Targeted Chemo-elimination (TCE) of Malaria

Plasmodium Falciparum Malaria Clinical Trial

— TME  

Official title:

Targeted Chemo-elimination (TCE) to Eradicate Malaria in Areas of Suspected or Proven Artemisinin Resistance in Southeast Asia and South Asia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01872702
• Other study ID #: BAKMAL1305
• Status: Completed
• Phase: N/A
• Start date: April 2013
• Est. completion date: July 2017

Study information

• Verified date: August 2017
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The overall aim of this study is two fold:

1. to pilot targeted chemo-elimination of plasmodium falciparum malaria in known areas of artemisinin resistance in South East Asia.

2. to understand the micro-epidemiology of malaria in these areas; chiefly, the prevalence and importance to on-going transmission of sub-clinical p.f malaria infections.

Description:

The spread of artemisinin resistance in Plasmodium falciparum, which compromises the therapeutic efficacy of artemisinin combination treatments (ACTs), is the greatest threat to current global initiatives to control and eliminate malaria and is considered the highest priority of the WHO Global Malaria Programme. If not eliminated, resistant parasites could spread across Asia to Africa, as happened with resistance to other antimalarials in the past.

Conventional descriptions of the epidemiology of malaria in low transmission settings suggest that malaria prevalences are low (<10%) and heterogeneous. Most or all infections are thought to be symptomatic so the focus of malaria control activities is on the identification and treatment of symptomatic individuals. We and others have shown recently that artemisinin resistant P. falciparum is prevalent in Western Cambodia, and that it is now also found along the Thailand-Myanmar border and Vietnam. We have recently developed highly sensitive quantitative PCR (uPCR) methods for parasite detection using >1mL of blood which are 5,000 times more sensitive than conventional microscopy, and 100 times more sensitive than currently used PCR.

We have studied villages along the Thai-Myanmar border which are typical for the region and are classified by conventional epidemiological techniques as low-transmission (5-20% malaria prevalence). Our studies suggest that the majority of the population is infected. In Pailin, Western Cambodia, in areas where the National Malaria Control Programme and WHO believe that malaria has been all but eliminated, we have also found very high rates (>80%) of sub-microscopic parasitaemia in patients with fever or history of fever who are RDT negative. Thus, there is a lot more asymptomatic malaria in low transmission settings than previously thought, suggesting that control and elimination activities need to be rethought.

Highly sensitive quantitative PCR (uPCR) requires a venous blood sample, a laboratory which can perform vacuum DNA extraction, and on average four weeks for processing. A rapid highly sensitive diagnostic test which can be performed at the point of care would be a technological breakthrough. Screening with highly sensitive RDTs and treating of asymptomatic carriers will have a range of public health applications. Such tests are becoming available in 2017 and will be evaluated side by side with uPCR.

This study is designed to conduct and evaluate the efficacy of pilot implementation of targeted chemo-elimination in selected areas with the goal of eliminating malaria in these regions. This differs from mass drug administration (MDA); it is a strategy used to identify specific areas where mass treatment is necessary, in this case to eliminate all malaria parasites. Elimination will be targeted at communities with significant levels of subclinical infection and transmission which will be identifiable in the future by comparing rates of positivity by RDT or microscopy from new population samples against our qPCR data, which shows the true falciparum prevalence.

The study will assess the feasibility, safety and acceptability of this strategy and its impact on the transmission of malaria and the progression of artemisinin resistance. In addition it will evaluate the contribution of low parasitaemia carriage to transmission of artemisinin resistant malaria. These pilot studies are a necessary prelude to future scale up and policy implementation.

Dihydroartemisinin-piperaquine (DP) is a highly efficacious and inexpensive ACT which is well tolerated by all age groups when used to treat uncomplicated multi-drug resistant falciparum malaria in South East Asia. Monthly DP treatments have proved highly effective and well tolerated. When used as part of a MDA strategy, the addition of a gametocytocidal drug contributes towards the goal of malaria elimination by adding a strong transmission blocking activity to the regimen. Primaquine (PQ), the only currently licensed 8-aminoquinoline, is relatively safe and very effective when used at a dose of 0.25 mg base/kg, and does not require G6PD screening. Thus, we propose to evaluate the potential of this strategy to eliminatie malaria focally in areas where artemisinin resistance in P. falciparum is prevalent using DP plus PQ.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8000
• Est. completion date: July 2017
• Est. primary completion date: July 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Months and older

Eligibility

OxTREC reference: 1017-13

Inclusion Criteria:

• Age =6 months, male or female,

• Written informed consent (by parent/guardian in case of children)

Exclusion Criteria:

• Pregnant women will not receive primaquine (urine pregnancy tests will be performed on women of appropriate age groups before drug administration at each TCE round)

• History of allergy or known contraindication to artemisinins, piperaquine or PQ

• Those who are, in the opinion of the study clinician, ill at the time of drug administration

OxTREC reference: 1015-13

Inclusion Criteria

• Age =6 months, male or female,

• Written informed consent (by legally acceptable representative in case of children)

• Healthy at the time of the survey or drug administration

• Not pregnant

Exclusion Criteria

• Significant non-compliance with study requirements

• Loss to follow up

• Suspected severe adverse events

• Severe illness

OxTREC reference: 23-15

Part 1. qPCR survey for identification of potential TMT villages;

Inclusion criteria:

• Males and females 18 and above

• Written informed consent

Exclusion criteria:

• Pregnant women in their first trimester

• Presence of any acute severe illness at the time of survey

Part 2. TMT villages will be given directly observed therapy (DOT) with DP for 3 days and PQ (0.25 mg/kg) will be given on day 1

Inclusion criteria for TMT

• Age =one year, male and female,

• Willing to provide consent for those 18 years and above. For children 10-18 years old, parents/guardians must provide consent, and the children must provide assent. For children below 10 years old, the parents/guardians must provide consent.

Exclusion criteria for TMT

• History of allergy or known contraindication to artemisinins, piperaquine or PQ.

• Refusal of treatment.

• Pregnant women in their 1st trimester.

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Plasmodium Falciparum Malaria

Intervention

Drug:
• malaria elimination using DP and low-dose primaquine
Treatment of all persons resident in the intervention villages including those who do not have malaria parasites as detected by rapid diagnostic test. This is to interrupt p.f malaria transmission by removing the reservoir of all potentially infectious people from the area.

Locations

Country	Name	City	State
Cambodia	Pailin	Pailin
Lao People's Democratic Republic	Savannakhet	Savannakhet
Myanmar	Mahidol Oxford Clincal Research Unit, Myanmar	Rangoon
Thailand	Shoklo Malaria Research Unit	Mae Sot	Tak
Vietnam	Oxford University Clinical Research Unit - Vietnam	Ho Chi Minh city

Sponsors (10)

Lead Sponsor	Collaborator
University of Oxford	FHI 360, Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Mahidol Oxford Tropical Medicine Research Unit, Myanmar Oxford Clinical Research Unit, National Centre for Parasitology, Entomology and Malaria Control, Cambodia, National Malaria Control Program, Myanmar, National Malaria Control Program, Vietnam, Oxford University Clinical Research Unit, Vietnam, Shoklo Malaria Research Unit

Countries where clinical trial is conducted

Cambodia,  Lao People's Democratic Republic,  Myanmar,  Thailand,  Vietnam, 

References & Publications (11)

(2011) Global Plan for Artemisinin Resistance Containment. Geneva: World Health Organisation.

Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, Zhou C, Mao S, Anderson JM, Lindegardh N, Jiang H, Song J, Su XZ, White NJ, Dondorp AM, Anderson TJ, Fay MP, Mu J, Duong S, Fairhurst RM. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012 Nov;12(11):851-8. doi: 10.1016/S1473-3099(12)70181-0. Epub 2012 Aug 30. — View Citation

Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, Leowattana W, Hutagalung R, Wilairatana P, Brockman A, Looareesuwan S, Nosten F, White NJ. Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis. 2004 Nov 15;190(10):1773-82. Epub 2004 Oct 18. Erratum in: J Infect Dis. 2005 Apr 1;191(7):1204. — View Citation

Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ, Nosten F. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis. 2005 Aug 15;41(4):425-32. Epub 2005 Jul 15. — View Citation

Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. — View Citation

Hien TT, Thuy-Nhien NT, Phu NH, Boni MF, Thanh NV, Nha-Ca NT, Thai le H, Thai CQ, Toi PV, Thuan PD, Long le T, Dong le T, Merson L, Dolecek C, Stepniewska K, Ringwald P, White NJ, Farrar J, Wolbers M. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J. 2012 Oct 26;11:355. doi: 10.1186/1475-2875-11-355. — View Citation

Myint HY, Ashley EA, Day NP, Nosten F, White NJ. Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc Trop Med Hyg. 2007 Sep;101(9):858-66. Epub 2007 Jul 19. Review. — View Citation

Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM, Singhasivanon P, Day NP, White NJ, Anderson TJ, Nosten F. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012 May 26;379(9830):1960-6. doi: 10.1016/S0140-6736(12)60484-X. Epub 2012 Apr 5. — View Citation

Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, Lindegardh N, Singtoroj T, Ashley E, Lwin S, Stepniewska K, White NJ. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet. 2006 Jun 24;367(9528):2075-85. Erratum in: Lancet. 2017 Apr 29;389(10080):1698. — View Citation

Tran TH, Dolecek C, Pham PM, Nguyen TD, Nguyen TT, Le HT, Dong TH, Tran TT, Stepniewska K, White NJ, Farrar J. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet. 2004 Jan 3;363(9402):18-22. — View Citation

White NJ, Qiao LG, Qi G, Luzzatto L. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malar J. 2012 Dec 14;11:418. doi: 10.1186/1475-2875-11-418. Review. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Effect on gametocyte carriage by targeted malaria elimination (1017-13 and 1015-13)	Effect on gametocyte carriage by targeted malaria elimination, measured by the proportions of gametocyte carriers over the 12 month period	12 months
Other	Characterize parasite carriage using highly sensitive techniques in four geographically separate sites where resistance to artemisinin has been documented (1017-13 and 1015-13)	Characterize parasite carriage using by molecular analysis of parasite genotypes, markers of resistance and parasite population genetic structure	12 months
Other	Acceptability of targeted Chemo-elimination of malaria measured by number of peaople participate (1017-13)		12 months
Other	Cost estimates of targeted Chemo-elimination of malaria by sampling strategy (1017-13)		12 months
Other	incidence of clinical malaria in the villages over the first 12 months (1015-13)		12 months
Other	The proportion of Artemisinin resistance - P.falciparum infections (23-15)		12 months
Other	Sensitivity of novel RDTs (HS RDT)	(Laos site only)	12 months
Other	Specificity of novel RDTs (HS RDT)	(Laos site only)	12 months
Primary	prevalence of falciparum malaria measured by qPCR (quantitative real time polymerase chain reaction), 12 months after the first administration of treatment with dihydroartemisinin-piperaquine and primaquine. (1017-13 and 23-15)	Percentage falls in asymptomatic malaria prevalence in the intervention villages vs control villages, as determined by highly sensitive qPCR, 12 months after the first administration of treatment with dihydroartemisinin-piperaquine and primaquine.	12 months
Primary	prevalence of falciparum malaria measured by qPCR (quantitative real time polymerase chain reaction), 12 months after the first administration of targeted malaria elimination (1015-13)	Percentage falls in asymptomatic malaria prevalence in the intervention villages vs control villages, as determined by highly sensitive qPCR, 12 months after the first administration of treatment with dihydroartemisinin-piperaquine	12 months
Primary	prevalence of falciparum malaria measured by qPCR (quantitative real time polymerase chain reaction), 4 months after the first administration of target malaria-elimination (23-15)	Percentage falls in asymptomatic malaria prevalence in the intervention villages vs control villages, as determined by highly sensitive qPCR, 4 months after the first administration of treatment with dihydroartemisinin-piperaquine and primaquine.	4 months
Secondary	Safety and acceptability of targeted malaria elimination (1017-13 and 1015-13)	Safety and acceptability of targeted malaria elimination, evaluated by questionnaires filled out by participants or care givers.	12 months

External Links

•   The Mahidol Oxford Tropical Medicine Research Unit