Monitoring Therapeutic Efficacy of Chloroquine Plus Primaquine in the Treatment of Uncomplicated Plasmodium Vivax Based on Clinical, Parasitologic and Hematologic Parameters in Shecha Health Center: Open Label Clinical Trial
Phase: PHASE4
Conditions: Efficacy, Malaria, Chloroquine, Vivax Malaria
Sponsor: Dinka Dugassa

  
 
 
                        INSTITUTE OF HEALTH SCIENCES 
                               DEPARTEMENT OF PHARMACY 
THERAPEUTIC EFFICACY OF CHLOROQUINE PLUS PRIMAQUINE 
IN THE TREATMENT OF UNCOMPLICATED PLASMODIUM VIVAX IN 
SHECHA HEALTH CENTER:OPEN LABEL CLINICAL TRIAL 
 
BY: - DINKA DUGASSA  
 
 
 
 
                                                                                               DECEMBER, 2022 
                                                            NEKEMTE, ETHIOPIA 
 

 
 
 
WALLAGA UNIVERSITY 
INSTITUTE OF HEALTH SCIENCES 
DEPARTEMENT OF PHARMACY 
 
THERAPEUTIC EFFICACY OF CHLOROQUINE PLUS PRIMAQUINE 
IN THE TREATMENT OF UNCOMPLICATED PLASMODIUM VIVAX IN 
SHECHA HEALTH CENTER:OPEN LABEL CLINICAL TRIAL 
 
           
                       BY: - DINKA DUGASSA  
 
 
 
 
 
 
 
                     
DECEMBER, 2022 
                                                                                  NEKEMTE,ETHIOPIA

2 
 
Background 
Malaria is a life-threatening disease caused by a parasite called Plasmodium. It is transmitted to 
humans through the bite of infected female Anopheles mosquitoes. Once inside the human body, 
the parasites multiply in the liver and then infect red blood cells, leading to destruction of the 
cells and the release of more parasites into the bloodstream.  
The symptoms of malaria include fever, headache, chills, and flu-like symptoms such as 
sweating, muscle aches, and fatigue. In severe cases, malaria can cause organ failure, seizures, 
coma, and death.  
Malaria is a major health problem in many parts of the world, particularly in sub-Saharan Africa, 
where it is a leading cause of death among children under the age of five. However, it is 
preventable and treatable with the use of antimalarial drugs, insecticide-treated bed nets, and 
indoor spraying of insecticides.  
Efforts to control and eliminate malaria have been ongoing for many years, with the goal of 
reducing the burden of the disease and ultimately eradicating it. These efforts include the 
development of new drugs and vaccines, as well as the implementation of prevention and control 
measures in affected areas. 
Uncomplicated malaria is a type of malaria that is not severe and has not yet affected vital organs 
like the brain or kidneys. It is caused by the Plasmodium parasite and is transmitted through the 
bite of infected mosquitoes.  
Plasmodium Vivax is a type of malaria parasite that causes uncomplicated malaria, which can be 
treated with anti-malaria drugs such as Chloroquine and Primaquine. However, there have been 
concerns about the emergence of drug-resistant strains of Plasmodium Vivax, which has led to 
the need for studies on the therapeutic efficacy of these drugs. Several clinical trials have been 
conducted to evaluate the effectiveness of Chloroquine and Primaquine in combination for 
treating uncomplicated Plasmodium Vivax malaria. These studies have shown that the 
combination therapy is highly effective in clearing the parasites from the blood and preventing 

 
 
relapses. However, the optimal dosages and duration of treatment for this combination therapy 
are still being investigated to improve its therapeutic efficacy. 
The treatment of uncomplicated malaria involves the use of antimalarial drugs such as 
Chloroquine, Artemisinin-based Combination Therapy (ACT), and Quinine-based regimens. The 
choice of drug and treatment regimen depends on the species of the malaria parasite, the severity 
of the infection, and the patient's age and weight.  
Antimalarial drugs work by killing the parasites in the blood and preventing them from 
multiplying. They are usually administered orally, and the duration of treatment varies depending 
on the drug used and the severity of the infection.  
In addition to drug treatment, supportive care such as hydration and management of symptoms 
like fever, headache, and nausea is also important in the treatment of uncomplicated malaria. 
Regular monitoring of patients is also necessary to ensure the effectiveness of treatment and 
detect any complications that may arise. 
Monitoring the therapeutic efficacy of antimalarial drugs is crucial for ensuring effective 
treatment of uncomplicated malaria. It involves the regular evaluation of the clinical and 
parasitological response of patients to the drugs. This is done through clinical examination, 
laboratory tests, and follow-up visits to assess the patient's symptoms and the presence of malaria 
parasites in the blood.  
The World Health Organization (WHO) has developed standardized protocols for monitoring the 
therapeutic efficacy of antimalarial drugs, which involve conducting clinical trials to evaluate the 
effectiveness of the drugs in different regions. These trials include evaluating the parasite 
clearance rate, the fever clearance time, and the rate of treatment failure.  
Regular monitoring of therapeutic efficacy is essential in detecting the emergence of drug-
resistant strains of malaria parasites and improving treatment regimens to ensure effective 
treatment and prevent the spread of drug resistance. 

 
 
Statement of the Problem 
Antimalarial drug resistance is a major barrier to the control and elimination of malaria. The 
emergence of drug-resistant strains of Plasmodium parasites has significantly impacted the 
effectiveness of antimalarial drugs in treating and preventing malaria.  
The burden of antimalarial drug resistance is particularly high in sub-Saharan Africa, where the 
majority of malaria deaths occur. Resistance to Chloroquine, once the most widely used 
antimalarial drug, is now widespread in many parts of Africa and other regions. Resistance to 
other drugs such as Sulphadoxine-pyrimethamine, Amodiaquine, and Artemisinin-based 
Combination Therapy (ACT) has also been reported in some regions.  
The emergence of drug resistance has increased the cost of malaria treatment and prevention, as 
alternative drugs and combination therapies must be used. It also poses a challenge to malaria 
control efforts, as it reduces the effectiveness of interventions such as insecticide-treated bed nets 
and indoor residual spraying.  
Efforts to combat antimalarial drug resistance include the development of new drugs and 
combination therapies, as well as the strengthening of surveillance and monitoring systems to 
detect and respond to drug resistance. 
Despite the widespread use of Chloroquine and Primaquine in combination for the treatment of 
uncomplicated Plasmodium Vivax malaria, there is still a need to investigate the optimal dosages 
and duration of treatment to improve therapeutic efficacy. The emergence of drug-resistant 
strains of Plasmodium Vivax also poses a challenge to the effectiveness of this combination 
therapy. Therefore, there is a need to conduct further studies to evaluate the therapeutic efficacy 
of Chloroquine and Primaquine in combination and to monitor the emergence of drug-resistant 
strains to improve the management of uncomplicated Plasmodium Vivax malaria. 

 
 
METHODS 
Study Area and Period 
The study will be carried out from December, 2022 to March, 2023 in Shecha Health Center, 
Arbaminch Town, South West Ethiopia, 2022/23. Shecha Health Center is found in Arbaminch 
Town,Southern Nations, Nationalities and Peoples of Ethiopia regional state,  South West 
Ethiopia.  
Shecha Health Center is found in Arbaminch Town Administration which will be established in 
1961 as a clinic and Upgraded to Health Centre in 2004.Currently the health center serving more 
than 31,434 populations. Among this, 15,654 were male and 15,780 were female. Shecha Health 
Centre offers a variety of service delivery units and clinics, including an emergency room, a unit 
for children under five, an adult outpatient unit, a unit for maternity and child health, a unit for 
young people, a laboratory unit, a pharmacy unit, a central medical store, an ART clinic, and a 
TB clinic. 
Study Design   
This Therapeutic Efficacy study is a prospective evaluation of clinical and parasitological 
responses to directly observed treatment for uncomplicated vivax malaria (51,52). People with 
uncomplicated plasmodium vivax malaria who meet the study inclusion criteria will be enrolled 
and treated on site with Chloroquine plus Primaquine for p.vivax infection and monitored up to 
42 days.  
The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and 
laboratory examinations. On the basis of the results of these assessments, the patients will be 
classified as having therapeutic failure (early or late) or an adequate response.  
The proportion of patients experiencing therapeutic failure during the follow-up period will be 
used to estimate the efficacy of the study drugs. Molecular analyses will be used to distinguish 
between a true recrudescence due to treatment failure and episodes of reinfection as well as 
determine polymorphisms of known resistance markers. In addition, drug level testing may be 
conducted depending on the availability of resources.  . 

 
 
Population  
Source Population  
All Malaria Patients who visit Shecha Health Centre during the study period. 
Study Population    
Confirmed mono p.vivax malaria patients visiting Shecha Health Centre during the study period 
who fulfilled the inclusion criteria set by the WHO protocol for the assessment of the therapeutic 
efficacy of Chloroquine plus Primaquine. 
 Eligibility Criteria 
Inclusion Criteria 
 Age > 6 months 
 Slide confirmed infection with P. vivax with > 250 asexual forms/μl 
 Lives within 5 km of the enrolling health facility 
 Weight ≥ 5.0 kg  
 Ability to swallow oral medication 
 Ability and willingness to comply with the protocol for the duration of the study and to 
comply with the study visit schedule 
 Informed consent from patient or from a parent or guardian in the case of children 
Exclusion Criteria 
 Sever malaria with complication sign and symptoms (see Annex I) 
 Signs or symptoms of severe malnutrition, defined as weight-for-age ≤ 3 standard 
deviations below the mean, symmetrical edema involving at least the feet, or mid-upper 
arm circumference <100 cm for children less than five years of age (NCHS/WHO 
normalized reference values; see Annex I)  
 Mixed plasmodium infection  
 Severe anemia, defined as hemoglobin (Hb) < 8 g/dl  

 
 
 Presence of febrile conditions caused by diseases other than malaria (e.g. measles, acute 
lower respiratory tract infection, severe diarrhea with dehydration) 
 Serious or chronic medical condition (e.g. cardiac, renal, hepatic diseases, sickle cell 
disease, HIV/AIDS)  
 Positive pregnancy test or breastfeeding  
 Unable or unwilling to take contraceptives for women of child-bearing age 
 Children weighing less than 5 kilograms 
 History of hypersensitivity reaction to any medication tested or used as an alternative 
treatment  
 Participants with history of prolonged QT conditions  
 Taking regular medication, which may interfere with antimalarial pharmacokinetics or 
efficacy (see Annex VII)?  
Sample Size Determination and Sampling Technique 
Sample Size Determination 
The sample size will be determined according to the WHO (2009) protocol(11); by using the 
single population proportion formula and calculated assuming 5% margin of error, 95% 
confidence interval (CI), and treatment failure of 5% and 20% loss to follow-up rate. 
Accordingly, a minimum of 73 patients will be enrolled. 
                            Sample size (n) =〖Z a/2)2 p(1 –p)      
                                                                         d^2                 (1.96)2 0.05 (1-0.05) = 73 
                                                                                                               (0.05)2 
Assuming an additional 20% loss to follow-up rate and withdrawal of consent (15 patients) 
during the study, at least 88 (73 + 15) patients will be required to bring about a representative 
sample size.n= (1+0.2) 73= 88       Where, n= sample size   
P=Expected treatment failure (5%)  
Z=confidence interval (95%) 
 d=margin of error (5%) 

 
 
 Sampling Technique 
Convenient sampling technique will be used to collect the selected sample size. Samples will be 
taken from all the patients with positive plasmodium vivax who fulfill the inclusion criteria. 
Study Variables  
Independent Variables 
 
Age, Sex,Weight, Axillary temperature, leukocyte count, asexual and/ or sexual parasites 
count, Hemoglobin count 
Dependent Variables  
 Therapeutic Efficacy of CQ+PQ 
Operational Definitions and Definition of Terms 
Loss to Follow-Up 
Loss to follow-up occurs when, despite all reasonable efforts, an enrolled patient does not attend 
the scheduled visits and cannot be found. No treatment outcome will be assigned to these 
patients. Every effort must be made to schedule a follow-up visit for patients who fail to return to 
the study site, especially during but also after administration of the study drug. These patients 
will be classified as lost to follow-up and censored or excluded from the analysis. Patients who 
are lost to follow-up but who subsequently return to the study site before day 42 will not be 
turned away and will be encouraged to return for check-up visits. The principal investigator will 
decide whether the patient is to be classified as lost to follow-up based on his or her history or is 
to be maintained for the analysis. 
 Patient Discontinuation or Protocol Violation 
Patients meeting any of the following criteria will be withdrawn:  
 Withdrawal of consent 
 Failure to complete the treatment 
o Vomiting both initial and replacement doses at any single time in the treatment 
(i.e. If the patient vomits both attempts to administer the morning dose that would 

 
 
require withdrawal; however, vomiting the initial morning dose but not the 
morning replacement dose would not require withdrawal), persistent vomiting 
o Severe side-effects necessitating hospitalization 
o Progression to severe malaria  
o Failure to attend the scheduled visit during the first 3 days 
 Enrolment violation 
o Severe malaria on day 0 
o Erroneous inclusion of a patient outside of the inclusion/exclusion criteria 
 Voluntary protocol violation: Antimalarial (or antibiotics with antimalarial activity) treatment 
administered by a third party or self-medication with antimalarial (or antibiotics with 
antimalarial activity) assessed by asking participants or their caretaker at follow-up visits 
(Annex VI) 
 Involuntary protocol violation 
o Occurrence during the follow-up of concomitant disease that would interfere with 
a clear classification of the treatment outcome 
o Detection of a mono-infection with another malaria species during follow-up 
o Misclassification of a patient due to a laboratory error (parasitemia) leading to the 
administration of the rescue treatment 
Treatment 
 Antimalarial Treatment 
 
P.vivax patients will receive CQ+PQ. The correct drug doses will be determined by the dosing 
chart (Annex III). All drugs administered in the facility will be under supervision by the staff. 
Patients will be observed for 60 minutes after treatment for adverse reactions or vomiting. Those 
patients vomiting their medication within the first 30 minutes will receive a repeat full dose, 
while those vomiting from 30-60 minutes will receive half dose. Patients who vomit twice will 
be referred to higher level of care for management with parenteral artesunate therapy and 
withdrawn from the study. This is standard practice for anti-malarial treatment. All study drugs 
will be obtained from WHO Ethiopia office through Ethiopian Pharmaceutical Supply Agency.  
 

 
 
Concomitant Treatment 
 
Using standard clinic procedures, clinic personnel will administer supportive treatment to 
patients as necessary: antipyretics will be given for temperatures > 38◦C.  All patients enrolled in 
the study will be given two additional doses of paracetamol for use at home. 
Patients/parents/guardians will be instructed in the use and application of tepid sponging and 
fanning.  
Rescue Treatment 
 
Patients failing in any arm will be treated with second line drug per National Guidelines. 
Whereas, patients failing with the second line will be administered as of severe malaria criteria 
that is an indication of treatment failure. 
 
 
The following are the known efficacy and adverse effects and pharmacokinetics of treatment 
drugs that will be used in the study:  
Chloroquine Plus Primaquine (CQ+PQ): Chloroquine Plus Primaquine is a WHO Pre-
qualified anti-malarial and FDA approved; WHO certifies the quality, safety and efficacy of the 
medication, and verifies that the manufacturer complies with WHO Good Manufacturing 
Practices. CQ+PQ is currently the first line anti-malarial recommended by Ethiopia FMOH for 
the treatment of uncomplicated falciparum infection. Adverse events are generally mild, most 
commonly GI (vomiting and diarrhea) and hematologic (anemia and eosinophilia).Its safety will 
be demonstrated in studies from Ethiopia and Uganda. Chloroquine has a half-life of 30-60 hours 
(53,54), while primaquine has a elimination half-life of 5-7 hours (54). 
Data Collection Instrument and Procedure 
Data Collection:  Data will be collected and recorded at the health facility by trained study staff 
members. All data entry will be checked for completeness. Laboratorians may complete brief 
reports on laboratory findings to share with clinicians who will transfer these results to the case 
report form of the appropriate patient, and the laboratory results will be entered into database.  
Data Entry, Editing, Handling, Storage and Disposition:  Some open-ended data including the 
names of specific drugs or diagnoses will be coded prior to data entry. A list of standard codes 
for these fields will be developed by hand once collection of data is complete.  All forms will 

 
 
then be coded and checked by two different team members.  
Systematic routines will be developed to check for data entry discrepancies and range and 
consistency.  If collected on paper, all discrepancies will be resolved by reference to the original 
checked data collection forms.  The final data set will be transformed to statistical software for 
analysis. 
Storage of Specimens: Specimens obtained in this study will be saved for the duration of 
specified testing.  Specimens will not be tested for HIV.  
Quality Control/ Assurance: Site supervisors will check data entry at the end of follow-up for 
completeness and accuracy of recording. Five percent of the slides will be read by WHO 
qualified microscopists for quality control. 
Personnel Training: Three days TOT will be provided for the central team prior to the study. 
Study clinicians and laboratory personnel are trained and licensed in Ethiopia. They will also 
receive approximately 1 week additional training to review and familiarize with the study 
protocol. In addition to technical aspects of specific laboratory techniques and clinical 
assessments, training will stress the importance of confidentiality and appropriate techniques for 
obtaining informed consent. The Lab staff will participate in practical exercises. Continued 
appropriate behavior with regard to informed consent will be reinforced through observation by 
the supervisor. The staff will include 1-2 laboratory technicians for microscopy and 1-2 staff 
persons for enrollment and clinical assessments. 
Bias in Data Collection, Measurement and Analysis:  Some bias may be introduced through 
the fact that both treating clinicians and parents will be aware of which treatment a subject 
received; as much as possible we will rely on objective measures of improvement (fever 
resolution, malaria parasitemia) which will be unaffected by knowing the treatment allocation. In 
addition, the microscopists reading the slides will be blinded to the treatment allocation. Other 
biases in data collection will be minimized by use of standardized data collection instruments.  
The principal investigator will ensure that the study protocol is strictly adhered to and that all 
data are collected and recorded correctly on the case report form. Laboratory and clinical data 
will be recorded daily on the case report form designed for the study. Data derived from source 

 
 
documents should be consistent with the source documents, or the discrepancies should be 
explained. Any change or correction to a case report form should be dated and explained and 
should not obscure the original entry. All case report forms will be checked for completeness. 
After the study has been completed, data will be entered into a database and/or by double 
independent data entry. The trial data will be stored in a computer database and confidentiality 
will be maintained. 
The principal investigator is responsible for keeping all screening forms, the case report form and 
the completed subject identification code list in a secure location. 
Evaluation Criteria 
Efficacy and Safety Evaluation 
Classification of Treatment Outcomes 
The primary outcome of this study will be to monitor the efficacy of AL for P. falciparum and CQ for P. 
vivax as a routine follow up study and develop baseline and complementary efficacy data for DHA-PPQ 
against P. falciparum and P. vivax malaria in Ethiopia.   
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 from WHO. Accordingly, all P. 
falciparum and P. vivax patients will be classified as having an ETF, LCF, LPF, or ACPR (Annex I).  
Safety endpoints 
The incidence of any adverse event will be documented. All patients will be asked routinely about 
previous symptoms and about symptoms that have emerged since the previous follow-up visit. When 
clinically indicated, patients will be evaluated and treated appropriately. All adverse events will be 
recorded on the case report form. Serious adverse events will be reported to all relevant authorities. 
Clinical Evaluation 
All patients will be evaluated clinically as described below. 
Physical Examination 
A standard physical examination will be performed at baseline (day 0 before dosing) and on days 
1, 2, 3, 7, 14, 21, 28, 35, and 42. A complete medical history, demographic information, and 
contact details will be recorded at baseline. 

 
 
Body Weight 
Body weight will be recorded on day 0 to the nearest kilogram on a scale or on a hanging scale 
for young children. The scales will be properly calibrated. Patients should not wear excessive 
clothing while being weighed as this can overestimate their true weight. All young children 
should only wear undergarments while being weighed. The screening weight will be used to 
satisfy the inclusion or exclusion criteria for weight and nutrition status as well as to calculate the 
dose (number of tablets) to be administered. The reliability of the scales will be verified before 
the study begins and checked at regular intervals. 
The circumference of the left mid-upper arm will be measured, at the mid-point between the 
elbow and the shoulder and will be recorded to the nearest 0.2 cm. Oedema will be assessed by 
thumb pressure for 3 seconds on the dorsal surface of both feet. 
Body Temperature 
Axillary temperature will be measured at baseline (day 0 before dosing) and on days 1, 2, 3, 7, 
14, 21, 28, 35, and 42. Temperature will be measured with a thermometer that has a precision of 
0.1 °C. Temperature will also be measured as clinically indicated. If the result is < 36.0 °C, the 
measurement will be repeated. The same route will be used throughout the study. The quality of 
the temperature-taking technique and the thermometers will be assessed regularly.  
Laboratory Examination 
Microscopic blood examination: thick and thin blood smears will be taken from all participants 
and prepared on the same slide for detection of parasites at all time-points during the 42-day 
follow-up period. Two smears will be prepared in each case; the first will be stained rapidly with 
10% Giemsa for 10–15 min for initial screening and examined by light microscopy immediately. 
On day 0, in order to rapidly confirm adherence to the lowest parasite density considered for 
enrollment, initial screening of patients will be made in 10% Giemsa-stained thick film after 
counting at least 1 parasite for every 6-8 WBCs, which corresponds to approximately 1000 
parasites/l.  
The second one will be stained slowly with 3% Giemsa 45–60 min to be examined later by an 
experienced technician to provide definitive parasite count and speciation. The below formula 
will be used to determine parasite density. 

 
 
 
 Two experienced laboratory technicians will examine slides independently. Parasite densities 
will be calculated from thick blood smears by counting the number of asexual parasites against 
200 WBC. If the count is <10 parasites/200 WBC, at least 500 WBC will be counted. A thick 
blood smear will be declared negative if no parasites are seen in 1000 WBCs and mixed infection 
has been excluded in 100 fields on thick film. Gametocytes will be detected and counted in thick 
film. Thin blood smears will be examined to determine parasite species. Gametocytes will be 
counted in thick blood films against 2000 WBCs.  
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 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. 
Hemoglobin: The hemoglobin concentrations will be measured using a portable 
spectrophotometer (HemoCue®, Anglom, Sweden), on days 0, 14, 28, and 42.  
Blood sample collection:To minimize discomfort to the patient due to repeated finger pricks, all 
samples will be collected from a single prick. Two slides, hemoglobin and two to three drops of 
blood will be collected on Whatman filter paper and 100µl of blood using capillary tube will be 
collected during enrolment. Blood spots will be collected only on enrollment, on day 3, 7 and 
during treatment failure (Annex: VI) 
Specimens will be labeled 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 analyzed. Samples will be kept in freezers in the study sites and eventually 
transferred to EPHI, to be frozen at -20ºC.  
Pregnancy Test:  Female patients of child-bearing age, defined as those who menstruate or are 
aged over 18 years (depending on situations), will be asked to take a urine pregnancy test before 
enrolment in the study. They will also be asked to take a urine pregnancy test on day 28/42 or on 
Parasite density (per µl) = number of parasites counted × (6000–8000) 
                                           Number of leukocytes counted ≈ 200 

 
 
early withdrawal from the study. Female participants of child-bearing age who are sexually 
active to control pregnancy for the duration of the study.  
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 
 Is a congenital anomaly or birth defect. 
‗Life-threatening‘ means that the person will be 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. The investigator will 
collect information on all people who become pregnant while participating in this study and will 
record the information on the appropriate form. The person will also be followed to determine 
the outcome of the pregnancy. 
Emergency Care 
Any patient with treatment failure or recrudescence will receive second line drugs.  This will be 
given orally unless the patient has persistent vomiting, in which case it will be given Artesunate 
IM/IV until the vomiting resolves and then will be switched to oral therapy.  
Patients with signs of severe malaria (altered mental status, coma, convulsions, hemoglobin 
<5g/dl, respiratory distress, circulatory collapse, or abnormal bleeding), persistent vomiting or 

 
 
severe side effects will be hospitalized and receive parenteral therapy with artesunate and 
relevant supportive treatments, according to National Guidelines.  
We will counsel patients and parents to return immediately if they or their child develops a raised 
rash (urticaria) or difficulty breathing suggestive of a severe allergic reaction. These patients will 
be treated with diphenhydramine or chlorpheniramine and will be withdrawn from the study. In 
addition, patient and or their parents, caretakers and family members will be counseled that the 
patient should not receive additional doses of the antimalarial they were given. These patients 
will be treated with oral quinine for seven days as per the rescue protocol. 
Adult patients and parents with children in the study will be encouraged to return to the clinic for 
any fever or other signs of illness on any day during the 42-day follow-up period, allowing for 
early detection and treatment of illness before it becomes severe. Any hospitalization which 
occurs during the 42-day follow-up period will be paid by the study team.  
Response to unexpected incidents 
If sufficient numbers of malaria cases are presenting to the clinic but enrolment is insufficient, 
the supervisor will need to determine the problem and take needed actions to rectify the problem. 
In case of low patient recruitment due to unusually low transmission of malaria, necessary steps 
will be taken to either rectify the problem or to find a new site.   
Screening and Enrollment Procedures 
Screening 
Screening for eligible patients at the study sites will be done in the following fashion: 
1. All patients over 6 months with temperature ≥37.5oC or a history of fever in the last 48 hours 
will have screening blood smear performed as per the national diagnosis and treatment 
guidelines at the health centers. Patients with microscopy confirmed P. falciparum or P. 
vivax, age greater than 6 months, and living within 5 km of the health center will be 
screened.   
2. For all facilities, if the patient meets the screening criteria and the patient or the parent or 
guardian consents to enrollment, they will be assigned a consecutive, unique number that 
will become the patient's study number and will be used to identify all forms and blood 
samples from that patient. Enrollment will be conducted by a staff member not involved in 

 
 
the clinical assessment of the participant to ensure that consent is freely given.  
3. A screening form containing demographic, clinical, and laboratory information will be 
started on each smear positive patient, thus allowing for appropriate tracking of each patient 
through the screening procedure.  
4. The patient‘s body weight will be measured to the nearest kilogram, using a hanging scale 
for weighing young children, or a floor scale for large children/ adults and recorded on the 
demographic form. The circumference of the left upper mid-upper arm will be measured at 
the mid-point between the elbow and shoulder, and will be recorded to the nearest 0.2 cm. 
Edema will be assessed by thumb pressure for 3 seconds on the dorsal surface of both feet. 
Enrollment and Follow-up 
If a patient meets the initial screening criteria and permission to participate in the study is 
obtained, the patient will go through the enrolling process. 
1. The patient will be evaluated by clinical staff for signs of febrile illness other than malaria, 
(including but not limited to pneumonia, otitis media, tonsillitis, measles, chicken pox, 
abscesses) and signs of severe disease/danger signs, as presence of any of these will 
exclude the patient from participating in the study.  Patients found to have any of these 
conditions will be treated appropriately per National Guidelines, and referred to the referral 
hospital as necessary. A standardized form listing demographic and clinical information 
will be completed on each patient. 
2. Urine pregnancy test will be conducted on all women of reproductive age. Anyone testing 
positive will be excluded. 
3. Those enrolled will have a second finger prick performed to assess for the following: 
 
●   Thin smear will be used to verify parasite species and to conduct a formal parasite 
count. Rapid test will also be done for better speciation. Two microscopists will 
independently read each smear; if the 2 readings are >50% discordant, a third expert 
microscopist will examine the slide and make the final decision.  
 Hemoglobin measurement (Hemocue™ Hb301+; HemoCue, Angelholm, Sweden) 
will be carried out and those with hemoglobin <5g/dL will be excluded. 
 Filter paper will be obtained for molecular testing and drug levels. 
4. Participants testing positive for P. Vivax will receive CQ+PQ. A Convenient sampling 
technique will be used. The study will not be blinded.  

 
 
5. After assignment, on day 0, each patient will receive the dose of treatment medication under 
direct observation and will be monitored for vomiting. Each patient will return on days 1 
and 2 for subsequent doses.  Clinical reassessments will be made on days 1- 3, 7, 14, 21, 
28, 35, and 42 (see Annex VI). Participants will be given 100 Ethiopian Birr for each visit 
to cover their travel expenses (this is a compensation for a round-trip transportation to the 
clinic). Patients will be advised to return on any day during the follow-up period if 
symptoms return and not to wait for scheduled visit days. Patients who do not present to the 
facility for follow-up visits will be followed at home. This is standard for in vivo studies 
based on the WHO protocol, but is not the standard for routine care. Typically, for patients 
not enrolled in a study, the parent would be given all the doses of the medicine to 
administer at home, and no follow-up would be scheduled. The parent would be told to 
return if they did not improve.  
6. Blood films (thick and thin) for parasite count and dried blood spot will be obtained and 
examined as described above. All samples will have the study ID number and date of 
collection, but no other personal identifiers.  The logbook that links the study ID number to 
the patient will be kept at the study site locked in a cabinet when not in use during the study 
enrollment period. After the completion of the study, this logbook will be stored at EPHI. 
7. If patients do not appear for scheduled follow-up, the study team will attempt to reach them 
at home. After day 3, patients who fail to return on their scheduled day but return one day 
early or one day late may still be included in the analysis.  
8.  A case report form will be used to record the general information and clinical observations 
on each patient enrolled into the study. The appointment schedule will be clearly explained, 
and a follow-up card with a personal identification number will be provided. The study 
schedule (Annex VI) and follow-up schedule is summarized in (Annex VII). 
Storage of specimens: Specimens obtained in this study will be saved for the duration of 
specified testing.  Specimens will not be tested for HIV. 
Data Management and Monitoring 
Enrollment and case record forms will be completed for each study subject. Their initials and 
study code on the case record form will be used to identify the participants. The principal 
investigator will be responsible to complete case record forms at each visit. All corrections will 

 
 
be made on the case record form by striking through the incorrect entry with a single line and 
entering the correct information adjacent to it. 
All clinical data will be recorded onto standardized case record forms by the principal 
investigator. Laboratory data will be recorded in a laboratory record book by the laboratory 
technician and then transferred to the case record forms by the principal investigator. Data will 
be transferred from the case record forms into a computerized database (IBM SPSS Version 26, 
WHO excel sheet and plain excel spread sheet). The WHO excel sheet is specially designed for 
the analysis of efficacy study data and it only performs the analysis when double entry is assured 
to verify accuracy of entry. Two backup files and the database will be stored on compact discs 
after each data entry session. 
Members of the central team (co-advisor) from EPHI will supervise the overall study progress of 
the study and reviewed all data records at the mid of the study period. All study record forms will 
be checked for completeness and accuracy. In addition, daily communication will be made with 
the members of the central team (co-advisor, other study team members). 
Data Quality Control 
The health personnel‘s (Medical Doctor, Health Officer, laboratory technician, and nurse 
(tracer)) involved in the study will be oriented on the use of the study procedure; following the in 
vivo study protocol designed by the World Health Organization WHO). Prior to the study, the 
laboratory technician will have a refresher training to ensure proper preparation of blood smear, 
correct identification of parasites and accurate parasite counting.  Giemsa stock solution and 
working solution will be prepared at EPHI laboratory.  
Microscopic results will be assessed following the procedure that emphasizes reproducibility of 
final outcome classification over reproducibility of exact parasite count s by crosschecking 10% 
of the total slides. To avoid errors in recording data, the study supervisors on a regular basis will 
review all case report forms during the assessment for completeness and accuracy.  
Data will be entered into compute double entry using WHO data analysis excel sheets and SPSS 
version 26 and a random sample of 10% of computerized records will be selected and compared 
to hard copy case report forms for confirmation of consistency. 

 
 
Statistical Analysis 
Every data from recruited patients will be imported into the WHO Excel sheet (double entry) 
which is designed for analysis of therapeutic efficacy study data. Data will be also entered in to 
IBM SPSS (version-26) software to calculate descriptive statistics (mean, median, standard 
deviations, range). Independent sample t-test will be used to compare baseline temperature and 
parasitemia between children and adults; mean blood Hb level at D0, D14, D28 and D42 between 
patients with parasitemia ≥ 10,000 and < 10,000/μl blood. Non-parametric (median) test for 
independent sample will be used to compare D1 parasitemia between children and adults and 
paired sample t-test will be used to compare mean Hb level between D0 and D14, D0 and D28, 
D14 and D28,D0 and D42,D28 and D42. All comparisons will be performed at 95% CI and 
significance level of 0.05. 
Kaplan Meier (K-M) survival analysis and per protocol (PP) analysis will be used for estimation 
of primary outcomes and PP analysis method will be used to analyze secondary outcomes. The 
K-M survival analysis method provides better approximation of cure rates as it incorporates 
probabilities for censored data (incomplete observations due to LFU and withdrawals) in to the 
analysis. The WHO excel sheet is especially designed for estimation of cure rate based on K-M 
survival estimator analysis method. 
Ethical Considerations 
All consented participants will be part of the study. Written informed consents will be obtained 
from all study participants (parents or caregivers for children under the age of twelve) after 
thorough information on the study will be provided in the local language. Name of study 
participants will not be mentioned and incorporated in to the final dataset.  
Medical services will be provided for volunteer study participants free of charge during the 
follow-up period. At all times, patient well-being will be given priority over his/her continuation 
in the study. In addition, round trip transport fare (100.00 Ethiopia Birr) will be provided for 
every patient every scheduled visit. The study protocol will be approved by Institute of Health 
Sciences Institutional Ethics Review Committee,Wallaga University and Ethiopian Public Health 
Institute Institutional Ethics Review Board. 

 
 
ANNEXES 
Annex 1. Patient Screening Form 
Patient Screening Form 
STUDY SITE CODE: ________                   TREATMENT GROUP:  ______ 
 
1. Names:  
2. Date: (dd/mm/yy) 
            /            /              
3.Weight (kg): 
4. Age*: years_______  months. _______ 
5. Gender:     M _______     F_______ 
 
1. 
Patient aged > 6 months /Both sex 
Yes: No: 
2. 
P. vivax  mono-infection asexual parasites/µl Pv 250-
100,000/µl  
Yes: No: 
3. 
Body weight > 5 kg  
Yes: No: 
4. 
Patient with fever  or history of fever in the previous 24 
hours 
Yes: No: 
5. 
Non-pregnant or breast-feeding female 
Yes: No: 
6. 
Ability to swallow oral medication 
Yes: No: 
7. 
Residents living within 5 km radius of the health centre and 
  agree to return for all scheduled follow up visits 
Yes:  
8. 
Willing to give informed consent  
Yes: No: 
9. 
Evidence of concomitant febrile illness 
If ―YES‖, indicate illness. If ―NO‖, leave blank. 
 Pneumonia/RTI           Measles 
 Otitis Media                UTI 
 Gastroenteritis         Other:    
Yes: No: 
10. Evidence of severe malaria / danger signs 
If ―YES‖ indicate criteria. If ―NO‖, leave blank. 
 Unarousable coma (if after convulsion, > 30 min) 
 Repeated convulsions (> 2 within 24 h) 
 Recent convulsions (1-2 within 24 h) 
 Altered consciousness(confusion, delerium,, coma) 
Yes: No: 

 
 
 
If any of the responses fall into the shaded area, exclude the patient from the study 
Annex 2.      Enrolment Form 
Enrolment Form 
 
STUDY SITE CODE: ________                  TREATMENT GROUP:  _ _____ 
 
 
 Lethargy 
 Unable to drink or breast feed 
 Vomiting everything 
 Unable to stand/sit due to weakness 
 Severe anaemia (Hb < 5.0 g/dL) 
 Respiratory distress (laboured breathing at rest) 
 Jaundice (yellow colouring of eyes) 
11. Known hypersensitivity to AL/CQ/DP 
Yes: No: 
1. Age…………….. 
2. Weight……………… 
3. Gender/Male……Female…… 
4. PIN/Study Number:……… 
5. Number of tablets………… 
6.  Start Date:  (dd/mm/yy) 
 
7.  Patients Full name: 
8. Family head: 
9. Mother‘s/Wife‘s (if married) name: 
10. Caregiver‘s name and relationship: 
11.Kebele/Street: 
12. Home parish: 
13 Village: 
14. Home address and localising features/Owners name/Direction: 
 
15. Phone number (s) and the owner(s):  

 
 
 
 
 
 
 
 
 
 
Annex 3.  Case Record Form 
CASE RECROD FORM 
 
Study site               Treatment Group             Name                               Pin No.                  No. of Tablets          .                                   
 Barcode no on it.    Fill all follow-up days on the first day to trace                                                                 
 
day 0  
day 1  
day 2  
day 3  
day 7  
day 14  
day 21  
day 28  
day 35  
day 42  
Ext
ra 
DA
Y 
1. Date 
 
 
 
 
 
 
 
 
 
 
 
2.Axillary To C 
 
 
 
 
 
 
 
 
 
 
 
16. Previous malaria attack:             Yes _____No _____ 
 
17.  Previous antimalarial intake:  Yes ______No ______ If yes, CQ         AL          ?  
 
18. Hold  Bed net:                     Yes ___No___   If yes,  Bed net use      Yes              No _______           
 
 

 
 
3. 
Parasite 
asexual 
 
 
 
 
 
 
 
 
 
 
 
4.Gametocyte 
No 
 
 
 
 
 
 
 
 
 
 
 
5.Hemoglobin 
 
 
 
 
 
 
 
 
 
 
 
7.DBS/PCR 
 
 
 
 
 
 
 
 
 
 
 
8.Adverse 
events* 
It is not 
drug 
related 
adverse 
event 
 
 
 
 
 
 
 
 
 
 
9.Concomitant 
treatment 
 
 
 
 
 
 
 
 
 
 
 
10.Reasons for 
withdrawal 
 
 
 
 
 
 
 
 
 
 
 
11.Remarks/ 
Rare Event 
 
Complete 
Annex 27 
 
 
 
 
 
 
 
 
 
 
12.Treatment 
outcome 
 
 
 
 
 
 
 
 
 
 
 
Completed 
by 
(Initials) 
 
 
 
 
 
 
 
 
 
 
 
 
*1. Headache 2. Anorexia 3. Nausea 4. Vomiting 5. Abdominal pain 6. Diarrhea 7. Cough 8 .Behavioral change   9. Dizziness 10. Skin rash 
11. Mouth ulcer 12. Joint pain 13. Weakness 14. Other specify__________ 
 
ANNEX 4: Classification of Treatment Outcomes (WHO, 2009) 
Classification of treatment outcomes for plasmodium vivax malaria WHO  

 
 
Definition of Treatment Outcomes for P. vivax infections, WHO 2009 
Early Treatment Failure (ETF) 
 Danger signs or severe malaria on day 1, day 2 or day 3 in the presence of parasitemia; 
 Parasitemia on day 2 higher than on day 0, irrespective of axillary temperature; 
 Parasitemia on day 3 with axillary temperature ≥37.5 ºC; 
 Parasitemia on day 3 ≥25% of count on day 0. 
Late Treatment Failure (LTF) 
Late Clinical Failure (LCF) 
 Danger signs or severe malaria in the presence of parasitemia on any day between day 4 and 42 
in patients who did not previously meet any of the criteria of Early Treatment Failure; 
 Presence of parasitemia on any day between 4 and day 42 with axillary temperature ≥37.5 ºC 
(or history of fever) in patients who did not previously meet any of the criteria of Early 
Treatment Failure. 
Late Parasitological Failure (LPF) 
 Presence of parasitemia on any day between day 7 and day 42 and axillary temperature <37.5 
ºC in patients who did not previous meeting any of the criteria of Early Treatment Failure or 
Late Clinical Failure. 
Adequate Clinical and Parasitological Response (ACPR) 
 Absence of parasitemia on day 42 irrespective of axillary temperature, in patients who did not 
previously meet any of the criteria of Early Treatment Failure, Late Clinical Failure, or Late 
Parasitological Failure. 
 
Treatment success: 
the absence of parasitaemia on day 28/42, irrespective of axillary temperature, in patients who did 
not previously meet any of the criteria of treatment failure. 

 
 
ANNEX 5: Drug Dosing and Regimens 
All patients will be weighed to determine the accurate weight-based dose for all drugs.  
 Chloroquine: Total of 25mg base per kg over 3 days (10 mg base/kg on Days 1 and 2, and 
5 mg base/kg on Day 3). 500 mg tablets. We will use the syrup (10mg/ml) formulation 
for children < 4 years of age, if available. 
Weight (kg) 
Age 
Day 1 
Day 2 
Day 3 
5–6 
<4 mo 
¼ tablet  
(5 ml syrup) 
⅛ tablet  
(5 ml syrup) 
⅛  tablet  
(2.5 ml syrup) 
7–10 
4–11 mo 
¼ tablet  
(7.5 ml syrup) 
¼ tablet  
(7.5 ml syrup) 
¼tablet  
(5 ml syrup) 
11–14 
1–2 yrs 
½ tablet  
(12.5 ml syrup) 
½ tablet  
(12.5 ml syrup) 
¼ tablet  
(7.5 ml syrup) 
15–18 
3–4 yrs 
½ tablet  
(15 ml syrup) 
½ tablet  
(15 ml syrup) 
½ tablet  
(15 ml syrup) 
19–24 
5–7 yrs 
¾ tablet  
(20 ml syrup) 
¾  tablet  
(20 ml syrup) 
½ tablet  
(15 ml syrup) 
25–35 
 
8–10 yrs 
1¼  tablet  
1¼  tablet  
½ tablet  
36–50 
 
11–13 yrs 
1½ tablet  
1½ tablet  
1 tablet  
> 50 
14+ yrs 
2 tablet  
2 tablet  
1 tablet  
Treatment Failure (TF) 
Clinical deterioration due to P. vivax illness requiring hospitalization in the presence of parasitemia 
Presence of parasitemia and axillary temperature ≥37.5oC on any day between day 3 and day 28/42 
Presence of parasitemia on any day between day 7 and day 28/42, irrespective of clinical condition 

 
 
 
Primaquine: 7.5 mg base tablet. Medication given as 0.25mg/kg daily for 14 days in people with 
normal G6PD levels. In people with G6PD deficiency, 0.75 mg/kg (45 mg) once a week for 8 
weeks. 
 
Body Weight (kg) 
Single dose of primaquine (mg base) 
5 to 10 
Weight-based using extemporaneous preparation as outlined 
by Sanofi 
10 to < 25 
3.75 
25 to <50 
7.5 
50 to 100 
15 
ANNEX 6: Definitions of Severe Malaria  
Impaired consciousness: A Glasgow Coma Score <11 in adults or Blantyre coma score <3 in 
children 
Acidosis: A base deficit of >8 meq/l or, if unavailable, a plasma bicarbonate of <15 mM or 
venous plasma lactate >5mM. Severe acidosis manifests clinically as respiratory distress – 
rapid, deep and laboured breathing  
Hypoglycaemia: Blood or plasma glucose <2.2mM (<40mg/dl) 
Severe malarial anaemia: A haemoglobin concentration <5g/dl or a hematocrit of <15%in 
children <12 years of age (<7g/dl and <20%, respectively, in adults) together with parasite count 
of > 10,000 µ/l 
Renal impairment (acute kidney injury): Plasma or serum creatinine>265 µM (3 mg/dl) or 
blood urea >20 mM 
Jaundice: Plasma or serum bilirubin >50 lM (3 mg/dl) together with a parasite count >100,000 
µ/l 

 
 
Pulmonary oedema:Radiologically confirmed, or oxygen saturation <92% on room air with 
respiratory rate >30/min, often with chest indrawing and crepitations on auscultation  
Significant bleeding: Including recurrent or prolonged bleeding from nose, gums, or 
venipuncture sites; haematemesis or melaena 
Shock: Compensated shock is defined as capillary refill ≥3 seconds or temperature gradient on 
leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic 
blood pressure < 70mm Hg in children or <80 mm HG in adults with evidence of impaired 
perfusion (cool peripheries of prolonged capillary refill)  
Hyperparasitemia: P. vivax>2% 
Annex 7. Medications with Antimalarial Activity that Should not be Used During 
the Study Period 
 Amtimalarials:-Chloroquine, Amodiaquine; Quinine, quinidine;Mefloquine, halofantrine, 
lumefantrine; Artemisinin and its derivatives (artemether, arteether, artesunate, 
dihydroartemisinin); Proguanil, chlorproguanil, pyrimethamine;Sulfadoxine, sulfalene, 
sulfamethoxazole, dapsone;Primaquine;  Aovaquone; 
 Antibiotics:Tetracycline*,Doxycycline,Erythromycin,Azythromycin,Clindamycin 
,Rifampicin ,Trimethoprim,Pentamidine 
 Tetracycline eye ointments can be used. 
ANNEX 8: Study Schedule 
 
Day 0: 
 
Screening 
 Clinical assessment including measurement of weight and height — referral in case of 
severe malaria/danger signs 
 Measurement of axillary temperature 
 Parasitological assessment 
 Informed consent 

 
 
 Pregnancy test, if indicated 
Enrollment 
o Treatment, first dose 
o Blood sampling for blood smears, hemoglobin and filter paper 
 
Day 1: 
 
o Clinical assessment — referral in case of severe malaria/danger signs 
o Measurement of axillary temperature  
o Blood sampling for blood smears and filter paper 
o Treatment, second dose or alternative treatment in case of early treatment failure 
 
Day 2: 
 
o Clinical assessment — referral in case of severe malaria/danger signs 
o Measurement of axillary temperature  
o Blood sampling for blood smears and filter paper 
o 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: 
 
o Clinical assessment — referral in case of severe malaria/danger signs 
o Measurement of axillary temperature 
o Blood sampling for blood smears and filter paper 
o Alternative treatment in case of treatment failure 
o Hemoglobin/hematocrit (Day 0, Day 14, Day 28, Day 42) 
Any other day: 
o Clinical assessment — referral in case of severe malaria/danger signs 

 
 
o Measurement of axillary temperature 
o Blood sampling for blood smears and filter paper 
o Hemoglobin/hematocrit if indicated clinically 
o Alternative treatment in case of treatment failure 

 
 
ANNEX 9: Schedule of Follow-Up Activities 
 
day 0 day 1 day 2 day 3 
day 7 
day 
14 
day 21 day 28 
ay 35 
ay 42 
Any other day 
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 
Hemoglobin 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Filter paper 
X 
 
 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
Drug 
adverse 
event 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
Drug to be given 
X 
X 
X 
 
 
 
 
 
 
 
(X) 
Rescue treatment 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
NOTES:  Parentheses denote conditional or optional activities. 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.  

 
 
Annex 10: Consent Procedure 
Categories of consent forms 
I. 
for children 6 months-11 years old parental/guardian permission will be obtained 
II. 
For patients 12 -17 years old assent from the patient and parental/guardian permission 
will be obtained 
III. 
For patients age 18 yrs. and older adult consent will be obtained 
Procedure 
1. Explain that he has P.vivax  malaria infection and proceed with the consent process,  
2. Read and Explain study objectives, procedures, the benefits and risks of taking part in the 
study.  
3. If the person/guardian can read, provide a copy of the consent form in their preferred 
language and ask them to read the entire document. If they state that they cannot read, 
review the entire consent form with them using their stated preferred language version 
(Amharic/Afan Oromo). When finished, ask if they have questions. 
4. Consenting participants and or their caretakers will be advised that they are free to decline 
any question or procedure and that they may terminate their participation at any time 
without loss of any benefits 
5. If they agree to join the study get those to sign the consent form with a witness (Obtain 
consent). Health worker/home visitor will act as a witness. 
6. If the participant/guardian is illiterate, make a thumbprint using the left thumb by rolling 
the thumb from side to side on an inkpad and again on the consent form.  
7. Once the consent form is completed, send it to the clinician to proceed 
ANNEX 11: CONSENT/ASSENT FORMS  
Consent/Assent Form in English 
 
Title: - Monitoring the efficacy of frontline antimalarial drugs in Ethiopia, 2022/23   
 
Consent form for informing adults (>18) or consent form for parental permission for child 
six month up to 11 years and  assent form for children aged in between 11-17 years old study 
participants enrolment form for malaria in vivo efficacy study (Flesch-Kincaid Reading 
Level 9.0)   

 
 
Contact Person:    
         Dinka Dugassa: Wallaga University, Institute of Health Sciences and the PI of the Research 
         Mobile Number:+251911176148,Nekemte, Ethiopia   
         Ibrahim Keder:  EPHI staff and EPHI-IRB director   
         Mobile Number:  +251 911 95 71 61 Addis Ababa, Ethiopia    
 
 
Anticipated Number of Subjects: 100 Voluntary Participants 
 
Purpose: This research study aims to find out how well malaria treatment works in Ethiopia and 
will assist National Malaria Elimination Program (NMEP) managers to make appropriate 
intervention strategies for tackling the emergence of resistance and improving the treatment of 
malaria. This may help you or someone you know in the future. Therefore, we are asking you or 
your child to be part of this study because your/your child‘s diagnoses result shows a malaria 
parasite in your blood. This study is supported by the Ethiopia Federal Ministry of Health 
(FMoH) and EPHI.  
Study duration: The study will take place over 42 days. During the study period, you will be 
asked to come to the health facility or to bring your child back to the clinic on scheduled s: 1st 
day, 2nd, 3rd, 7th, 14th, 21st, 28th,35th and 42 days.   
Procedures:  During each follow-up visit, we would like to obtain finger prick blood samples 
from you or your child by qualified lab personnel that would be used for blood hemoglobin level 
determination and malaria diagnoses to detect the presence of drug resistance markers, thus to 
see the outcome of treatment. 
Risks There is very minimal risk in participating but you or your child may experience a small 
pain during finger pricking. The pain should disappear within a day. The drugs can cause an 
upset stomach, vomiting, diarrhoea, headache, dizziness, mild skin rash, and itching. But these 
are mostly mild and soon go away. Patients showing deterioration in their clinical status will be 
followed and immediately admitted to the clinic free of charge for appropriate treatment 
according to the national treatment guidelines until they recover. 

 
 
Benefits You may or may not get personal (direct) benefits from participating in this study but 
will not get paid for participating. There are possible benefits of participating in this study: You 
will not have to pay fees for any clinic visits during this study, including any other illnesses 
during the 28/42 days of follow-up. You or your child will be closely followed for the next 28/42 
days to see how well the administered treatments are working. 
Injuries፡Staff members will assist you in obtaining medical treatment, including emergency 
treatment, hospital care, and follow-up care as needed. Any hospital stays which occur during the 
28/42 days follow-up period will be paid for. Signing this consent form does not give up any of 
your legal rights.  
Compensation፡You will receive 100 Ethiopian Birr for each visit to pay for your travel to the 
clinic 
Participation፡Taking part in this study is your choice. You can decide not to take part in or stop 
being in the study at any time. Your choice will not affect the treatment you receive for malaria. 
Also, none of the treatments you receive will be affected. You may leave the study at any time. 
This will not affect your health care, and you will still receive malaria treatment for free. If a 
staff member needs to take you out of the study for any valid reason, we will not continue 
following you. If you are removed from the study before the treatment is complete, or if the 
medicine did not make you better, then you will be referred to the clinic and treated with another 
treatment as noted in Ethiopia‘s malaria treatment guidelines.  
Statement of Consent   
By signing or placing my thumbprint below, I am saying that:    
I have read this form, or it has been read to me; I have been able to ask questions about it, and 
my      questions have been answered.    
1 Children 6 months-11 years: parental/guardian permission: my child‘s participation is 
voluntary and that I can leave the study at any time without it affecting my care.   

 
 
2 Children aged 12-17 years: I understand that my participation is voluntary and that I can 
leave the study at any time without it affecting my care. My decision to participate is 
supported by my parent/ guardian (parental/guardian permission will be obtained) but not 
forced by him/her.  
3 For adults (18 years & older): I understand that my or my child‘s participation is 
voluntary and that I can leave the study at any time without it affecting my care.    
I agree to enroll in this study. I agree to report any unexpected or unusual symptoms.  
I 
have 
received 
a 
copy 
of 
this 
form. 
Signing this form does not waive any of my legal rights. 
Circle the category of consent/assent below: 
       1. 6 months-11 years       2. 12-17 years of age      3.  18 years & older 
Person Obtaining Consent/Assent 
     Print 
Name: 
______________________________ 
Signature: 
________________Date: 
___/____/____ 
Participant 
Print Name: __________________ Signature: ________________ Thumbprint: _________ Date: 
__/____/____           
Parent or guardian   
Print Name: ______________________ Signature: _________Thumbprint: _________ Date: 
___/____/____ 
Witness: 
 
   Print Name: ______________________ Signature: __________Date: ___/____/____