level from day 0 till day 3 and till day 42 will be compared. The concentration of the antimalarial drug in the blood samples taken at the visit before the re-parasitaemia will be capered to the concentrations in children without re-parasitaemia.
Assuming a 20% loss to follow up a total of 346 children should be included. For the children included, health care and medications at Bandim Health Centre will be free during the study period but no other gifts or payments will be made.
Results will be presented to the staff at the Bandim health centre and the ministry of Health and will be published in an international peer reviewed journal.
详细描述
Background Plasmodium falciparum causes malaria and approximately 665 000 deaths each year. Previously chloroquine (CQ) and sulphadoxine-pyrimethamine were the principle drugs for the treatment of malaria. Due to widespread resistance to these drugs1, the World Health Organization recommends that P. falciparum in Africa should be treated with artemisinin + amodiaquine, artemether + lumefantrine (AL) or dihydroartemisinin + piperaquine2 (DP). However, resistance to artemisinins appears to be developing3,4, resistance to amodiaquine exists2 and treatment with AL rapidly selects for parasites with increased tolerance (5 times higher inhibitory concentration) to lumefantrine5-7.
In Guinea-Bissau, CQ remained efficacious until replaced by AL. This is explained by the use of a unique well tolerated high dose treatment schedule 8-10. Since the introduction of AL in 2008, the number of children with malaria has increased manyfold in Bissau in contrast with other African countries. Our data suggests that this increase is due unavailability of AL, poorer than expected effectiveness of AL and to an increased use of the second-line drug quinine. Quinine is typically given for 3 instead of 7 days and has very poor efficacy when used thus11. To counter this Guinea-Bissau needs an alternative cheap and easily dosed 2nd line drug that can also be used when AL is not available or when funding for AL no longer exists.
Dihydroartemisinin+piperaquine is a safe and well tolerated artemisinin based combination12. DP is taken once daily and has been shown to be highly efficacious (>95%) in several African settings13,14. DP also protects from re-infection for longer than AL14. As such this is a drug that could become an attractive treatment option in Guinea-Bissau. It has however, never been used in the country.
Aim Conduct an efficacy study with artemether + lumefantrine and dihydroartemisinin + piperaquine
- To measure the efficacy and safety of AL and DP in children aged 6 months to 12 years suffering from uncomplicated P. falciparum malaria.
- To determine the capacity of each drug combination to protect against re-infection.
- To differentiate recrudescence from re-infections using PCR based methods
- To determine whole blood concentrations of lumefantrine and piperaquine the week before reparasitaemia
- To determine haemoglobin values on days 0, 3 and 42
- To determine differential white blood cell counts on days 0, 3, 7, 14 and 21
- To determine genetic polymorphisms in P. falciparum causing reparasitaemia,
- To culture parasites from 50 children for further characterisation of P. falciparum geno- and phenotypes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A) Age ≥6 months, and <13 years. B) Mono-infection with P. falciparum detected by microscopy. C) Parasitemia of 1.000-200.000/µl asexual forms. D) Axillary temperature ≥37.5 ˚C or a history of fever within 24 hours. E) Ability to swallow oral medication.
- •F) Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule. G) Informed consent from a parent or guardian
排除标准
- •A) Signs or symptoms of severe malaria, incl. hyperparasitaemia (>200.000/ µl asexual forms) B) Presence of general danger signs in children under 5 C) Presence of severe malnutrition. D) Any evidence of chronic disease or acute infection other than malaria. E) Regular medication which may interfere with antimalarial pharmacokinetics. F) History of hypersensitivity reactions or contraindications to AL, DP or quinine.
- •G) Domicile outside the study area.
研究组 & 干预措施
Artemether-lumefantrine
6-dose regime will be used:
干预措施: Artemether-lumefantrine (Drug)
Dihydroartemisinin-piperaquine
A 3 dose regime will be used
干预措施: Dihydroartemisinin-piperaquine (Drug)
结局指标
主要结局
Adequate clinical and parasitological response rate
时间窗: 42 days
The data will be analysed using survival estimates of per protocol treatment failure rates but also intention to treat treatment failure rates.
次要结局
- the safety of AL and DP(42 days)