TME: Targeted Chemo-elimination (TCE) of Malaria

Sponsor
University of Oxford (Other)
Overall Status
Completed
CT.gov ID
NCT01872702
Collaborator
Mahidol Oxford Tropical Medicine Research Unit (Other), National Centre for Parasitology, Entomology and Malaria Control, Cambodia (Other), FHI 360 (Other), Oxford University Clinical Research Unit, Vietnam (Other), National Malaria Control Program, Vietnam (Other), Myanmar Oxford Clinical Research Unit (Other), National Malaria Control Program, Myanmar (Other), Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit (Other), Shoklo Malaria Research Unit (Other)
8,000
5
2
51
1600
31.4

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
  • Drug: malaria elimination using DP and low-dose primaquine
N/A

Detailed 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
8000 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Targeted Chemo-elimination (TCE) to Eradicate Malaria in Areas of Suspected or Proven Artemisinin Resistance in Southeast Asia and South Asia
Actual Study Start Date :
Apr 1, 2013
Actual Primary Completion Date :
Jul 1, 2017
Actual Study Completion Date :
Jul 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: malaria elimination using DP and low-dose primaquine

Two villages randomly allocated to intervention (chemo-elimination) at each of the 4 sites (population approximately 500 people in each village). In these villages the entire population will be invited to receive three, monthly rounds of treatment with dihydroartemisinin-piperaquine and primaqunine to kill malaria parasites. The micro-epidemiology of malaria will be studied and prevalence and patterns of transmission used for comparison. NB, in Cambodia there will be no intervention villages and all four villages will be used to study the micro-epidemiology of malaria transmission in the absence of malaria elimination.

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.
Other Names:
  • Three monthly rounds of:
  • Dihydroartemisinin-piperaquine
  • Low-dose primaquine
  • No Intervention: Control villages

    Two villages randomly allocated to control (no chemo-elimination) at each of the 4 sites (population approximately 500 people in each village). In these villages only the micro-epidemiology of malaria will be studied and prevalence and patterns of transmission used for comparison. NB, in Cambodia there will be no intervention villages and all four villages will be used to study the micro-epidemiology of malaria transmission in the absence of malaria elimination. From June 2013 to June 2014 Cambodia site conducted surveys with no medical intervention (treatment arm). In July 2015 Cambodia implemented the TCE protocol with two intervention and two control villages. Primaquine is not used in the TCE treatment regimen in Cambodia. Both studies were approved under OxTREC reference no. 1017-13 and 1015-13.

    Outcome Measures

    Primary Outcome Measures

    1. 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) [12 months]

      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.

    2. 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) [12 months]

      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

    3. 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) [4 months]

      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.

    Secondary Outcome Measures

    1. Safety and acceptability of targeted malaria elimination (1017-13 and 1015-13) [12 months]

      Safety and acceptability of targeted malaria elimination, evaluated by questionnaires filled out by participants or care givers.

    Other Outcome Measures

    1. Effect on gametocyte carriage by targeted malaria elimination (1017-13 and 1015-13) [12 months]

      Effect on gametocyte carriage by targeted malaria elimination, measured by the proportions of gametocyte carriers over the 12 month period

    2. Characterize parasite carriage using highly sensitive techniques in four geographically separate sites where resistance to artemisinin has been documented (1017-13 and 1015-13) [12 months]

      Characterize parasite carriage using by molecular analysis of parasite genotypes, markers of resistance and parasite population genetic structure

    3. Acceptability of targeted Chemo-elimination of malaria measured by number of peaople participate (1017-13) [12 months]

    4. Cost estimates of targeted Chemo-elimination of malaria by sampling strategy (1017-13) [12 months]

    5. incidence of clinical malaria in the villages over the first 12 months (1015-13) [12 months]

    6. The proportion of Artemisinin resistance - P.falciparum infections (23-15) [12 months]

    7. Sensitivity of novel RDTs (HS RDT) [12 months]

      (Laos site only)

    8. Specificity of novel RDTs (HS RDT) [12 months]

      (Laos site only)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    6 Months and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes

    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pailin Pailin Cambodia 372
    2 Savannakhet Savannakhet Lao People's Democratic Republic
    3 Mahidol Oxford Clincal Research Unit, Myanmar Rangoon Myanmar
    4 Shoklo Malaria Research Unit Mae Sot Tak Thailand
    5 Oxford University Clinical Research Unit - Vietnam Ho Chi Minh city Vietnam Ward 1, District 5

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Nicholas J White, PhD, University of Oxford

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    University of Oxford
    ClinicalTrials.gov Identifier:
    NCT01872702
    Other Study ID Numbers:
    • BAKMAL1305
    First Posted:
    Jun 7, 2013
    Last Update Posted:
    Aug 28, 2020
    Last Verified:
    Aug 1, 2017

    Study Results

    No Results Posted as of Aug 28, 2020