TES Artemether-lumefantrine for Pf and Chloroquine (CQ) for Pv
TES Artemether-lumefantrine for Pf and Chloroquine (CQ) for Pv
Purpose: To assess the efficacy of the current first line of treatment policy.

 Objectives:

 To assess the safety and efficacy of Artemether-lumefantrine for the treatment of
 uncomplicated P. falciparum infections in the Philippines.

 To assess the efficacy of Artemether-lumefantrine for the treatment of P. vivax infections in
 the Philippines.

 Study Sites:

 Rural Health Unit, Bataraza, Palawan Rural Health Unit, Rizal, Palawan

 Study Design: one-arm, prospective study

 Patient Population: Febrile patients aged > 6 months to 59 years old, with confirmed
 uncomplicated P. falciparum infection only or P. vivax infection only, and non- pregnant
 and/or breastfeeding for female.

 Sample Size: A minimum of 50 and maximum of 75 patients will be enrolled for both Plasmodium
 falciparum and Plasmodium vivax malaria.

 Treatments and follow-up: Clinical and parasitological parameters will be monitored over a
 28/34 day follow-up period to evaluate drug efficacy.

 Primary endpoints: The proportion of patients with early treatment failure, late clinical
 failure, late parasitological failure or an adequate clinical and parasitological response as
 indicator of efficacy. Recrudescence will be distinguished from re-infection by polymerase
 chain reaction (PCR) analysis.

 Secondary endpoints: The frequency and nature of adverse events.

 Optional exploratory endpoints: to determine the polymorphism of molecular markers for name
 of the antimalarial drug(s) resistance.
1. BACKGROUND In 2002, the Philippines changed its antimalarial drug policy to the
 combination treatment, CQ+ Sulphadoxine-pyrimethamine (SP) as 1st-line treatment and
 artemether-lumefantrine as 2nd-line treatment. The Department of Health (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 further study on
 its efficacy were done before making it as 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 2018 drug policy, chloroquine was replaced by artemether-lumefantrine as the
 primary treatment for P. vivax (Pv) malaria, with primaquine as anti-relapse drug. The
 last TES of AL as firstline drug of choice for falciparum malaria was made in 2017 and
 this will be the first time that AL will be assessed as treatment for uncomplicated
 vivax malaria. Monitoring of antimalarial drug efficacy through molecular analysis of
 known drug resistance associated genes can also provide complementary information.
 Previous analysis of drug resistance markers for CQ, SP and artemisinin (pfcrt, pfdhps,
 pfdhfr, pfmdr1, Kelch13 for Pf, and pvcrt, pvmdr, pvdhps, pvdhfr for Pv) of Philippine
 TES samples revealed variations in genotypes that can be assessed in relation to TES
 clinical outcomes. These information are relevant baseline information that have future
 use in determining parasite lineage during post malaria-elimination status, in addition
 to the crucial monitoring for drug resistance.

 The results of this study will be used to assist the Department of Health of Philippines
 in assessing the current national treatment guidelines for uncomplicated P. falciparum
 and P. vivax malaria, and to update the policy if necessary.

 2. OBJECTIVES The general objective of this study is to assess the therapeutic efficacy and
 safety artemether-lumefantrine for the treatment of uncomplicated P. falciparum
 infections and of P. vivax infections in the Philippines.

 The primary 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
 measure the clinical and parasitological efficacy of Chloroquine among patients aged
 between > 6 months and 59 years old suffering from uncomplicated vivax 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 differentiate
 recrudescences from new infections by the Polymerase Chain Reaction (PCR) analysis;

 The secondary objectives are:

 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.

 The exploratory objective:

 To determine the polymorphism of molecular markers for artemether-lumefantrine and
 chloroquine resistance.

 3. INVESTIGATIONAL PLANNING 3.1. Study Design 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 malaria and vivax malaria. Individuals
 with uncomplicated malaria who meet the study inclusion criteria will be enrolled,
 treated on site with AL and monitored for a period of 28 days if they have falciparum
 malaria, and with chloroquine if with vivax malaria for a period of 34 days. The
 follow-up will consist of a fixed schedule of check-up visits and corresponding clinical
 and laboratory examinations. Study patients will be classified as therapeutic failures
 (early or late) or adequate responders based on the results of these assessments. The
 proportion of patients experiencing therapeutic failure during the follow-up period will
 be used to estimate the efficacy of the study drug(s). Polymerase Chain Reaction (PCR)
 analysis will help distinguish between a true recrudescence due to treatment failure and
 episodes of reinfection.

 3.2. Study site The study site will be conducted in the Rural Health Unit in selected
 municipalities of Palawan. Several factors influenced the selection of sites were:
 adequate numbers of patients with symptomatic, uncomplicated P. falciparum or P. vivax
 malaria; willingness and availability of the selected health care facility staff to
 participate in the surveillance study and to support the work with laboratory space;
 access of patients to the health facility for weekly follow-ups; availability of the
 Municipality Health Officer (MHO), the nurse and a trained Medical Technologist to take
 responsibility for conducting the study, and security.

 3.3. Timing and duration of study The study will be conducted from September 2019 to
 September 2020.

 3.4. Study population The study population will consists of patients aged between > 6
 months to 59 years old diagnosed with uncomplicated falciparum and vivax malaria
 attending the study health clinic, and having given, or whose parents or legal guardians
 have given an informed consent for study inclusion and assent in children as
 appropriate. All adult patients who are 18 years, age of majority in this country, will
 sign an informed consent form for participation. Parents or guardians will give informed
 consent on behalf of children who have not reached 18 years of age. Children aged 12 to
 17 years old will be required to consent for participation by signing an informed assent
 form.

 3.5. Inclusion criteria Above 6 months old to 59 years old;

 Mono-infection with P. falciparum or P. vivax, with parasitemia of:

 - P. falciparum: 1000-100 000 asexual forms per µl; P. vivax : ≥ 250 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 female of child-bearing potential and from their parent or
 guardian if under 18 years old.

 3.6. Exclusion criteria Presence of general danger signs among children <5 years old or
 other signs of severe and complicated falciparum malaria according to World Health
 Organization (WHO) definitions; Severe malnutrition Mixed Plasmodium species detected by
 microscopy; Presence of severe malnutrition (defined as a child whose weight-for-height
 is below -3 standard deviation or less than 70% of the median of the National Center for
 Health Statistics (NCHS)/WHO normalized reference values, or who has symmetrical oedema
 involving at least the feet or who has a Mid Upper Arm Circumference Mid-Upper arm
 circumference [MUAC] <110 mm); 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); Regular medication, which may interfere with
 antimalarial pharmacokinetics; History of hypersensitivity reactions or
 contraindications to any of the drug(s) being tested or used as alternative treatment;
 Positive pregnancy test or breastfeeding; and Unable to or unwilling to take pregnancy
 test or to use contraception for women or child-bearing age and who are sexually active.

 3.7. Loss to follow-up Loss to follow-up occurs when, despite all reasonable efforts
 within 48 hrs period of the visit, an enrolled patient that does not attend the
 scheduled visits cannot be found. No treatment outcome will be assigned to these
 patients. These patients will be classified as lost to follow-up and excluded from the
 per protocol analysis. Patients who are lost to follow-up, but who subsequently come
 back to the study site before day 28 for participants with Plasmodium falciparum and
 before day 34 for Plasmodium vivax participants, will not be turned away and will also
 be encouraged to return for check-up visits. Nevertheless, these patients will also be
 classified as lost to follow-up. Every effort must be made to schedule a follow-up visit
 for patients who fail to return to the study site especially during or but also after
 administration of the study drug.

 3.8. Patient discontinuation or protocol violation Study patients meeting any of the
 following criteria classified as withdrawn.

 Withdrawal of consent A patient may withdraw consent at any time, without prejudice for
 further follow up or treatment by the study site.

 Failure to complete the treatment due to either:

 Persistent vomiting of the treatment. A patient who vomits twice study medication will
 be withdrawn from the study and given rescue treatment.

 Failure to attend the scheduled visits during the first 3 days; Serious adverse events
 necessitating termination of the treatment before the full course of the treatment is
 completed. A patient can be discontinued from the study if the principal investigator
 decides that a patient should be withdrawn for safety reasons due to an adverse event of
 such a nature or intensity to recommend withdrawal from the study. In this case,
 information concerning the adverse event and symptomatic treatment given must be
 recorded on the case record form (CRF). If the adverse event is serious, the principal
 investigator must notify the sponsor or its designee immediately and the reporting
 procedures described in the safety section must be followed.

 Enrolment Violation Severe malaria on Day 0; Erroneous inclusion of patient who does not
 meet the inclusion criteria.

 Voluntary protocol violation Self or third party administration of antimalarial (or
 antibiotics with antimalarial activity) (see Annex 2)

 Involuntary protocol violation Severe malaria occurring on Day 0 Occurrence during the
 follow-up of concomitant disease that would interfere with a clear classification of the
 treatment outcome Detection of another malaria species during the follow-up Erroneous
 inclusion of a patient who do not meet the inclusion criteria Misclassification of a
 patient due to a laboratory error (parasitaemia) leading to the administration of the
 rescue treatment

 Patients who are withdrawn will nevertheless be follow-up until day 28 for Plasmodium
 falciparum and until day 34 for Plasmodium vivax or until recovery, if possible.
 However, no treatment outcome will be assigned to these patients and excluded from the
 per protocol analysis. The reason for discontinuation or protocol violation will always
 be recorded on the CRF.

 4. TREATMENT 4.1. Antimalarial treatment P. falciparum: artemether-lumefantrine will be
 administered for 3 days according to body weight (Days 0, 1 and 2). Correct drug dosage
 will be determined using the dosing chart (in accordance with national treatment
 guidelines, details provided in Annex 3). Primaquine 0.75 mg/kg body weight single dose
 will be given on Day 3 (in accordance with national treatment guidelines, details
 provided in Annex 3).

 P. vivax: Chloroquine will be administered according to body weight at a total dose of
 25mg base/kg over 3 days (10mg base/kg on Day 0; 10mg base/kg on Day 1 and 5mg base/kg
 on Day 2) Primaquine will be withheld for 28 days. It will be given after Day 28
 follow-up, at 0.25 mg base/kg per day for 14 days.

 Quinine, doxycycline, tetracycline, clindamycin and primaquine (15 mg base per tablet)
 as well as other anti-malarial drugs for rescue treatment will be sourced from the
 Department of Health.

 All doses of drugs including rescue treatment will be administered under the supervision
 of Municipal Health Officer and Public Health Nurse, and/ or Project Staff Nurse
 designated by the principal investigator. Study patients will be observed for 30 minutes
 after drug administration for adverse reactions or vomiting. Any patient who vomits
 during this observation period will be retreated with the same dose of drug and observed
 for an additional 30 minutes. If the patient vomits again he/she will be withdrawn and
 offered rescue therapy. The study patients will be required to return to Rural health
 unit (RHU) for each dosing dosing day.

 4.2. Concomitant treatments and forbidden medication Treatment of fever over 38 °C is
 permitted with paracetamol or acetaminophen. Parents/guardians will be instructed in the
 use of tepid sponging for children <5 years old.

 Prior treatment with antimalarial drugs will not be considered as an exclusion
 criterion. But, during the follow-up, if infections other than malaria require the
 administration of drugs with antimalarial activity, the patient will be withdrawn from
 the study. Patients given tetracycline as eye ointment will not be excluded (see Annex
 2). Similarly, patients will be withdrawn from the study in case of self-medication or
 if an antimalarial drug or antibiotics with antimalarial activity is administered by a
 third party.

 Adverse events requiring treatment will be checked and treated by the municipal heath
 officer and inform Principal Investigator within 24 hours of occurrence of the event.
 Should there be a clinical indication for any additional medication during the course of
 the study including medication given to treat an adverse event related to the study
 drug, the name of the drug, the dosage, and the date and time of administration must be
 recorded in the CRF.

 4.3. Rescue treatment If the patient vomits twice he/she will receive parenteral therapy
 with quinine at 10mg/kg bw every 8 hours for 2-3 days, followed by AL for 3 days when
 he/she can tolerate oral meds, and he/she will be withdrawn from the study.

 For any sign of severe Pf or Pv malaria, the study patient will be hospitalized and
 receive parenteral therapy with Quinine at 10mg/kg bw every 8 hours for 2-3 days,
 followed by AL for 3 days, as well as relevant supportive treatments.

 If a patient meets one of the criteria for therapeutic failure, he/she will receive oral
 Quinine at 10mg/kg bw every 8 hours for 7 days, in combination with tetracycline (250 mg
 4x/ day for 7 days), clindamycin (10 mg/kg twice a day for 7 days) or doxycycline (3
 mg/kg once a day for 7 days) for Pf patients and Pv patients + Primaquine for 14 days
 for Pv patients, according to the current national recommendations. If the patient is
 re-infected with another malaria species he/she will receive treatment according to the
 current national recommendations.

 5. Evaluation criteria Valid end-points of the study include completion of the follow-up
 period without treatment failure, treatment failure, and loss to follow-up, and
 withdrawal from study (voluntary or involuntary, and voluntary or involuntary protocol
 violation). At all times, the well-being of the study patient will take priority over
 the continuation of the involvement of that patient in the study.

 5.1. Efficacy and safety evaluation 5.1.1. Classification of treatment outcomes The
 classification of treatment outcomes will be based on an assessment of the
 parasitological and clinical outcome of antimalarial treatment according to the latest
 guidelines of WHO. Accordingly, all patients will be classified as having an Early
 Treatment Failure, a Late Clinical Failure, a Late Parasitological Failure, or an
 Adequate Clinical and Parasitological Response, as defined in Annex 4.

 As parasitological cure is the goal of antimalarial therapy, all study subjects who
 present with a treatment failure will be treated with the rescue treatment and dropped
 from further follow-up.

 5.2. Clinical evaluations

 Clinical evaluations will be undertaken in all patients using the following parameters:

 5.2.1. Physical Examination A standard physical examination will be performed at
 baseline (Day 0 pre-dose) as well as on days 1, 2, 3, 7, 14, 21, 28. A complete medical
 history, demography and location of contact address and details will be taken at
 baseline.

 5.2.2. Weighing and presence of edema Body weight will be recorded at day 0. Weight will
 be measured at to the nearest kg on a Salter scale or some other hanging scale for
 weighing young children properly calibrated with only undergarments kept on the patient.
 The screening weight will be used to satisfy the inclusion/exclusion for nutrition
 status as well as to calculate the dose (number of tablets) to be administered. The
 reliability of scales will be verified using known standard weights prior to
 commencement of study and will be checked at regular intervals.

 MUAC will be measured on the left arm, at the mid-point between the elbow and the
 shoulder and will be recorded to the nearest 0.2 cm. Edema will be assessed by thumb
 pressure for 3 seconds on the dorsal part of both feet.

 5.2.3. Measurement of body temperature Axillary temperature will be performed at
 baseline (Day 0 pre-dose) as well as on Days 1, 2, 3, 7, 14, 21,and 28. Temperature will
 be measured using a thermometer with a precision of 0.1°C. Temperature will additionally
 be measured as clinically indicated. If the result is <36.0°C, the measurement will be
 repeated.

 Quality of temperature-taking technique and thermometers should be regularly tested in a
 water-bath of known temperature prior to study commencement and at regular intervals
 during study.

 5.2.4. Microscopic blood examination A pair of Giemsa-stained thick and thin blood films
 will be obtained from each patient and examined at a magnification of 1000x to identify
 parasite species and to determine the level of parasitemia at screening on Day 0 to
 confirm inclusion/exclusion criteria. Thick and thin blood films will be also examined
 on Days 1, 2, 3, 7, 14, 21 and 28 or on any other day if the patient spontaneously
 returns and parasitological reassessment is required. Specimens will be labelled
 anonymously (study number, day of follow-up, date taken). The other pair of blood film
 will be kept in a separate box as back-up blood films. The study number of the patient,
 the date and day of follow-up will be recorded on the frosted edge of the slide.

 The second blood smear (Days 0, 1, 2, 3, 7, 14, 21, and 28,) will be used to calculate
 the parasite density, by counting the number of asexual parasites in a set number of
 white blood cells (typically 200) with a hand tally counter. Once a field has been
 started, it must be counted to completion; the final number of white blood cells will
 therefore rarely be exactly 200. If more than 500 parasites have been counted before 200
 white blood cells have been reached, the count will be stopped after the reading of the
 last field has been completed. Parasite density, expressed as the number of asexual
 parasites per µl of blood, will be calculated by dividing the number of asexual
 parasites by the number of white blood cells counted and then multiplying by an assumed
 white blood cell density (typically 6000 per µl).

 The same technique will be used to establish the parasite count on each subsequent blood
 film. When the number of asexual parasites is less than 100 per 200 white blood cells in
 follow-up smears, counting will be done against at least 500 white blood cells (i.e. to
 completion of the field in which the 500th white blood cell is counted).

 5.2.5. Genotyping of malaria parasites In order to differentiate a recrudescence (same
 parasite strain) from a newly acquired infection (different parasite strain), a
 genotypic analysis based on the extensive genetic diversity displayed by the malaria
 parasite genes, msp1, msp2 and glurp will be performed. Genotypic profiles of the pre-
 and post parasite strains will be compared.

 5.2.6. Pregnancy test Female patients of child-bearing age (≥ 12 years), defined as
 those who menstruate and who are sexually active, will be asked to take a urine
 pregnancy test before enrolment in the study, because name of the antimalarial drug(s)
 or drug combination(s) is contraindicated during the first trimester. They will also be
 asked to take a urine pregnancy test on day 28 or on early withdrawal from the study.

 5.2.7. Haematological assessment Hemoglobin will be determined at Day 0, Day 3, Day 7,
 Day 14 (optional) follow-up among patients enrolled in the Pf study and on Day 0, Day 3,
 Day 7, Day 14 (optional), Day 28, Day 31, and Day 34 among enrolled Pv patients using
 the Hemocue method, requiring 60 ul from a finger-prick blood sample.

 5.3. Safety assessment Safety will be assessed by recording the nature and incidence of
 adverse events and serious adverse events. Adverse events will be assessed by direct
 questioning. An adverse event is defined as any unfavourable, unintended sign, symptom,
 syndrome or disease that develops or worsens with the use of a medicinal product,
 regardless of whether it is related to the medicinal product. All adverse events must be
 recorded on the case report form.

 6. STUDY ASSESSMENTS 6.1. Screening and enrolment procedures All patients meeting the basic
 enrolment criteria (age, fever or history of fever, presence of symptoms of malaria,
 absence of signs of severe malaria, absence of severe malnutrition, pregnancy, etc)
 during the screening procedure will be assigned a consecutive screening number and
 evaluated in greater depth by clinical staff. Special care will be taken to detect the
 presence or early signs of febrile diseases other than malaria, as these will probably
 necessitate exclusion of the patient from the evaluation. Among paediatric populations,
 the most frequent confounding condition is lower respiratory tract infections: cough or
 difficult breathing, together with fast breathing, is an indicator for identifying and
 excluding patients suffering from such conditions. Fast breathing is defined as a
 respiratory frequency >50/minute in infants under 12 months of age and >40/minute in
 children aged 12-59 months. Other relatively common febrile conditions are otitis media,
 tonsillitis, measles and abscesses. Patients with these conditions will not be enrolled,
 but obviously need to be treated both for malaria (if they have parasitaemia) and the
 other infection as appropriate. Patients will be screened and enrolled at the Rural
 Health Unit and required to return for follow-up visits.

 6.2. Follow-up procedure Patients meeting all enrolment criteria will be given a
 personal identification number and receive treatment only after they have had the study
 fully explained to them and have willingly provided their informed consent. Any subject
 who decides not to participate in the study will be examined and treated by the health
 facility staff as usual. They will be treated and followed-up according to the standard
 of care established by the Department of Health.

 The day that the patient is enrolled and receives the first dose of drugs is designated
 as "day 0". All antimalarial treatment will be given by a study team member under
 supervision. Enrolled patients will be observed for at least 30 minutes after treatment
 to ensure that they do not vomit the medicine. If vomiting occurs within 30 minutes of
 treatment, the full treatment dose will be repeated. Ancillary treatments, such as
 antipyretics, may be required and will be provided to patients by the study team and
 documented on the CRF. Patients with persistent vomiting (i.e. necessitating more than a
 single repeat dose) will be excluded from the study and immediately referred to the
 health facility staff for appropriate management.

 7. DATA MANAGEMENT The principal investigator will ensure that the study protocol is
 strictly adhered to throughout, and that all data are collected and recorded correctly
 on the CRF. Laboratory and clinical data will be recorded on a daily basis in the CRF
 designed for the study. Data that are derived from source documents should be consistent
 with the source documents or the discrepancies should be explained. Any change or
 correction to a CRF should be dated, and explained and should not obscure the original
 entry. All CRF will be checked for completeness.

 After the study has been completed, data will be entered onto a database using double
 independent data entry. The data will be stored in a computer database maintaining
 confidentiality in accordance with the national data legislation.

 The principal investigator is responsible for keeping all the screening forms, the CRF
 and the completed subject identification code list in a secure location.

 8. STATISTICAL METHODS 8.1. Minimum sample size Treatment failure to AL in the area being
 0-5 %, 5% has been chosen as the estimated therapeutic failure rate of the drug. At a
 confidence level of 95% and with a precision around the estimate of 10%, 18 patients
 will be needed. With a 20% increase to allow losses to follow-up and withdrawals during
 the 28-day follow-up period, 22 patients need to be included. But in order for the
 sample to be representative, a minimum of 50 P. falciparum and 50 P.vivax patients need
 to be included and maximum of 75 patients for both P. falciparum and P. vivax will be
 enrolled.

 8.2. Analysis of data The Epidemiology-information (EPI-INFO) 6.0 software from USA and
 Excel sheet program (designed from WHO Headquarter [HQ] for monitoring P. falciparum and
 P.vivax resistance to antimalarial drugs) will be used for data entry, management and
 analysis. Data will be analysed by two methods: the Kaplan-Meier method and per-protocol
 analysis (including those who were withdrawn from the study or who were lost to
 follow-up). In addition to the reasons for withdrawal listed in section 3.8, patients
 will be considered withdrawn from the analysis if the PCR results are unclassifiable or
 if the results of PCR indicate that the failure is due to reinfection with P.
 falciparum.

 The final analysis will include:

 The description of all the patients screened as well as the distribution of the reasons
 for non-inclusion in the study The description of all the patients included in the study
 The proportion and/or percentage of adverse events and serious adverse events for all
 the patients included in the study The proportion and/or percentage of patients who are
 lost to follow-up or withdrawn with 95% confidence intervals and a list of reasons for
 exclusion The proportion and/or percentage of Early treatment failure (ETF), late
 clinical failure (LCF) and late parasitological failure (LPF) and adequate clinical
 parasitological failure (ACPR) on day 28 with 95% confidence intervals using both
 methods of analysis Guidelines on calculating the cumulative success or failure rate,
 the proportion of adequate clinical and parasitological response and treatment failure
 are given in Annex 9.

 8.3. Dissemination of results At the end of the study, the principal investigator will
 submit a report on the study and the main outcome. This report will be shared with the
 National Malaria Program of Department of Health, Philippines and will allow to
 formulate recommendations and enable to make informed decisions about whether the
 current national anti-malarial treatment guidelines should be updated.

 The patient data will be included in the global database. The results will also be
 presented during the scientific meeting and also be disseminated to the study sites.

 8.4. Amendments to the protocol Before the study, official approval to conduct the study
 will be obtained from RITM institutional review board. After the protocol has been
 accepted, no change may be made without the agreement of the principal investigator, the
 sponsor(s), and the Institutional Review Board (IRB).

 9. ETHICAL CONSIDERATIONS 9.1. Approval by the national ethical committee Prior to the
 study, official approval to conduct the study will be obtained from Research Institute
 for Tropical Medicine Institutional and Ethical Review Board.

 9.2. Patient Information Sheet and Informed consent Inclusion in the study will occur only if
 the patient or the parent/guardian of the child gives an informed consent and informed assent
 from any minor participant aged 12 - 17 years. The consent request, available in English and
 Tagalog, will be read entirely to the patient or the parents/guardians. The Patient
 Information Sheet, available in English and in Tagalog, showing the details about the trial
 and its benefits and potential risks will be explained, and after answering to any potential
 questions, signature on the document will be requested (Annex10). If the patient is
 illiterate, a literate witness must sign (if possible, this person will be selected by the
 participant and will have no connection to the research team). The principal investigator
 must also obtain the assent of children over the age of 12 years, but their assent should
 normally be completed by the permission of a parent or guardian.

 9.3. Confidentiality All information regarding the patients will remain confidential within
 the study team. Unique numerical identifiers will be used for the computer-based data entry
 and blood samples. In all cases, principal investigator will seek to ensure that screening
 forms, CRF and completed subject identification code list are kept in locked files.

 9.4. Health care services Free health care during the duration of the follow-up for illness
 related to malaria will be provided to the study patients regardless of treatment outcome;
 this includes any necessary expenses related with hospital admission and to adverse drug
 reactions, if required.

 When prospective or actual subjects are found to have diseases unrelated to malaria, the
 principal investigator should advise them to obtain, or refer them for medical care.

 Any subject who decides not to participate or cannot be enrolled in the study because they do
 not meet the criteria, will be referred to the health facility staff. They will be treated
 with and followed-up according to the standard of care established by the Department of
 Health. The principal investigator must ensure that this antimalarial drug is available at
 the health center. If a patient is withdrawn from the study before the full course of the
 treatment is completed, the physician must make all necessary arrangements to provide the
 patient with the full dose of the drug currently tested or with a full course of Quinine
 10mg/kg bw every 8 hours for 7 days, as recommended by the national policy.
Inclusion Criteria:

 -  Above 6 months old to 59 years old;

 -  Mono-infection with P. falciparum or P. vivax, with parasitemia of: P. falciparum:
 1000-100 000 asexual forms per µl; P. vivax : ≥ 250 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 female of child-bearing potential and from their
 parent or guardian if under 18 years old.

 Exclusion Criteria:

 -  Severe malnutrition

 -  Mixed Plasmodium species detected by microscopy;

 -  Presence of severe malnutrition (defined as a child whose weight-for-height is below
 -3 standard deviation or less than 70% of the median of the NCHS/WHO normalized
 reference values, or who has symmetrical oedema involving at least the feet or who has
 a Mid Upper Arm Circumference [MUAC] <110 mm);

 -  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);

 -  Regular medication, which may interfere with antimalarial pharmacokinetics;

 -  History of hypersensitivity reactions or contraindications to any of the drug(s) being
 tested or used as alternative treatment;

 -  Positive pregnancy test or breastfeeding; and

 -  Unable to or unwilling to take pregnancy test or to use contraception for women or
 child-bearing age and who are sexually active.