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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2015 by University of Oxford
Sponsor:
Collaborators:
Mahidol Oxford Tropical Medicine Research Unit (MORU), Thailand
Shoklo Malaria Research Unit (SMRU), Thailand
National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Family Health International, Cambodia
Oxford University Clinical Research Unit (OUCRU), Vietnam
National Malaria Control Program, Vietnam
Myanmar Oxford Clinical Research Unit (MOCRU), Myanmar
National Malaria Control Program, Myanmar
Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit (LOMWRU), Laos
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01872702
First received: June 4, 2013
Last updated: December 22, 2015
Last verified: December 2015
  Purpose

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 Intervention
Plasmodium Falciparum Malaria
Drug: malaria elimination using DP and low-dose primaquine

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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:
  • Safety and acceptability of targeted malaria elimination (1017-13 and 1015-13) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Safety and acceptability of targeted malaria elimination, evaluated by questionnaires filled out by participants or care givers.


Other Outcome Measures:
  • Effect on gametocyte carriage by targeted malaria elimination (1017-13 and 1015-13) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Cost estimates of targeted Chemo-elimination of malaria by sampling strategy (1017-13) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • incidence of clinical malaria in the villages over the first 12 months (1015-13) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • The proportion of Artemisinin resistance - P.falciparum infections (23-15) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 8000
Study Start Date: April 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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 (qPCR) 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.

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.

  Eligibility

Ages Eligible for Study:   6 Months and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01872702

Contacts
Contact: Nicholas J White, PhD +66 (0)22036333 nickwdt@tropmedres.ac
Contact: Arjen Dondorp, PhD +66 (0)22036333 arjen@tropmedres.ac

Locations
Cambodia
Pailin Recruiting
Pailin, Cambodia, 372
Contact: Rupam Tripura, MD    +66 857795804    Rupam@tropmedres.ac   
Contact: Chea Nguon, MD    +855 12532946.    cheanguon@yahoo.com   
Principal Investigator: Char Meng Chuor, MD         
Principal Investigator: Chea Nguon, MD         
Sub-Investigator: Rupam Tripura, MD         
Sub-Investigator: Song Ngak         
Lao People's Democratic Republic
Savannakhet Recruiting
Savannakhet, Lao People's Democratic Republic
Contact: Mayfong Mayxay, MD         
Contact: Paul Newton, MD PhD         
Myanmar
Mahidol Oxford Clincal Research Unit, Myanmar Recruiting
Rangoon, Myanmar
Contact: Kyaw Myo Tun, MD         
Contact: Frank Smithuis         
Principal Investigator: Frank Smithuis, MD         
Thailand
Shoklo Malaria Research Unit Recruiting
Mae Sot, Tak, Thailand
Contact: Francois Nosten, PhD       francois@tropmedres.ac   
Contact: Khin M Lwin, MD         
Principal Investigator: Francois Nosten, PhD         
Vietnam
Oxford University Clinical Research Unit - Vietnam Recruiting
Ho Chi Minh city, Vietnam, Ward 1, District 5
Contact: Tran Tinh Hien, PhD    +84 (8) 3923 7954    hientt@oucru.org   
Principal Investigator: Tran T Hien, PhD         
Sponsors and Collaborators
University of Oxford
Mahidol Oxford Tropical Medicine Research Unit (MORU), Thailand
Shoklo Malaria Research Unit (SMRU), Thailand
National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Family Health International, Cambodia
Oxford University Clinical Research Unit (OUCRU), Vietnam
National Malaria Control Program, Vietnam
Myanmar Oxford Clinical Research Unit (MOCRU), Myanmar
National Malaria Control Program, Myanmar
Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit (LOMWRU), Laos
Investigators
Principal Investigator: Nicholas J White, PhD University of Oxford
  More Information

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT01872702     History of Changes
Other Study ID Numbers: BAKMAL1305 
Study First Received: June 4, 2013
Last Updated: December 22, 2015
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University of Oxford:
Malaria elimination
Chemotherapy
Epidemiology
South East Asia
Artemisinin resistance
Dihydroartemisinin piperaquine
Primaquine

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Primaquine
Piperaquine
Artemisinins
Dihydroartemisinin
Artemisinine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on December 02, 2016