TES of Artemether-lumefantrine for Pf in the Philippines in 2015

Study Overview
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Brief Summary
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Artemether-lumefantrine has been used as a first-line treatment for uncomplicated Plasmodium falciparum infection since 2009 in the Philippines. The 28 day therapeutic efficacy study was conducted between February 2015 and December 2015, in accordance with WHO guidelines in the three (3) municipalities (Bataraza, Brookes and Rizal) of Palawan. Attempt was made to include Panglima-Sugala, Tawi-Tawi; however, due to the decline in the number of malaria cases, no evaluable subject was enrolled. The study subjects were febrile individuals between > 6 months old and 59 years old with confirmed uncomplicated P. falciparum. They were treated with artemether-lumefantrine (20 mg and 120 mg, respectively) administered 3 days (Days 0, 1 and 2) according to body weight. Primaquine (0.75 mg base/kg body weight single dose) was given on Day 3. Outcomes were classified as early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR).

Detailed Description
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In 2002, the Philippines changed its antimalarial drug policy to the combination treatment, CQ+SP as 1st-line treatment and artemether-lumefantrine as 2nd-line treatment. The DOH prescribed the use of artemether-lumefantrine (AL) combination as the second-line drug, limiting its use only in the treatment of confirmed Plasmodium falciparum until a further study on its efficacy was done before making it the first-line treatment. Consequently, AL became the first-line drug for falciparum malaria in the 2009 revised drug policy. The DOH in the past 6 years (2002-2007) adopted the use of AL in the highly endemic areas of the country and conducted therapeutic efficacy studies (TES) in 3 sentinel sites: Kalinga-Isabela, Palawan, and several Mindanao provinces showing 97-100% efficacy. Whereas CQ+SP showed variability and declining efficacy, results ranged from 70%-95% (CARAGA region). In Sultan Kudarat province, results in 2006-2007 showed 90% efficacy of CQ+SP and 96% for AL for falciparum malaria. In the 2009 drug policy, chloroquine (CQ) remains the primary treatment for P. vivax malaria, with primaquine as an anti-relapse drug. Previous studies (1999-2005) elsewhere in the country have shown 100% efficacy of CQ or the CQ+PQ combination. However, in 2011, a recurrence of parasitemia was observed in one of 117 enrolled patients in Palawan. The last TES of AL as a first-line drug of choice for falciparum malaria was made in 2007. This study will update this drug's efficacy for this parasite. STUDY OBJECTIVES The general objective of this study is to assess the therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum infections in Palawan province, the Philippines in 2015. The specific objectives are: To measure the clinical and parasitological efficacy of artemether-lumefantrine (AL) among patients aged between > 6 months and 59 years old suffering from uncomplicated falciparum malaria, by determining the proportion of patients with Early Treatment Failure (ETF), Late Clinical Failure (LTF), Late Parasitological Failure (LPF), or with an Adequate Clinical and Parasitological Response (ACPR) as indicators of efficacy; To evaluate the incidence of adverse events; To formulate recommendations to enable the Department of Health to make informed decisions about the possible need for updating of the current national antimalarial treatment guidelines. MATERIALS AND METHODS. The design of this surveillance study is a one-arm, prospective evaluation of the clinical and parasitological response to directly observed treatment for uncomplicated falciparum. Individuals with uncomplicated malaria who met the study inclusion criteria were enrolled, treated on-site with AL, and monitored for a period of 28 days if they had falciparum malaria. The follow-up consisted of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. Study patients had been classified as therapeutic failures (early or late) or adequate responders based on the results of these assessments. The proportion of patients experiencing a therapeutic failure during the follow-up period had been used to estimate the efficacy of the study drug(s). Polymerase Chain Reaction (PCR) analysis will also help distinguish between a true recrudescence due to treatment failure and episodes of re-infection. Barangay Health Workers and Barangay Malaria Microscopists were mobilized to recruit febrile patients (patients with body temperature ≥37.5 °C). Screened individuals were re-examined at the main health center for malaria symptoms, body temperature, and weight. All laboratory procedures and tests were carried out by trained staff. STUDY AREA / SETTINGS. The study was conducted in the Rural Health Units (RHU) of Rizal, Bataraza, and Brookes Point. Several factors influenced the selection of sites: (a) adequate numbers of patients with symptomatic, uncomplicated P. falciparum; (b) willingness and availability of the selected healthcare facility staff to participate in the trial and to support the work with laboratory space; (c) access of patients to the health facility for weekly follow-ups; and (d) willingness of the Municipality Health Officer (MHO), the nurse and a trained Medical Technologist to take responsibility for conducting the trail, and security. An attempt was made to include Panglima-Sugala, Tawi-Tawi as a TES site. Health staff was trained in malaria microscopy and TES procedures. However, no evaluable subject was enrolled for a period of seven months. Arrangements were made to conduct a limited survey to confirm the low number of cases. In the end, it was decided that the site be closed. STUDY PARTICIPANTS. The population of interest consisted of patients aged between > 6 months to 59 years old diagnosed with uncomplicated falciparum malaria attending the study health clinic and having given, or whose parents or legal guardians had given informed consent for study inclusion and assent in children as appropriate. ETHICAL CONSIDERATIONS Participants were recruited after the study received favorable approval of the protocol, participant information sheet, and written informed consent form from RITM Institutional Review Board (IRB). The study document versions given written approval by the IRB were used. The study was carried out according to the ethical guidelines in the Declaration of Helsinki (version 2008), applicable guidelines of ICH-GCP (E6); and applicable regulations of the Department of Health, Manila. The participant's written informed consent was secured before enrolment and prior to initiating procedures specific to this study. For potential participants below 18 years old, this consent was obtained from either parent or a legally accepted guardian. An independent witness was present during the process of obtaining informed consent from a participant or parents/legal guardian who was illiterate.

Official Title
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Efficacy and Safety of Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Philippines in 2015

Conditions
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Malaria,Falciparum, Malaria Recrudescence

Intervention / Treatment
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* Drug: Artemether-lumefantrine
* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Above 6 months old to 59 years old; Mono-infection with P. falciparum (1000-100 000 asexual forms per µl) Axillary temperature ≥37.5 °C or oral/rectal temperature of ≥38 °C; Ability to swallow medication; Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; Informed consent from the patient or from a parent or legal guardian in the case of children less than 18 years old; Informed assent from any minor participant aged 12 - 17 years; and Consent for pregnancy testing from females of child-bearing potential and from their parent or guardian if under 18 years old. Exclusion Criteria: Presence of general danger signs among children <5 years old or other signs of severe and complicated falciparum malaria according to current WHO definitions Mixed Plasmodium species; Presence of severe malnutrition Presence of febrile conditions due to diseases other than malaria (measles, acute lower tract respiratory infection, severe diarrhea with dehydration, etc.), or other known underlying chronic or severe diseases (e.g. cardiac, renal, hepatic diseases, HIV/AIDS) History of hypersensitivity reactions to any of the drug(s) being tested or used as an alternative treatment.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients detected with Plasmodium falciparum (Artemether-lumefantrine)<br>Patients with mono-infection of Plasmodium falciparum with 1,000-100,000 asexual forms per µl | Drug: Artemether-lumefantrine<br>* Artemether-lumefantrine will be administered for 3 days according to body weight (Days 0 and 8 hours after, 1 and 2). Dosage depending on body weight or age if weight cannot be determined. Dosage: 1 tablet contains 20 mg artemether and 120 mg lumefantrine Dosage per weight: 1 tablet (5 to <16kg); 2 tablets (15 to <25kg); 3 tablets (25 to <35kg), 4 tablets for >35 kg) Dosage per age, if weight cannot be determined: 1 tablet (6 months old to 3 years old); 2 tablets (4 to 8 years old); 3 tablets (9-13 years old), 4 tablets (>13 years old)<br>* Other names: Coartem;Drug: Primaquine<br>* For Pf patients, primaquine at 0.75 mg base/kg body weight single dose will be given on Day 3 for Pf patients; For Pv patients primaquine will be withheld for 28 days and will be given after Day 28 follow-up, at 0.25 mg base/kg per day for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Early Treatment Failure (ETF) | The number of patients with the following criteria based on microscopy results without PCR: Development of danger signs or severe malaria on day 1, day 2, or day 3 in the presence of parasitemia; Parasitaemia on day 2 higher than day 0 count irrespective of axillary temperature; Parasitaemia on day 3 with axillary temperature ≥37.5 ºC; Parasitaemia on day 3 ≥25% of count on day 0. | Day 1-3 | 
| Number of Patients with Late Clinical Failure (LCF) | The number of patients with the following criteria based on microscopy results without PCR: Development of danger signs or severe malaria on any day from day 4 to day 28 in the presence of parasitemia, without previously meeting any of the criteria of Early Treatment Failure; Presence of parasitemia and axillary temperature ≥37.5 ºC (or history of fever in low/moderate transmission areas) on any day from day 4 to day 28, without previously meeting any of the criteria of Early Treatment Failure. | Day 4-28 | 
| Number of Patients with Late Parasitological Failure (LPF) | The number of patients with the presence of parasitemia on any day from day 7 to day 28 and axillary temperature <37.5 ºC, without previously meeting any of the criteria of Early Treatment Failure or Late Clinical Failure. | day 7 to day 28 | 
| Number of Patients with Adequate Clinical and Parasitological Response (ACPR) | The number of patients with absence of parasitemia on day 28 irrespective of axillary temperature without previously meeting any of the criteria of Early Treatment Failure or Late Clinical Failure or Late Parasitological Failure. | Day 0-28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MALARIA, TES, Plasmodium falciparum, Artemether-lumefantrine