Efficacy and Safety of Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Philippines in 2015
Conditions: Malaria,Falciparum, Malaria Recrudescence
Sponsor: Research Institute for Tropical Medicine, Philippines

2003-25-03 version date 19 July 2016 
  Title 
Efficacy and safety of artemether-lumefantrine for the treatment of 
uncomplicated Plasmodium falciparum malaria, and chloroquine for the 
treatment of Plasmodium vivax in the Philippines.  
Protocol submission date 
19 July 2016 
Protocol number 
2003-25-03 
 
Participating institutions 
 
Rural Health Unit 
Bataraza, Palawan, Philippines 
 
Rural Health Unit 
Brooke’s Point, Palawan, Philippines 
 
Rural Health Unit 
Rizal, Palawan, Philippines 
 
Study dates 
May 2013 – December 2018 
Sponsor 
Government of the Philippines 

2003-25-03 version date 19 July 2016 
Contents 
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium 
falciparum malaria, and chloroquine for the treatment of Plasmodium vivax in the Philippines. .............. 1 
1. BACKGROUND................................................................................................................................. 4 
2. OBJECTIVES ..................................................................................................................................... 5 
3. INVESTIGATIONAL PLAN .............................................................................................................. 5 
3.1. Study Design ................................................................................................................................ 5 
3.2. Study site ..................................................................................................................................... 6 
3.3. Timing and duration of study ........................................................................................................ 6 
3.4. Study population .......................................................................................................................... 6 
3.5. Inclusion criteria .......................................................................................................................... 6 
3.6. Exclusion criteria ......................................................................................................................... 6 
3.7. Loss to follow-up ......................................................................................................................... 7 
3.8. Patient discontinuation or protocol violation ................................................................................. 7 
4. TREATMENT .................................................................................................................................... 8 
4.1. Antimalarial treatment .................................................................................................................. 8 
4.2. Concomitant treatments and forbidden medication........................................................................ 8 
4.3. Rescue treatment .......................................................................................................................... 8 
5. Evaluation criteria ............................................................................................................................... 9 
5.1. Efficacy and safety evaluation ...................................................................................................... 9 
5.1.1. Classification of treatment outcomes .............................................................................. 9 
5.1.2. Safety endpoints ............................................................................................................ 9 
5.2. Clinical evaluations ...................................................................................................................... 9 
5.2.1. Physical Examination ..................................................................................................... 9 
5.2.2. Weighing and presence of edema ................................................................................... 9 
5.2.3. Measurement of body temperature ............................................................................... 10 
5.2.4. Microscopic blood examination ................................................................................... 10 
Parasite density/µl = number of parasites counted x 6000 ...................................................................... 10 
5.2.5. Genotyping of malaria parasites ................................................................................... 11 
5.2.6. Pregnancy test. ............................................................................................................. 11 
5.2.7. Haematological assessment .......................................................................................... 11 
5.2.9 Molecular markers for antimalarial drug resistance .................................................... 12 
5.2.10 Storage of unused samples ......................................................................................... 12 
5.3. Safety assessment ....................................................................................................................... 12 
6.  STUDY ASSESSMENTS ................................................................................................................ 12 
6.1. Screening and enrolment procedures .......................................................................................... 12 
6.2. Follow-up procedure .................................................................................................................. 13 
8. STATISTICAL METHODS .............................................................................................................. 15 
8.1. Minimum sample size ................................................................................................................ 15 
8.2. Analysis of data.......................................................................................................................... 15 
8.3. Dissemination of results ............................................................................................................. 16 
8.4. Amendments to the protocol ....................................................................................................... 16 
9. ETHICAL CONSIDERATIONS ....................................................................................................... 16 
9.1. Approval by the national ethical committee ................................................................................ 16 
9.2. Patient Information Sheet and Informed consent ......................................................................... 16 
9.3. Confidentiality ........................................................................................................................... 16 
9.4. Health care services .................................................................................................................... 16 
9.5 Reimbursement and Travel Compensation ................................................................................... 17 
9.6. Community ................................................................................................................................ 17 
10. TES MONITORING ....................................................................................................................... 17 
Following recommendations of the just concluded 2nd Pacific Malaria Drug Resistance Network 
Meeting held in Manila, Philippines, this TES will be monitored by identified individuals from WHO 
Representative Office, Manila and WPRO.  They will follow applicable procedures of the WHO-TDR 
clinical monitoring standard operating procedures (SOPs). .................................................................... 17 
11. REFERENCES ................................................................................................................................ 17 

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Annex 1. Definition of severe falciparum malaria .................................................................................. 18 
Annex 2. Medications (with antimalarial activity) that should not be used during the study period IN 
ADDITION TO THE STUDY DRUG(s) ............................................................................................... 19 
MAJOR SIDE-EFFECTS OF THE STUDY DRUGS ............................................................................ 19 
Annex 3. DRUG DOSAGE ................................................................................................................... 20 
Annex 4. Classification of treatment outcomes ...................................................................................... 21 
Annex 5. Case screening LOG............................................................................................................... 22 
Annex 6. Schedule of follow-up activities ............................................................................................. 23 
Appendix 7. Serious adverse event report form ...................................................................................... 25 
Appendix 8. Guidelines for analysis of results ....................................................................................... 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SYNOPSIS 
 

2003-25-03 version date 19 July 2016 
Title: Efficacy and safety of Artemether-Lumefantrine for the treatment of uncomplicated 
Plasmodium falciparum malaria and chloroquine for the treatment of Plasmodium vivax malaria in the 
Philippines. 
 
Purpose: To assess the efficacy of the current first line of treatment policy. 
 
Objectives:  
a) To assess the safety and efficacy of Artemether-lumefantrine for the treatment of 
uncomplicated P. falciparum infections in the Philippines.  
b) To assess the efficacy of Chloroquine for the treatment of P. vivax infections in the 
Philippines. 
 
Study Sites: 
a) Rural Health Unit, Bataraza, Palawan 
b) Rural Health Unit, Brooke’s Point, Palawan 
c) Rural Health Unit, Rizal, Palawan 
 
Study Period: January 2018 – December 2018 
 
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+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 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. 

2003-25-03 version date 19 July 2016 
          In the 2009 drug policy, chloroquine (CQ) remains as the primary treatment for P. vivax 
malaria, with primaquine as anti-relapse drug.  Previous studies (1999-2005) elsewhere in the country 
have shown 100% efficacy of CQ or the CQ+PQ combination.  However in 2013, recurrence of 
parasitemia was observed in one of 84 enrolled patients in Palawan.  The last TES of AL as firstline 
drug of choice for falciparum malaria was made in 2015.  This protocol will update this drug’s 
efficacy for this parasite and of that P. vivax. 
 
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 chloroquine for the 
treatment of uncomplicated 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-lumifantrine and 
chloroquine resistance. 
 
3. INVESTIGATIONAL PLAN 
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.  
 

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3.2. Study site 
The study site will be conducted in the Rural Health Units in the municipalities of Rizal, Brooke’s 
Point, and Bataraza, 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 during the malaria transmission season, from January 2018 to December 
2018.  
 
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 µl1; 
- P. vivax : ≥ 250 per µl 
• 
Axillary temperature ≥37.5 °C or oral/rectal temperature of ≥38 °C2; 
• 
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 WHO definitions (see Annex 1); 
• 
Weight under 5 kg; 
• 
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; 
                                                   
1  In areas of low-to-moderate transmission, the cut-off point is set between 1000 and 100 000 asexual forms per 
µl. 
2  When enrolment proves difficult, in particular in areas of low-to-moderate transmission, proven fever or a 
history of fever within the previous 24 h is acceptable. 

2003-25-03 version date 19 July 2016 
• 
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 
 

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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; 10 mg base/kg on Day 1 and 5 mg base/kg on Day 2). Correct 
drug dosage will be determined using the dosing chart (in accordance with national treatment 
guidelines, details provided in Annex 3). 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. 
 
Tablets of AL (Coartem™ 20/120 mg per tablet artemether/lumefantrine); chloroquine (250 mg 
base/tablet 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 will be administered under supervision by qualified staff member of the team 
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 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 may be treated according to local practice. 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. 
 
The use of herbal remedies during the course of the study should be avoided and subjects should be 
encouraged to return to the study site for treatment if they are feeling unwell in the first instance. 
However, if any herbal remedies are taken during the study, this should be captured in the CRF, in 
the section Study Medication Administration. 
 
4.3. Rescue treatment 
If the patient vomits twice the treatment 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. 

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With 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 QID x 7 days), 
clindamycin (10 mg/kg BID x 7 days) or doxycycline (3 mg/kg OD x 7 days) for Pf patients or AL 
for 3 days + 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, 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. 
 
5.1.2. Safety endpoints 
Incidence of any adverse event will be documented. All patients will be routinely asked about old 
symptoms and new symptoms emerging since previous visit during the follow-up. Where clinically 
indicated, patients will be evaluated and treated appropriately. All adverse events will be recorded on 
the CRF. Serious adverse events must be reported to the co-investigator and principal investigator.  
 
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. 
 

2003-25-03 version date 19 July 2016 
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. 
  
Giemsa stain solution will be freshly prepared at least once a day depending on the number of blood 
films being processed.  Giemsa-stained thick and thin blood films will be examined at a magnification 
of 1000x to identify parasite species (for both Pf and Pv) and determine parasite density.   
 
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). 
 
 
Parasite density/µl = number of parasites counted x 6000 
 
 
 
number of leukocytes counted 
 
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). 
 
A blood slide will be considered negative when examination of 1000 white blood cells or 100 fields 
containing at least 10 white blood cells per field reveals no asexual parasites. The presence of 
gametocytes on an enrolment or follow-up slide will be recorded, but this information will not 
contribute to basic evaluation. 
 
In addition, 100 fields of the second thick film at day 0 will be examined to exclude mixed infections; 
in case of any doubt, the thin film will be examined for confirmation. If examination of the thin film 
is not conclusive, the patient will be excluded from the analysis after complete treatment and follow-
up. 
 
To detect the presence of gametocyte, at least 1000 white blood cells should be counted. 
 
Two qualified microscopists will read all the slides independently, and parasite densities will be 
calculated by averaging the two counts. Blood smears with discordant results (differences between the 

2003-25-03 version date 19 July 2016 
two microscopists in species diagnosis, in parasite density of > 50% or in the presence of parasites) 
will be re-examined by a third, independent microscopist, and parasite density will be calculated by 
averaging the two closest counts. 
 
 
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. 
 
Two to three drops of blood will be collected on a filter paper Whatmann3 from each patient on Day 0 
and on any succeeding scheduled or un-scheduled follow-up visit where the repeat blood film shows 
the presence of asexual parasitemia (see Annex – WHO classification of response to treatment). 
 
The filter paper will be labeled anonymously (study number, Day 0 and Day of treatment failure, if 
any and date taken), kept in individual plastic bags with desiccant pouches and protected from light, 
humidity and extreme temperature until analyzed. When such room temperature conditions are not 
possible, for example in extremely humid environments where air-conditioning is not available, 
storage in a refrigerator will be considered, but great care will be taken to protect samples from frost 
and moisture. The PCR technique used will…….. be done in RITM molecular biology laboratory. 
Paired filter papers will be used for parasite DNA extraction and genotyping. All filter papers will be 
destroyed immediately after the PCR analyses have been completed, otherwise kept in safe locations 
for further research with patient’s consent. The sponsor will provide instructions to the principal 
investigator regarding shipment or destruction procedures of biological specimen collected during the 
study. 
  
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. 
Female participants of child-bearing age, defined as those who menstruate and who are sexually 
active should avoid pregnancy, preferably by using barrier contraceptive devices for the duration of 
the study. Appropriate contraceptive method (condom, pills) will be provided by the Public Health 
Nurse or study team at the time informed consent is obtained, with appropriate counselling about the 
risks of becoming pregnant and exposing the fetus to the study medicines. 
 
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 Hemacue method, requiring 60 ul from a finger-prick blood 
sample. 
 
5.2.8. Chloroquine blood assays for vivax patients 
100 ul finger prick blood samples for determining blood chloroquine levels will be collected from P. 
vivax patients at Day 0, Day 3, Day 7, Day 14, Day 21, Day 28 and day of treatment failure, if any. 
This will be blotted on filter papers (chromatography paper 31ETCHR®, Whatman), and kept in 
individual plastic bags with desiccant pouches and sealed, protected from light, humidity and extreme 
temperature. Specimens will be labelled ( Study number, day of follow-up, and day of treatment 
failure, if any, and date taken) anonymously. These will be stored in appropriate conditions and later 
sent to RITM laboratory for processing and assay. 
 

2003-25-03 version date 19 July 2016 
5.2.9 Molecular markers for antimalarial drug resistance  
Two to three drops of blood will be collected on filter paper on day 0 and day of failure to study the 
polymorphism, parasite DNA extraction and genotyping which are considered as markers of 
resistance to name of the antimalarial drug(s) or metabolite(s). The PCR technique used will…….. 
and be done in RITM molecular biology laboratory. Specimens will be labelled anonymously (study 
number, day of follow-up, date), kept in individual plastic bags with desiccant pouches and protected 
from light, humidity and extreme temperature until analysed. 
 
5.2.10 Storage of unused samples  
All samples will be destroyed immediately after the analyses have been completed, otherwise kept in 
safe locations for further research with patient’s consent.  
 
 
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. 
 
A serious adverse event is defined as any untoward medical occurrence that at any dose: 
• 
results in death, is life threatening; 
• 
requires hospitalization or prolongation of hospitalization; 
• 
results in a persistent or significant disability or incapacity; or 
• 
is a congenital anomaly or birth defect. 
‘Life-threatening’ means that the person was at immediate risk for death; it does not refer to an 
adverse event that might have caused death if it were more severe. ‘Persistent or significant disability 
or incapacity’ means that a person’s ability to carry out normal life functions is substantially 
disrupted. 
 
All serious adverse events occurring during the study must be recorded and reported by the principal 
investigator to the sponsor, regardless of whether the principal investigator considers the events to be 
related to the investigated medicine. 
 
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. 
 
The screening record form will be used to record the general information and the clinical observations 
of each patient under screening. If the patient meets the clinical criteria, he/she will be examined for 
parasitaemia. Once the patients meets all the enrolment criteria (see section above), he/she or the 

2003-25-03 version date 19 July 2016 
parent/guardian will be asked for consent to participate in the study. Children between 12-17 years old 
will also need to provide their assent to participate. 
 
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 basic follow-up schedule is summarized in Annex 6. A Case Report Form (CRF) (Annex 7) will 
be used to record the general information and clinical observations for each patient enrolled into the 
study. The appointment scheduled will be clearly explained and a follow-up card mentioning the 
personal identification number will be handed out. 
 
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. 
Thereafter, the schedule calls for clinical reassessments and blood films for malaria (parasites and  
parasite count) to be made on days 1, 2, 3, 7, 14, 21, and 28. Patients will always be advised to return 
on any day during the follow-up period if symptoms return and not to wait for scheduled visit day. 
Clinical reassessments will be sufficiently thorough to ensure patient safety and will include 
assessments not only for potential treatment failure but also for potential adverse reactions to the 
treatment drug. Additionally, blood films will be obtained whenever parasitological reassessment is 
requested by the clinical staff for reasons of patient safety. 
 
 
AL drugs require multiple-day dosing and the initial visits are critical not only for the efficacy 
assessment but also for patient safety; defaulters at this stage who will not have received a complete 
course of treatment may be at risk for clinical deterioration. All reasonable efforts will be made to 
find defaulters to ensure complete treatment.  Similarly, the ultimate success of the study rests on 
minimizing loss to follow-up.  Subjects treated with AL will be asked to return on the same days but 
they will need to be seen twice on Days 0, 1 and 2 because of the twice daily dosing.  It is imperative 
that this second dose be observed therefore either the study participant returns to the health center or a 
health worker (BHW or midwife) connected to the study visits the person at their home, or they are 
admitted at the district hospital during the 3-day treatment, whichever is applicable. For subjects 
treated with CQ, Primaquine is withheld until Day 28 follow-up. It is important that a health worker 
will follow-up the patinets in their homes to give the daily dose of Primaquine for 14 days by Direct 
Observed Treatment (DOTs). Since only ambulatory patients with uncomplicated malaria and drugs 
with well-known safety profiles are being assessed as part of this protocol, there is no need for daily 
follow-up through the course of the study.  Subjects and parents/guardians (in the case of children) 
will be encouraged to return to the clinic for further clinical and parasitological assessment (repeat 
blood smears) and/or treatment at any time during follow-up at which the subject is perceived to be 
ill.  A repeat Hgb count will also be done on Day 3, 7, 14 (optional), and 28, and additional Day 31 
and 34 for Pv patients.  The Barangay Health Worker (BHW) or the malaria field worker will 
specifically look for them in place of residence for follow-up on Days 3, 7, 14, 21 and 28 if they do 
not return.  
 
While patients are encouraged to return on their own for scheduled follow-up visits, it is essential that 
provisions be made ahead of time for locating patients at home if they do not attend as requested. This 

2003-25-03 version date 19 July 2016 
requires obtaining detailed directions to the home during enrolment, study team members familiar 
with the community responsible for home visits, and means of transportation. The schedule for 
treatment and follow-up examination given in this protocol must be followed rigorously to ensure data 
integrity. Patients who fail to return on day 1 and day 2 and miss one dose of the treatment are 
withdrawn from the study definitively. After day 3, patients who fail to return on day 7 but are present 
on day 8 (likewise days 14/15, days 21/22, and days 28/29) may still be included in the study group. 
Deviation from the protocol of more than 1 day cannot be allowed, both for the safety of the patient 
and for the relevance of the data. 
 
Summary of Detailed Procedures for Patient Enrolment, Scheduled Follow-up Visits 
 
Procedures 
Schedule of Screening, Recruitment and Enrolment Days, and Follow-up Visits 
D0 
D1 
D2 
D3 
D7 
D14 
D21 
D28 
 
 
D31 
 
 
D34 
 
D35 
(opti
onal) 
D42 
(opti
onal 
 Un- 
schedul
ed day 
Screening Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
   History taking 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Clinical Assessment 
Signs/symptoms (assess if no severe 
malaria danger signs)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment and Enrolment 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
If patient has satisfied the inclusion 
criteria and is a potential enrollee3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Signs/symptoms (refer to next level 
of care in case of severe 
malaria/danger signs  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
   Axillary Temperature 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
   Respiratory Rate 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
Laboratory Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Blood smear, including parasite count 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
  Filter paper (PCR) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
 Filter paper for CQ assay (for Pv 
participants only) 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Haematological assessment (Pf) 
X 
 
 
X 
X 
(X) 
(X) 
 
 
 
X 
X 
(X) 
Haematological assessment (Pv) 
X 
 
 
X 
X 
(X) 
 
X 
X 
X 
 
 
 
Medicine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Pf participants: AL 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
                                PQ 
 
 
 
X 
 
 
 
 
 
 
 
 
 
For Pv participants: CQ 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
                                 PQ 
To be given after Day 28 (see summary table below) 
   
                                                   
3 Using the information sheet as guide, explain to patient the study protocol.  If patient has understood the the study protocol 
(procedures to be done on him/her during the study period, follow-up visits, etc) secure a written informed consent 

2003-25-03 version date 19 July 2016 
Procedures 
Schedule of Screening, Recruitment and Enrolment Days, and Follow-up Visits 
D0 
D1 
D2 
D3 
D7 
D14 
D21 
D28 
 
 
D31 
 
 
D34 
 
D35 
(opti
onal) 
D42 
(opti
onal 
 Un- 
schedul
ed day 
Rescue treatment (refer to next level 
of care) 
 
 
 
 
 
 
 
 
 
 
 
 
 
      Pf patient - QN + antibiotic 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
(X) 
      Pv patient - AL 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
 
Note: Parenthesis denote conditional or optional activities 
 
Medicine 
Schedule of Primaquine treatment days* 
*Note: Give on Day 29 
Primaquine 
D2
9 
D30 
D31 
D32 
D33 
D34 
D35 
D36 
D37 
D38 
D39 
D40 
D41 
D42 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
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 EPI-INFO 6.0 software from USA and Excel sheet program (designed from WHO 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 

2003-25-03 version date 19 July 2016 
• 
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 ETF, LCF and LPF and 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 wheter 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 dessiminated 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 IRBs. 
 
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 advice 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 

2003-25-03 version date 19 July 2016 
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 centre.  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. 
 
9.5 Reimbursement and Travel Compensation 
Subject shall be reimbursed for their transport to attend all visits to the RHU. This will occur on 
each follow up visit and will cover expenses of transport for the next visit.  
 
9.6. Community 
At the end of the study, the community, through a meeting with the LGU, RHU staff and village 
health workers will be informed of the results of the study.  The Malaria Awareness Day celebration, 
World Malaria Day and national Malaria Month are fora for information dissemination in lay terms.  
 
10. TES MONITORING 
Following recommendations of the just concluded 2nd Pacific Malaria Drug Resistance Network 
Meeting held in Manila, Philippines, this TES will be monitored by identified individuals from WHO 
Representative Office, Manila and WPRO.  They will follow applicable procedures of the WHO-TDR 
clinical monitoring standard operating procedures (SOPs).4 
 
11. REFERENCES 
 
International ethical guidelines for biomedical research involving human subjects. Geneva, Council 
for International Organization of Medical Sciences, 2002. 
 
Declaration of Helsinki. Ethical principles for medical research involving human subjects. 
 
ICH Topic E8. Note for guidance on general considerations for clinical trials. London, European 
Agency for the Evaluation of Medicinal Products, 1997 (CPMP/ICH/291/95). 
 
Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated 
falciparum malaria. Geneva, World Health Organization, 2009.  
 
 
 
                                                   
4Necessary permission and approval will be sought from the concerned 
groups. 

2003-25-03 version date 19 July 2016 
Annex 1. DEFINITION OF SEVERE FALCIPARUM MALARIA6 
Severe manifestation of P. falciparum malaria in adults and children 
Clinical manifestations 
• 
prostration, 
• 
impaired consciousness, 
• 
respiratory distress (metabolic acidosis), 
• 
multiple convulsions, 
• 
circulatory collapse, 
• 
pulmonary oedema (radiological), 
• 
abnormal bleeding, 
• 
jaundice, 
• 
haemoglobinurea. 
Laboratory findings 
• 
severe anaemia (haemoglobin < 5 g/dl, haematocrit < 15%), 
• 
hypoglycaemia (blood glucose < 2.2 mmol/l or 40 mg/dl), 
• 
acidosis (plasma bicarbonate < 15 mmol/l), 
• 
hyperlactataemia (venous lactic acid > 5 mmol/l), 
• 
hyperparasitaemia (> 4% in non-immune patients), 
• 
renal impairment (serum creatinine above normal range for age). 
Classification of severe malaria in children 
Group 1: children at increased risk for death 
• 
prostration 
• 
respiratory distress 
Group 2: children at risk for clinical deterioration 
• 
haemoglobin < 5 g/dl, haematocrit < 15% 
• 
two or more convulsions within 24 h  
Group 3: children with persistent vomiting 
                                                   
6  World Health Organization. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000, 
94(Suppl. 1):1–90. 

2003-25-03 version date 19 July 2016 
Annex 2. MEDICATIONS (WITH ANTIMALARIAL ACTIVITY) THAT SHOULD NOT BE USED 
DURING THE STUDY PERIOD IN ADDITION TO THE STUDY DRUG(S) 
• 
chloroquine, amodiaquine; 
• 
quinine, quinidine; 
• 
mefloquine, halofantrine, lumefantrine; 
• 
artemisinin and its derivatives (artemether, arteether, artesunate, dihydroartemisinin); 
• 
proguanil, chlorproguanil, pyrimethamine; 
• 
sulfadoxine, sulfalene, sulfamethoxazole, dapsone; 
• 
atovaquone; 
• 
antibiotics: tetracycline*, doxycycline, erythromycin, azythromycin, clindamycin, rifampicin, trimethoprim; 
• 
pentamidine. 
* Tetracycline eye ointments can be used. 
MAJOR SIDE-EFFECTS OF THE STUDY DRUGS 
• 
Artemether-lumefantrine 
Abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of 
appetite, rush, nausea, vomiting. 
• 
Artesunate 
Abdominal pain, diarrhoea, dizziness, nausea, vomiting. 
• 
Artesunate-amodiaquine 
abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting. 
• 
Artesunate-mefloquine 
Abdominal pain, asthenia, diarrhoea, dizziness, fever, headache, insomnia, joint and muscle pain, loss 
of appetite, palpitation, rush, nausea, vomiting. 
• 
Artesunate-pyronaridine 
Abdominal pain, diarrhoea, dizziness, headache, nausea, vomiting. 
• 
Dihydroartemisinin-piperaquine 
Asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting. 

2003-25-03 version date 19 July 2016 
Annex 3. DRUG DOSAGE 
Dose and schedule of Artemether-Lumefantrine (Coartem™) and Primaquine (PQ) in the Treatment 
of Uncomplicated Plasmosium falciparum Malaria Infection  
 
       AL is preferably taken with high fat meal 
 
 
 
 
 
 
 
 
 
 
 
 
Day of 
Treatment 
Artemether-Lumefantrine (AL) 
(1 tablet contains 20 mg artemether and 120 mg lumefantrine)  
(1) Use body weight in kgs as basis  
5 - <15 kg 
15 - <25 kg 
25 - <35 kg 
≥35 kg 
(2) If weight cannot be taken, use age as basis 
(6 mos.– 3 y.o.) 
(4- 8 y.o.) 
(9-13 y.o.) 
If (> 13 y.o.) 
Day 1 
1 tab 
2 tabs 
3 tabs 
4 tabs 
8 hrs after 
1 tab 
2 tabs 
3 tabs 
4 tabs 
Day 2 
1 tab BID 
2 tabs BID 
3 tabs BID 
4 tabs BID 
Day 3 
1 tab BID 
2 tabs BID 
3 tabs BID 
4 tabs BID 
Day 4 
 
Primaquine (PQ) 
(1 tablet contains 15 mg base primaquine) 
(1) Use body  weight in kgs as basis: use 0.75 mg-base/kg bw single dose 
(2) If weight cannot be taken, use age as basis 
< 1 y.o. 
1-3 y.o. 
4-6 y.o. 
7-11 y.o. 
> 12 y.o  
contra-
indicated 
½ Primaquine 
single dose 
1 Primaquine 
tablet single 
dose 
2 Primaquine 
tablets single 
dose 
3 Primaquine      
tablets single 
dose 

2003-25-03 version date 19 July 2016 
Annex 4. CLASSIFICATION OF TREATMENT OUTCOMES7 
 
 
Classification of treatment outcomes - WHO, 2005 
Early Treatment Failure (ETF) 
 
• 
Development of danger signs or severe malaria on day 1, day 2 or day 3 in the presence of parasitaemia; 
• 
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. 
Late Treatment Failure (LTF) 
 
Late Clinical Failure (LCF) 
• 
Development of danger signs or severe malaria  on any day from day 4 to day 28 in the presence of 
parasitaemia, without previously meeting any of the criteria of Early Treatment Failure; 
• 
Presence of parasitaemia 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. 
 
Late Parasitological Failure (LPF) 
• 
Presence of parasitaemia 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. 
 
Adequate Clinical and Parasitological Response (ACPR) 
• 
Absence of parasitaemia 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. 
 
 
                                                   
7 WHO. Susceptibility of Plasmodium falciparum to antimalarial drugs. Report on global monitoring 1996–2004. Geneva, World Health 
Organization, 2005 (WHO/HTM/MAL/2005.110) (http://www.who.int/malaria/resistance). 

2003-25-03 version date 19 July 2016 
Annex 5. CASE SCREENING LOG 
 
 
 
 
Date of 
Screening 
Screening 
Number 
Name of 
Patient 
Initial 
Age 
Gender 
Address/ 
Contact No. 
Enrolled 
(Y/N) 
Date 
Enrolled 
Specie 
Patient 
ID No. 
Remarks/ 
comment why 
not enrolled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2003-25-03 version date 19 July 2016 
Annex 6. SCHEDULE OF FOLLOW-UP ACTIVITIES 
 
 
D0 
D1 
D2 
D3 
D7 
D14 
D21 
D28 
D35 
(optional) 
D42 
(optional) 
Un-scheduled 
(fever) 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Blood slide for parasites 
count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Urine sample for Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
Hemoglobin 
X 
 
 
X 
X 
(X) 
 
 
 
 
 
 
 
Blood for PCR 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
 
(X) 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
AL 
X 
X 
X 
 
 
 
 
 
 
 
 
Primaquine 
 
 
 
X 
 
 
 
 
 
 
 
Rescue treatment 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
NOTES:  Parentheses denote conditional or optional activities. For example, treatment on days 1 and 2 would occur only for drugs requiring 3-day dosing. On day 1, the patient should be examined for 
parasitaemia if she or he has any danger sign. Rescue treatment could be given on any day, provided that the patient meets the criteria for treatment failure. Extra days are any days other than regularly 
scheduled follow-up days when the patient returns to the facility because of recurrence of symptoms. On extra days, blood slides may be routinely taken or at the request of the clinical staff for reasons of 
patient safety.   
 

2003-25-03 version date 19 July 2016 
 
Page 24 of 27 
 
Day 0: 
Screening 
Clinical assessment including measurement of weight and height — referral in case of severe 
malaria/danger signs 
Measurement of axillary temperature 
Respiratory rate 
Parasitological assessment 
Informed consent 
Enrolment 
Treatment, first dose 
Blood sampling for PCR  
Hemoglobin test 
 
Day 1: 
            Clinical assessment – referral in case of severe malaria/danger signs 
Measurement of axillary temperature  
Respiratory rate 
Parasitological assessment  
Treatment, second dose or alternative treatment in case of early treatment failure 
 
 
Day 2: 
            Clinical assessment – referral in case of severe malaria/danger signs 
 
Measurement of axillary temperature  
Respiratory rate 
Parasitological assessment 
Treatment, third dose or alternative treatment in case of early treatment failure 
 
Day 3, Day 7, Day 14, Day 21 Day 28, Day 35 and Day 42 (Optional)_____________ 
 
Clinical assessment — referral in case of severe malaria/danger signs 
 
Measurement of axillary temperature 
 
Respiratory rate 
 
Parasitological assessment 
Hemoglobin test: Day 3, Day 7, Day 14 (optional) 
 
Alternative treatment in case of treatment failure 
 
Blood sampling for PCR (any scheduled day in case of failure 
 
Any other unscheduled day:____________________________________________________ 
 
Clinical assessment — referral in case of severe malaria/danger signs 
 
Measurement of axillary temperature 
 
Parasitological assessment 
 
Alternative treatment in case of treatment failure 
 
blood sampling for PCR (in case of failure) 
                
 
 
 

2003-25-03 version date 19 July 2016 
 
Page 25 of 27 
 
Appendix 7. SERIOUS ADVERSE EVENT REPORT FORM 
SERIOUS ADVERSE EVENT FORM 
Health center name:_______________________ 
Study number: _______2003-25-03__________ 
                                    Philippines 
Patient identity number: ___________________ 
Municipality:_________________________ 
Date of visit (dd-mm-yy): _______ 
Province: ___________________________ 
Follow-up day: ______________________ 
Demographic data 
Date of birth (dd-mm-yy): ____________ 
or estimated age: _____ in: 
 months or 
 years 
Height (cm): _____  
Weight (kg): _____  
 
Sex: 
 Male 
 Female  
If female, is the patient pregnant? 
 Yes 
 No 
 Not sure 
If pregnant, provide the date of the last menstrual period (dd-mm-yy): _________ 
Serious adverse event  
Type of event: 
Severity 
Relationship to the study drug 
 Death  
 Mild 
 None 
 Life-threatening 
 Moderate 
 Possible 
 Hospitalization or 
prolongation of hospitalization 
 Severe 
 Probable 
 Permanent disability  
 Life-threatening 
 Definite  
 Congenital anomaly or birth 
defect 
 
 
Date of occurrence (dd-mm-yy): _________ 
Describe the serious adverse event (include all relevant laboratory results): 
 
 
 
 
 
 
Describe how the reaction was treated: 
 
 
 
 
 
 
 
 
 
 
 

2003-25-03 version date 19 July 2016 
 
Page 26 of 27 
 
Serious adverse event report form (page 2) 
Comments (e.g. relevant medical history, drug allergies, previous exposure to similar drugs, other 
laboratory data, whether reaction abated after stopping the drug, whether reaction reappeared after 
reintroduction): 
 
 
 
 
 
 
Outcome 
 Recovered completely  
 Not yet recovered  
 Recovered with long-term consequences 
If patient recovered, provide date of recovery (dd-mm-yy): __________ 
Medicines (list the medicine suspected of causing the serious adverse event as well as all concomitant 
medicines) 
Brand name, batch 
number, 
manufacturer name 
(list suspected medicine 
first) 
Daily 
dose 
Route 
Start date 
End date 
Indications for use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting officer 
Name: ____________________________________________ 
Qualification: ______________________________________ 
Address: __________________________________________ 
Phone: ________________________ 
 
Fax:__________________________ 
 
Email: ________________________ 
Signature: _____________________ 
Date: _____________ 

 
Page 27 of 27 
 
Appendix 8. GUIDELINES FOR ANALYSIS OF RESULTS 
End-point for day X 
(X = 28 or 42) 
PCR-uncorrected results 
Cumulative success or 
failure rate (Kaplan-Meier 
analysis) 
Proportion 
(per-protocol analysis) 
Adequate clinical and parasitological 
response on day X 
Success 
Success 
Early treatment failure 
Failure 
Failure 
Late clinical failure before day 7 
Failure 
Failure 
Late clinical failure or late parasitological 
failure on or after day 7 
Failure 
Failure 
Other species infection 
Censored day of infection 
Excluded from analysis 
Lost to follow-up 
Censored last day of follow-
up according to timetable 
Excluded from analysis 
Withdrawal and protocol violation 
Censored last day of follow-
up according to timetable 
before withdrawal or 
protocol violation 
Excluded from analysis 
 
End-point for day X 
(X = 28 or 42) 
PCR-corrected results 
Cumulative success or 
failure rate (Kaplan-Meier 
analysis) 
Proportion 
(per-protocol analysis) 
Adequate clinical and parasitological 
response at day X 
Success 
Success 
Early treatment failure 
Failure 
Failure 
Late clinical failure before day 7 
Failure 
Failure 
Late clinical failure or late parasitological 
failure on or after day 7 
 
 
• 
falciparum recrudescence* 
Failure 
Failure 
• 
falciparum reinfection* 
Censored day of reinfection 
Excluded from analysis 
• 
other species mixed with 
falciparum recrudescence 
Failure 
Failure 
• 
other species mixed with 
falciparum reinfection 
Censored day of reinfection 
Excluded from analysis 
• 
other species infection 
Censored day of infection 
Excluded from analysis 
• 
undetermined or missing PCR 
Excluded from analysis 
Excluded from analysis 
Lost to follow-up 
Censored last day of follow-up 
according to timetable 
Excluded from analysis 
Withdrawal and protocol violation 
Censored last day of follow-up 
according to timetable before 
protocol violation or 
withdrawal 
Excluded from analysis 
* WHO. Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations.  
Geneva, World Health Organization, 2008 (http://www.who.int/malaria/resistance).