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Targeted Chemo-elimination (TCE) of Malaria (TME)

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ClinicalTrials.gov Identifier: NCT01872702
Recruitment Status : Completed
First Posted : June 7, 2013
Last Update Posted : August 10, 2017
Sponsor:
Collaborators:
Mahidol Oxford Tropical Medicine Research Unit
National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Family Health International, Cambodia
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 (LOMWRU), Laos
Shoklo Malaria Research Unit
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE June 4, 2013
First Posted Date  ICMJE June 7, 2013
Last Update Posted Date August 10, 2017
Actual Study Start Date  ICMJE April 2013
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2015)
  • 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) [ Time Frame: 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.
  • 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) [ Time Frame: 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
  • 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) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 4, 2013)
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. [ Time Frame: 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.
Change History Complete list of historical versions of study NCT01872702 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2015)
Safety and acceptability of targeted malaria elimination (1017-13 and 1015-13) [ Time Frame: 12 months ]
Safety and acceptability of targeted malaria elimination, evaluated by questionnaires filled out by participants or care givers.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2013)
Safety and acceptability of targeted malaria elimination [ Time Frame: 12 months ]
Safety and acceptability of targeted malaria elimination with dihydroartemisinin-piperaquine and low dose primaquine, evaluated by questionnaires filled out by participants or care givers.
Current Other Pre-specified Outcome Measures
 (submitted: May 8, 2017)
  • Effect on gametocyte carriage by targeted malaria elimination (1017-13 and 1015-13) [ Time Frame: 12 months ]
    Effect on gametocyte carriage by targeted malaria elimination, measured by the proportions of gametocyte carriers over the 12 month period
  • Characterize parasite carriage using highly sensitive techniques in four geographically separate sites where resistance to artemisinin has been documented (1017-13 and 1015-13) [ Time Frame: 12 months ]
    Characterize parasite carriage using by molecular analysis of parasite genotypes, markers of resistance and parasite population genetic structure
  • Acceptability of targeted Chemo-elimination of malaria measured by number of peaople participate (1017-13) [ Time Frame: 12 months ]
  • Cost estimates of targeted Chemo-elimination of malaria by sampling strategy (1017-13) [ Time Frame: 12 months ]
  • incidence of clinical malaria in the villages over the first 12 months (1015-13) [ Time Frame: 12 months ]
  • The proportion of Artemisinin resistance - P.falciparum infections (23-15) [ Time Frame: 12 months ]
  • Sensitivity of novel RDTs (HS RDT) [ Time Frame: 12 months ]
    (Laos site only)
  • Specificity of novel RDTs (HS RDT) [ Time Frame: 12 months ]
    (Laos site only)
Original Other Pre-specified Outcome Measures
 (submitted: June 4, 2013)
  • Effect on gametocyte carriage by targeted malaria elimination [ Time Frame: 12 months ]
    Effect on gametocyte carriage by targeted malaria elimination, measured by the proportions of gametocyte carriers over the 12 month period
  • Characterize parasite carriage using highly sensitive techniques in four geographically separate sites where resistance to artemisinin has been documented [ Time Frame: 12 months ]
    Characterize parasite carriage using by molecular analysis of parasite genotypes, markers of resistance and parasite population genetic structure
 
Descriptive Information
Brief Title  ICMJE Targeted Chemo-elimination (TCE) of Malaria
Official Title  ICMJE Targeted Chemo-elimination (TCE) to Eradicate Malaria in Areas of Suspected or Proven Artemisinin Resistance in Southeast Asia and South Asia
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Plasmodium Falciparum Malaria
Intervention  ICMJE 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: malaria elimination using DP and 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.

Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 4, 2013)
8000
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2017
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Exclusion criteria:

• Pregnant women in their first trimester

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Cambodia,   Lao People's Democratic Republic,   Myanmar,   Thailand,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01872702
Other Study ID Numbers  ICMJE BAKMAL1305
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • Mahidol Oxford Tropical Medicine Research Unit
  • National Centre for Parasitology, Entomology and Malaria Control, Cambodia
  • Family Health International, Cambodia
  • 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 (LOMWRU), Laos
  • Shoklo Malaria Research Unit
Investigators  ICMJE
Principal Investigator: Nicholas J White, PhD University of Oxford
PRS Account University of Oxford
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP