"Aiming at Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in an Era of Imminent Plasmodium Falciparum Resistance in Bagamoyo District, Tanzania - New Strategies With Old Tools"
Phase: PHASE4
Conditions: Malaria,Falciparum
Sponsor: Muhimbili University of Health and Allied Sciences

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MUHAS/ KAROLINSKA INSTITUTET /UPPSALA UNIVERSITY 
 
Clinical Research Protocol 
 
“Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in 
an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new 
strategies with old tools”. 
 
 
DR. LWIDIKO EDWARD MHAMILAWA-  PHD STUDENT 
MUHAS 
Muhimbili University of Health and Allied Sciences 
JULY 4, 2017 

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MUHAS/ KAROLINSKA INSTITUTET /UPPSALA UNIVERSITY 
Clinical Research Protocol 
 
“Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in an 
era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new 
strategies with old tools”. 
 
Protocol Number: 
01.05.2017 – ALU -PQ 
Version Date: 
04th July  2017 Version 05 
Investigational Product: 
Artemether-Lumefantrine and Primaquine 
Development Phase: 
Phase IV  
Sponsors: 
Muhimbili University of Health and Allied Sciences; 
Dept. of Parasitology and Medical Entomology 
P. O. Box 65001 Upanga, 
Dar es salaam Tanzania, 
 
Karolinska Institutet, 
Dept of Molecular, Tumor and Cell Biology, 
Nobelsväg 16 
171 77 Stockholm, Sweden 
 
Uppsala University,  
Dept. 
of 
Women's 
and 
Children's 
Health, 
IMCH, 
Drottninggatan 4, 75310 Uppsala 
Sweden 
 
Funding Organization: 
Swedish International Development Agency (SIDA) & 
Swedish Research Council 
Principal Investigator: 
Name: Dr. Lwidiko Edward Mhamilawa 
 
Telephone: +255712865206 
Fax: 
 
 
E-mail: lwidikoedward@gmail.com 

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Co-investigators / 
supervisors: 
Name: Dr. Billy Ngasala                                      
Address: P.O Box 65011 DSM                              
Mobile: 0754316359       
Email:bngasala70@yahoo.co.uk  
 
Name: Prof. Anders Bjorkman 
 
Address: Solnavägen 1, 171 77 Solna, Sweden 
Mobile:  +46 (0) 8-524 868 29.                 
Email: Anders.Bjorkman@ki.se 
 
Name: Prof. Andreas Mårtensson  
 
Address: Kapellgränd 6A, 13146 Nacka, Sweden             
Mobile: +46-737454034                         Email: 
andreas.martensson@kbh.uu.se  
 
 
Coordinating Center: 
Muhimbili University of Health and Allied Sciences; 
Dept. of Parasitology and Medical Entomology 
P. O. Box 65001 Upanga, 
Dar es salaam Tanzania, 
 
 
Approval: 
 
 
 
Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless state law or regulations require such disclosure.  Subject to the foregoing, 
this information may be disclosed only to those persons involved in the study who have a need to know, 
with the obligation not to further disseminate this information.   

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing Muhimbili 
University of Health and Allied Sciences (MUHAS), Karolinska Institutet (KI) and Uppsala 
University, with complete and timely information, as outlined in the protocol.  It is understood that 
all information pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and 
myself, I agree to maintain the procedures required to carry out the study in accordance with 
accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Number:  01.05.2017 
 
Protocol Title:  Aiming at prolonging the therapeutic life span of artemisinin-based 
combination therapies in an era of imminent Plasmodium falciparum resistance in 
Bagamoyo District, Tanzania - new strategies with old tools. 
 
Protocol Date:  04th  July 2017 
 
 
 
July 4th 2017 
Investigator Signature  
 
Date 
Dr. Lwidiko Edward Mhamilawa 
Print Name and Title 
Site # 
01 
 
Site Name 
Yombo Dispensary  
Address 
 P. O. Box  
 
Chasimba 
 
Bagamoyo – Pwani 
 
Tanzania 
Phone Number 
+255712865206 

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TABLE OF CONTENTS 
Table of Contents 
1 
BACKGROUND 
16 
1.1 
OVERVIEW OF CLINICAL STUDIES 
17 
2 
STUDY RATIONALE 
17 
2.1 
RISK / BENEFIT ASSESSMENT 
18 
3 
STUDY OBJECTIVES 
19 
3.1 
BROAD OBJECTIVE 
19 
3.2 
SPECIFIC OBJECTIVES 
19 
4 
STUDY DESIGN 
20 
4.1 
STUDY AREA 
20 
4.2 
STUDY OVERVIEW 
20 
5 
CRITERIA FOR EVALUATION 
20 
5.1 
PRIMARY EFFICACY ENDPOINT 
20 
5.2 
SECONDARY EFFICACY ENDPOINTS 
20 
5.3 
SAFETY EVALUATIONS 
21 
6 
SUBJECT SELECTION 
21 
6.1 
STUDY POPULATION 
21 
6.2 
INCLUSION CRITERIA 
21 
6.3 
EXCLUSION CRITERIA 
21 
7 
CONCURRENT MEDICATIONS 
22 
7.1 
ALLOWED MEDICATIONS AND TREATMENTS 
22 
8 
STUDY TREATMENTS 
23 
8.1 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
23 
8.2 
BLINDING 
23 
8.3 
FORMULATION OF TEST AND CONTROL PRODUCTS 
23 
8.3.1 
FORMULATION OF TEST PRODUCT 
23 
8.3.2 
FORMULATION OF CONTROL PRODUCT 
24 
8.3.3 
PACKAGING AND LABELING 
24 
8.4 
SUPPLY OF STUDY DRUG AT THE SITE 
24 
8.4.1 
DOSAGE/DOSAGE REGIMEN 
24 
8.4.2 
DISPENSING 
26 
8.4.3 
STORAGE 
26 
8.4.4 
STUDY DRUG ACCOUNTABILITY 
26 
8.5 
MEASURES OF TREATMENT COMPLIANCE 
26 

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9 
STUDY PROCEDURES AND GUIDELINES 
26 
9.1 
CLINICAL ASSESSMENTS 
27 
9.1.1 
CONCOMITANT MEDICATIONS 
27 
9.1.2 
DEMOGRAPHICS 
27 
9.1.3 
MEDICAL HISTORY 
27 
9.1.4 
PHYSICAL EXAMINATION 
27 
9.1.5 
VITAL SIGNS 
27 
9.1.6 
ECG 
27 
9.1.7 
PREGNANCY SCREENING 
27 
9.1.8 
ADVERSE EVENTS 
27 
9.2 
CLINICAL LABORATORY MEASUREMENTS 
27 
9.2.1 
BLOOD COLLECTION PROCEDURES: 
27 
9.2.2 
MICROSCOPY 
28 
9.2.3 
LOOP MEDIATED ISOTHERMAL AMPLIFICATION (LAMP) 
30 
9.2.4 
HAEMOGLOBIN 
31 
9.2.5 
URINALYSIS 
31 
9.2.6 
BLOOD CHEMISTRY PROFILE 
31 
9.3 
RESEARCH LABORATORY MEASUREMENTS 
31 
9.3.1 
MOLECULAR GENOTYPING 
31 
9.3.2 
PHARMACOKINETIC MEASUREMENTS 
32 
10 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
32 
10.1 
ADVERSE EVENTS 
32 
10.2 
SERIOUS ADVERSE EXPERIENCES (SAE) 
33 
10.2.1 
SERIOUS ADVERSE EXPERIENCE REPORTING 
34 
10.3 
MEDICAL MONITORING 
34 
11 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
34 
11.1 
EARLY DISCONTINUATION OF STUDY DRUG 
34 
11.2 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
35 
11.3 
REPLACEMENT OF SUBJECTS 
35 
12 
PROTOCOL VIOLATIONS 
35 
13 
DATA SAFETY MONITORING 
36 
14 
STATISTICAL METHODS AND CONSIDERATIONS 
36 
14.1 
DATA SETS ANALYZED 
36 
14.2 
PATIENTS FLOW DIAGRAM 
36 
14.3 
PRIMARY ANALYSIS PLAN 
37 
14.4 
ANALYSIS OF SECONDARY ENDPOINTS 
37 
14.5 
INTERIM ANALYSIS 
37 
14.6 
SAMPLE SIZE AND RANDOMIZATION 
37 
15 
DATA COLLECTION, RETENTION AND MONITORING 
38 
15.1 
DATA COLLECTION INSTRUMENTS 
38 

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15.2 
DATA MANAGEMENT PROCEDURES 
38 
15.3 
DATA QUALITY CONTROL AND REPORTING 
38 
15.4 
ARCHIVAL OF DATA 
39 
15.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
39 
15.6 
MONITORING 
39 
15.7 
SUBJECT CONFIDENTIALITY 
39 
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
39 
16.1 
PROTOCOL AMENDMENTS 
40 
16.2 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES 
40 
16.3 
INFORMED CONSENT FORM 
40 
16.4 
PUBLICATIONS 
41 
17 
BUDGET 
41 
17.1 
BUDGET JUSTIFICATION 
43 
17.2 
WORK PLAN 
44 
17.3 
INVESTIGATOR RESPONSIBILITIES 
46 
18 
BIBLIOGRAPHY 
47 
19 
APPENDIX I. SCHEDULE OF EVENTS DURING STUDY VISITS 
49 
 
53 
20 
APPENDIX II: INFORMED CONSENT 
53 
20.1 
ENGLISH VERSION 
53 
20.2 
SWAHILI VERSION 
59 
21 
APPENDIX III: INFORMED ASSENT FORM 
65 
21.1 
ENGLISH VERSION 
65 
21.2 
SWAHILI 
69 
22 
APPENDIX IV: CASE RECORD FORM (CRF): 
73 
23 
APENDIX IV: SERIOUS ADVERSE EVENT REPORT FORM: 
79 
24 
APENDIX V: ADVERSE EVENT FORM 
81 
24.1.1 
APPENDIX VB 
82 
24.1.3 
APPENDIX VB 
88 
24.1.4 
PROCEDURE FOR INVESTIGATION OF SUSPECTED HEMOLYSIS 
92 
24.1.5 
PROCEDURE FOR MANAGEMENT OF HEMOLYSIS 
92 
 
 

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LIST OF ABBREVIATIONS 
AE 
ACT 
AL 
adverse event 
Artemisinin-Based Combination Therapy 
Artemether-Lumefantrine 
ALT 
Alanine aminotransferase 
CRF 
Case report form 
DAPI 
(4',6-diamidino-2-phenylindole)  
DBS 
Dried Blood Spot 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electro- Cardiogram 
FDA 
Food and Drug Authority 
GCP 
Good Clinical Practice 
GCT 
Gametocyte Clearance Time 
Hb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
KI 
Karolinska Institutet 
LAMP 
Loop-mediated isothermal Amplification 
LLIN 
Long Lasting Insecticide Treated Nets 
MoMic 
Mobile Microscopy 
mRDT 
Malaria Rapid Diagnostic Test 
MUHAS 
Muhimbili University of Health and Allied Sciences 
mRNA 
Messenger Ribonucleic Acid 
NMCP 
National Malaria Control Program  
PCR 
Polymerase Chain Reaction 
PCR- RFLP 
PCR-Restriction Fragment Length Polymorphism 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PQ 
Primaquine 
QT-NASBA 
Quantitative Nucleic Acid Sequence Based Assay 
SAE 
serious adverse experience 
RNA 
Ribonucleic Acid 
SIDA 
Swedish International Development Agency 

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SPSS 
Statistical Package for Social Science 
SNP 
Single Nucleotide Polymorphism 
WBC 
White Blood Cells 
WHO 
World Health Organization 

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PROTOCOL SYNOPSIS 
TITLE 
Aiming at prolonging the therapeutic life span of artemisinin-based 
combination therapies in an era of imminent Plasmodium falciparum 
resistance in Bagamoyo District, Tanzania - new strategies with old 
tools. 
SPONSOR 
Muhimbili University of Health and Allied Sciences; 
Dept. of Parasitology and Medical Entomology 
P. O. Box 65001 Upanga, 
Dar es salaam Tanzania, 
 
Karolinska Institutet, 
Dept of Molecular, Tumor and Cell Biology, 
Nobelsväg 16 
171 77 Stockholm, Sweden 
 
Uppsala University,  
Dept. of Women's and Children's Health, IMCH, Drottninggatan 4, 
75310 Uppsala, Sweden 
 
FUNDING 
ORGANIZATION 
Swedish International Development Agency (SIDA) & Swedish 
Research Council 
NUMBER OF SITES 
ONE 
RATIONALE 
Despite documented high cure rates of ACT in Tanzania, and Africa 
elsewhere, clinical trials conducted in Tanzania with SIDA and 
Swedish Research Council support, provide evidence for in vivo 
selection of lumefantrine tolerant/resistant parasites among recurrent 
infections[1], [2]. Similarly, molecular epidemiology studies from 
Bagamoyo District, Tanzania, have shown temporal selection of 
lumefantrine associated genetic tolerance/resistance markers in the 
parasite population following wide scale use of artmether-lumefantrine, 
but without signs of compromised treatment efficacy [3]. 
During the last decade, and despite the documented rapid microscopy 
determined parasite clearance of artemether-lumefantrine in Bagamoyo 
District, interest has developed in understanding the observation of high 
residual PCR determined positivity rate on day 3 after supervised 
artemether-lumefantrine treatment in the magnitude of almost 30% in 
previous assessments from 2015 [4]. Using deep sequencing 
approaches studies have recently detected PCR determined delayed 
parasite clearance curves in P. falciparum sub-populations in 
Bagamoyo District, [5]. The clearance times by PCR of these sub-
populations were similar to artemisinin resistant parasites in Myanmar 
as assessed by microscopy, but the former did, importantly, not harbor 
any of the described mutations in Kelch13 propeller associated with 

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artemisinin resistance. However, these Tanzanian parasite sub-
populations need to be further studied and characterized since they may 
provide important clues to the understanding of artemisinin survival 
strategies among the East African P. falciparum parasite population.      
Taken together, our longitudinal clinical and molecular data described 
above from a defined geographical area of Tanzania, East Africa, 
extending from pre-ACT implementation, i.e. before 2006, to a decade 
of wide scale artemether-lumefantrine use in Bagamoyo district, 
provide evidence for declining susceptibility to ACT, both to 
artemether and lumefantrine, among the P. falciparum population. 
These parasites (“last man standing”) that survived 10 years of ACT 
exposure have indeed shown excellent survival instincts and may thus 
be particularly resistant prone. However, if we loose ACT to P. 
falciparum resistance in Africa, this will have devastating effects on 
malaria morbidity and mortality and may swiftly ruin the improvements 
the global malaria community achieved during the past decade with 
ACT as a key component for success. 
Based on the above we suggest prolonged treatment with ACT and 
addition of transmission blocking treatment using a single low dose of 
primaquine administered on the last day of ACT treatment.  
STUDY DESIGN 
A two arm randomized, single-blinded clinical trial. The intervention 
arm will receive a six days treatment course of artemether-lumefantrine 
together with a single low-dose of primaquine (0.25 mg/kg) 
administered at the sixth day of treatment. The control arm will receive 
standard 3-day course of artemether-lumefantrine followed by placebo. 
The blinded party shall be the patients enrolled.  Enrolled patients will 
be receiving Directly Observed Therapy during the treatment phase. 
Follow-up will be 42 days. 
PRIMARY 
OBJECTIVE 
To assess the therapeutic efficacy of standard versus extended 
artemether-lumefantrine treatment from 3 to 6 days and the effect of a 
single low-dose of primaquine administered on day 6 on gametocyte 
clearance in an era of imminent P. falciparum resistance in Bagamoyo 
District, Tanzania.  
 

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SECONDARY 
OBJECTIVES 
1. To compare the therapeutic efficacy of standard 3 day 
course versus an extended 6 day course of artemether-
lumefantrine on PCR determined parasite clearance, PCR 
corrected cure rate on days 28 and 42, post treatment 
prophylaxis and safety in patients with uncomplicated P. 
falciparum during high transmission season.  
2. To assess if the addition of single low-dose of primaquine 
(0.25 mg/kg) on the 6th day of ACT treatment would 
improve the therapeutic efficacy of primaquine in malaria 
transmission blocking by reducing PCR determined 
gametocyte carriage/clearance.     
3. To characterize molecular markers of individual P. 
falciparum sub-populations that exhibit delayed PCR-
determined parasite clearance in relation to known genetic 
markers associated with ACT resistance/tolerance. 
4. To compare the diagnostic accuracy of MoMic, LAMP, and 
conventional microscopy with PCR as gold standard in 
determination of day 3 parasitemia.  
NUMBER 
OF 
SUBJECTS 
280 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria:  
1. Age more than 1 year and less than 65 years. 
2. Weight 10 kg and above; 
3. Body temperature ≥37.5°C or history of fever in the last 24 
hours;  
4. Microscopy determined asexual P. falciparum mono-
infection regardless of parasitemia 
5. Normal – QTc Interval in Baseline ECG of less than 440ms 
in male and 460ms in females 
Exclusion Criteria: 
1. Symptoms/signs of severe malaria or danger signs; 
2. Pregnancy, Breastfeeding or unwilling to practice birth 
control during participation in the study. 
3. Known allergy to study medications;  
4. Hb <8 g/dl;  
5. Reported antimalarial intake within last 2 weeks;  
6. On regular medication, which may interfere with 
antimalarial pharmacokinetics and  
7. Blood transfusion within last 90 days. 

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CONTROL 
PRODUCT, 
DOSE 
AND 
ROUTE 
OF 
ADMINISTRATION  
1. Artemether-lumefantrine (AL) 
 Enrolled patients in the control arm will be treated with artemether-
lumefantrine (Coartem®, Novartis or any other WHO prequalified 
ALU) according to body weight and Tanzanian national treatment 
guidelines for uncomplicated P. falciparum malaria, as follows: One 
tablet to those weighing 5-14 kg; two tablets to children with 15-24 kg 
or three tables to children with 25 – 34 kg.  The full course of treatment 
for all study patients consists of 6-doses given twice daily, at 0, 8, 24, 
36, 48, 60 hours, with the dose being given as directly observed by a 
health worker, and the second dose should strictly be given after 8 
hours. A fatty snack (biscuits) will be administered together with all 
artemether-lumefantrine doses to optimise absorption. Participants will 
be observed for 30 minutes after each drug dose. 
 
2.  Placebo 
This is a placebo controlled study where patients who will be in the 
control arm will receive placebo tablets and a placebo aqueous solution 
in place of the Primaquine that will be given with the 12th dose of ALU.  
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
1. Artemether-lumefantrine (AL) 
In the intervention arm, extended from 3 to 6 days. In the control arm, 
patients will be receiving placebo after completion of the standard 3 
days-six dose regimen. For practical purposes, a simpler dosage 
regimen is recommended in order to improve compliance; subsequent 
doses could be given twice daily (morning-evening) in the second and 
third days of treatment until completion of the doses. A fatty snack 
(biscuits) will be administered together with all artemether-
lumefantrine doses to optimise absorption. Participants will be 
observed for 30 minutes after each drug dose. 
 
2. Primaquine 
For patients allocated to the prolonged treatment course, a single 0.25 
mg/kg primaquine dose (Primaquine phosphate, Sanofi) will be 
administered concomitantly with the last (i.e. twelfth) artemether-
lumefantrine dose. Primaquine will be prepared and administered in an 
aqueous solution [6]. To preserve the accuracy of lower weight-based 
doses, all primaquine doses will be administered in aqueous solution 
and measured using a sterile syringe. The primaquine dose will be given 
based on weight bands. A snack will also be made available to reduce 
the side effects like abdominal discomfort.  

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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be in the Study for about 42 days 
Screening:  at Day 0 
Active Treatment:  3-6 days depending on the treatment Arm  
Follow-up: 42 days 
The total duration of the study is expected to be SIX Months.  Four (4) 
months for subject recruitment and two (2) for final subject follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed: Paracetamol or acetaminophen according to national 
treatment guidelines. Patients given tetracycline as an eye ointment will 
not be excluded 
 
Prohibited: in the case of self-medication or if an antimalarial drug or 
an antibiotic with antimalarial activity is administered by a third party. 
EFFICACY 
EVALUATIONS 
1. PCR Determined Parasite clearance by day 5 and 7 
2. Crude and PCR Corrected Cure Rate by day 28 and 42 
3. Gametocyte clearance on Day 7 and 14 
PRIMARY ENDPOINT 
The primary outcome is proportion of PCR detectable parasitemia on 
days 5 and 7 in the respective arms.  
SECONDARY 
ENDPOINTS 
Secondary outcomes include: 
1. Microscopy and PCR determined parasite clearance times, 
2. selection of genetic drug resistance markers during the early 
treatment phase,  
3. PCR determined gametocyte carriage/clearance times,  
4. Hemoglobin recovery,  
5. Fever clearance time 
6. Crude and PCR corrected cure rates by day 28,  
7. Safety and tolerability, and  
8. Day 7 plasma lumefantrine concentrations in the respective 
arms. 
OTHER 
EVALUATIONS 
Pharmacokinetics of Artemisinin and its derivatives, Lumefantrine and 
its derivatives  
SAFETY 
EVALUATIONS 
Change in clinical safety labs from baseline in the following 
investigations: 
1. Drop in Hb by more than 2 g/dl 
2. Hematuria observed color change will be gauged against the 
Hillmen color chart 
3. Prolongation QTc Interval in ECG above the upper limits of the 
normal range  
Incidence of adverse events: All adverse events, drug-related or not, 
will be recorded on the case report form. Serious adverse events must 

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be reported to the sponsor. At the end of the trial, all relevant clinical 
and molecular results will be reported to the sponsor and the Ministry 
of Health. Signs and symptoms such as fatigue, weakness, dizziness, 
headache, palpitations or allergic drug reactions (rash), diarrhea, 
abdominal pain, dizziness, itching, fever and Hb  prior, during and after 
treatment will be recorded and determined to whether they are related 
to the trial medicine. 
PLANNED 
INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study through 
Visit 10, an interim analysis for safety will be conducted by an 
independent data monitoring committee. Serious adverse events will be 
monitored by the committee on an ongoing basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
Data will be double entered into a password protected SPSS V. 20 
database. Data will be cleaned by visual inspection for outliers. 
Preliminary univariate and bivariate analyses will be carried out to 
estimate the effects of lumefantrine level, age, and parasitemia and host 
polymorphisms. Descriptive statistics such as mean, standard deviation 
and percentages will be reported in the univariate analysis according to 
the type of the data and using ANOVA statistical output will be 
obtained. Comparison of fever to parasite clearance among treatment 
arms will be done using Kaplan-Meiyer’s Curves and the Logistic 
Regression Model. Both adjusted and unadjusted analysis by 
confounding factors will be implemented. Interaction terms will be 
used to assess effect measure modification. P< 0.05 will be considered 
significant.  
Rationale for Number of 
Subjects 
The sample size was calculated based on an assumed clinically 
meaningful difference between the arms in PCR positivity rate of 15% 
on day 5 (20% after standard 3-day artemether-lumefantrine treatment 
and 5% in the interventional arm). To be able to show this difference 
with 80% power at 0.05 significance level, 116 patients are needed in 
each arm. To allow for 20% attrition, a total of 140 patients will be 
included in each arm.  
 
 

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1 
BACKGROUND 
General background 
Wide scale use of artemisinin-based combination therapy (ACT) for treatment of uncomplicated 
Plasmodium falciparum in malaria endemic areas during the past decade has dramatically 
improved malaria case management and the possibility to ensure parasitological cure. This has in 
turn resulted in large number of deaths avarted, especially among African children below 5 years 
of age and pregnant women, i.e. the two most vulnerable groups for severe malaria disease and 
death. Thus, ACT has significantly contributed to the recent decline in global malaria burden [7]. 
Its importance for global health was highlighetd when Professor You You Tu received the Nobel 
Prize 2015 "for her discoveries concerning a novel therapy against Malaria", i.e. artemisinin. 
 
The rationale behind ACT is to improve treatment efficacy and delay development of resistance 
by the use of two or more drugs with different modes of action, including an artemisinin-derivative 
with rapid and effective reduction of the parasite bio-mass (the effect being particularly 
pronounced on asexual ring stages in the erythrocytic lifecycle) and gametocyte carriage (with 
effect on young gametocytes only), combined with a partner drug with longer duration of action. 
To improve rational use and delay development and spread of ACT resistance, WHO recommends 
ACT to be solely prescribed to patients with a parasite-based malaria diagnosis, either rapid 
diagnostic test (RDT) or microscopy [8]. 
 
In 2009 the first report of emerging artemisinin resistance in P. falciparum malaria from Southeast 
Asia was published. The resistance is phenotypically characterized by delayed parasite clearance 
times following ACT treatment [9]. Microscopy based P. falciparum positivity rate on day 3 after 
initiation of ACT treatment is considered an important determinant, and if the day-3 positivity rate 
exceeds 10% this is considered an alert for artemisinin resistance. The initial reports of artemisinin 
resistance originated from western Cambodia (Pailin), where also chloroquine and sulfadoxine-
pyrimethamine resistance was first documented. Despite containment campaigns parasites with 
delayed clearance post-ACT treatment has spread geographically and are presently found in five 
countries in the Mekong region (Myanmar, Thailand, Cambodia, Laos and Vietnam) [7]. 
 
The molecular basis for artemisinin resistance in Southeast Asia has been linked to mutations in 
the P. falciparum Kelch13 propeller domain. This was first described by Ariey et al. 2014. Kelch13 
encods a 726 amino acid protein containing a BTB/POZ domain and a C-terminal 6-blade propeller 
domain [10]. Mutations in the Kelch13 propeller domain, particullarly in position M4761, Y493H, 
R539T, I543T and C580Y, are associated with both in vivo and ex vivo artemisinin resistance 
[11]. Large-scale in vivo studies conducted in Africa and Asia have revealed around 20 non-
synonymous Kelch13 mutations associated with delayed parasite clearance following ACT 
treatment [12], whereas molecular epidemiological studies have reported 60 non-synonymous 
mutations.  
 
If these resistant parasites, in line with the historical experiences from chloroquine and 
sulfadoxine-pyrimethamine resistance, will spread westward across Asia and the Indian sub-
continent and eventually reach Africa, or emerge independently on the African continent, this will 

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have devastating effects on malaria morbidity and mortality globally. However, in Africa there has 
to date been no clear evidence of artemisinin resistant P. falciparum [7]. 
1.1 
Overview of Clinical Studies 
Specific background 
Few WHO prequalified ACT combinations are available. The most commonly used ACT in Africa 
is artmether-lumefantrine [8]. Tanzania, East Africa, where this project will be conducted, 
introduced artemether-lumefantrine as first-line treatment for uncomplicated malaria in 2006.  
The development of tolerance/resistance against lumefantrine, and other long acting partner drugs 
in ACT, has been suggested to start through post-treatment selection among recurrent infections 
of less sensitive P. falciparum parasites, as re-infecting parasites need to be able to survive the 
exposure of sub-therapeutic blood levels of lumefantrine. This hypothesis is supported by our own 
data from Bagamoyo District, indicating that re-infecting parasites carrying the pfmdr1 
N86/184F/D1246 haplotype were able to withstand 15-fold higher lumefantrine blood 
concentrations than those with the alternative haplotype (86Y/Y184/1246Y) [13]. This may in turn 
lead to a gradually shortened post-treatment prophylactic period, long before clinical treatment 
failures are apparent, why temporal surveillance of genetic antimalarial drug resistance markers of 
P. falciparum have been proposed as an early warning system of evolution of ACT 
tolerance/resistance. 
While awaiting development of alternative, but hopefully equally efficacious antimalarial drugs, 
it is critical to be proactive and identify and scientifically evaluate new strategies to protect/prolong 
the therapeutic lifespan of ACT. We propose two practical and feasible means in this regard, one 
is extending the ACT regimen by three days and the other is introducing a single low dose 
primaquine (0.25mg/kg) administered on the 6th day of artemether-lumefantrine treatment with the 
12th dose. 
The utility of the proposed new strategies with old tools are feasible interventions that can be 
programmatically rolled out without delay since the tools are well known and already in place. 
The assessment of these new strategies will provide an opportunity to further characterize the PCR 
determined day-3 and even day-5 positive parasite sub-population to improve the understanding 
of the genetic repertoire and thus artemisinin survival strategies among the East-African P. 
falciparum population and comparing them with the previously described Kelch13 mutations 
associated with artemisinin resistance. 
 
 
2 
 STUDY RATIONALE 
Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials 
conducted in Tanzania with SIDA and Swedish Research Council support, provide evidence for 
in vivo selection of lumefantrine tolerant/resistant parasites among recurrent infections [1], [2]. 
Similarly, molecular epidemiology studies from Bagamoyo District, Tanzania, have shown 
temporal selection of lumefantrine associated genetic tolerance/resistance markers in the parasite 
population following wide scale use of artmether-lumefantrine, but without signs of compromised 
treatment efficacy [3]. 

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During the last decade, and despite the documented rapid microscopy determined parasite 
clearance of artemether-lumefantrine in Bagamoyo District, interest has developed in 
understanding the observation of high residual PCR determined positivity rate on day 3 after 
supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous 
assessments from 2015 [11]. Using deep sequencing approaches studies have recently detected 
PCR determined delayed parasite clearance curves in P. falciparum sub-populations in Bagamoyo 
District, [12]. The clearance times by PCR of these sub-populations were similar to artemisinin 
resistant parasites in Myanmar as assessed by microscopy, but the former did, importantly, not 
harbor any of the described mutations in Kelch13 propeller associated with artemisinin resistance. 
However, these Tanzanian parasite sub-populations need to be further studied and characterized 
since they may provide important clues to the understanding of artemisinin survival strategies 
among the East African P. falciparum parasite population.      
Taken together, our longitudinal clinical and molecular data described above from a defined 
geographical area of Tanzania, East Africa, extending from pre-ACT implementation, i.e. before 
2006, to a decade of wide scale artemether-lumefantrine use in Bagamoyo district, provide 
evidence for declining susceptibility to ACT, both to artemether and lumefantrine, among the P. 
falciparum population. These parasites (“last man standing”) that survived 10 years of ACT 
exposure have indeed shown excellent survival instincts and may thus be particularly resistant 
prone. However, if we loose ACT to P. falciparum resistance in Africa, this will have devastating 
effects on malaria morbidity and mortality and may swiftly ruin the improvements the global 
malaria community achieved during the past decade with ACT as a key component for success. 
2.1 
Risk / Benefit Assessment 
Potential Risks 
The primary risk associated with this study is the drawing of frequent blood samples. In the first 
134 hours, there will be 8 sampling points, each requiring less than 2 milliliters of blood. The total 
volume collected over the course of the study (42 days) 6mls is significantly less than 5% of a 
participant’s total blood volume. This amount is generally considered acceptable for research 
studies.  It should also be acceptable to participants and their families.  In order to ensure that 
harms are reduced, we have planned a hemoglobin check at enrollment (baseline) and at day 5 
before receiving low dose primaquine (0.25 mg/kg). Then Hb level will be assessed at subsequent 
visits as well as at any ill visit to ensure that significant anemia does not occur in the children. Any 
children with a significant drop in hemoglobin will be admitted for further evaluation.  In addition 
to anemia, blood draws can be associated with pain, bruising and bleeding. Symptomatic control 
of all of these complications will be provided. 
A secondary risk associated with the study is breach of confidentiality. Measures will be in place 
to ensure confidentiality of participants and data generated.  Malaria is a common childhood illness 
in both trial site locations and does not carry any significant stigma associated with it. 
 
Potential Benefits 
In the local context it is standard to provide some level of remuneration to participants/families at 
each site. For the first 6 days, patients who are living far from the site will be retained at the hospital 
after the first dose to allow for adequate sample collection, but also providing close clinical 
monitoring during initial follow-up and Directly Observed Therapy (DOT). They will receive 
payment such as food and transportation allowance reimbursement equivalent of the local 

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transportation cost for the participant and families during the observations period at the hospital, 
since they will need to come twice a day. In addition, participants will be receiving high quality 
care during a febrile illness. Patients will receive treatment for their malaria infection according to 
National Treatment Guidelines. They will then benefit from routine weekly follow-up to ensure 
resolution of infection during the 42 day follow up period.  
3 
STUDY OBJECTIVES 
3.1 
Broad Objective 
To assess the therapeutic efficacy of extended artemether-lumefantrine treatment from 3 to 6 days 
and the effect of a single low dose of primaquine administered on day 6 on gametocyte clearance 
in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania 
3.2 
Specific Objectives 
1. To compare the therapeutic efficacy of standard 3 day course versus extended 6 day 
course of artemether-lumefantrine on PCR determined parasite clearance, post 
treatment prophylaxis and safety in patients with uncomplicated P. falciparum during 
high transmission season.  
 
2. To assess if the addition of single low-dose of primaquine (0.25 mg/kg) on the 6th day 
of ACT treatment would improve the therapeutic efficacy of Primaquine in malaria 
transmission blocking by reducing PCR determined gametocyte carriage/clearance. 
 
3. To characterize molecular markers of individual P. falciparum sub-populations that 
exhibit delayed PCR-determined parasite clearance in relation to known genetic 
markers associated with ACT resistance/tolerance. 
 
4. To compare the diagnostic accuracy of MoMic, LAMP, and conventional microscopy 
with PCR as gold standard in determination of day 3 parasitemia.  
 
 
 
 
 

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4 
STUDY DESIGN 
4.1 
Study Area 
Bagamoyo district, Coast region, Tanzania, has an estimated population of about 3 117,400 most 
of whom are peasants and fishermen [14]. Bagamoyo District is divided into 6 divisions, and 22 
wards, comprising 97 villages and 67 health facilities, including 1 hospital, 5 health centers and 
59 dispensaries, 44 of which belong to government institutions, 5 to voluntary agencies, and 10 
are privately run [15]. The proposed study site, i.e. Yombo primary health care clinic serves a total 
population of more than 8000 people, within easy access to the referral hospital in Bagamoyo 
town.  
Yombo dispensary has access to two clinical officers, two nurses and one laboratory technician, 
all trained in malaria case management, microscopy and good clinical practice. Malaria 
transmission is moderate, and perennial with peaks related to the rainy seasons. After the 
introduction of artemether-lumefantrine as first line treatment for uncomplicated malaria in 2006 
together with insecticidal treated bed-net distribution campaigns the burden of malaria has 
declined significantly. P. falciparum is the predominant species responsible for >95% of diagnosed 
malaria cases. 
4.2 
Study Overview 
A two arm randomized, single-blinded clinical trial. The intervention arm will receive a six days 
treatment course of artemether-lumefantrine together with a single low-dose of primaquine (0.25 
mg/kg) administered at the sixth day of treatment. The control arm will receive standard 3-day 
course of artemether-lumefantrine followed by placebo for 3 days. 
The blinded party shall be the patients enrolled.  Enrolled patients will be have an option of 
remaining at the during the treatment phase to avoid coming twice a day for medication and blood 
sampling. Follow-up will be 42 days.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study. The study is planned to 
have 280 subjects. Total duration of subject participation will be six weeks.   
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary outcome is proportion of PCR detectable parasitemia on days 5 and 7 in the respective 
arms. 
5.2 
Secondary Efficacy Endpoints 
Secondary outcomes include microscopy and PCR determined parasite clearance times, fever 
clearance time, selection of genetic drug resistance markers during the early treatment phase, 
gametocyte carriage/clearance times, hemoglobin recovery, crude and PCR corrected cure rates 
by day 28, safety and tolerability, and day 7 plasma lumefantrine concentrations in the respective 
arms. Analysis will be done using both intention-to-treat and per-protocol approaches. 

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5.3 
Safety Evaluations 
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 will 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. Safety 
will be assessed by direct questioning and recording the nature and incidence of adverse events 
and serious adverse events. Signs and symptoms such as fatigue, weakness, dizziness, headache, 
palpitations or allergic drug reactions (rash), diarrhea, abdominal pain, dizziness, itching, fever 
and Hb prior, during and after treatment will be recorded and determined to whether they are 
related to the trial medicine. patients will also be asked to observe the color of their urine, and 
whenever they observe a change they will be advised to collect it in a white container, and then 
the observed color change will be gauged against the Hillmen color chart. A color change of ≥5 
scores represents hemolysis.  
Moreover due to prolonged use of lumefantrine, prolonged QTc interval in ECG above the highest 
limit will be monitored at baseline and 4-5 hours after the last treatment dose. It is expected to be 
less than 440 milliseconds in men and less than 460 in women. 
In addition, data safety monitoring board (DSMB) will be installed; clinically relevant hemolytic 
events, hospital admissions, blood transfusions and deaths will be reported within 72 hours to the 
DSMB. 
 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Study participants will be recruited from patients attending the study site (Yombo Dispensary) 
with suspected uncomplicated malaria infection and screened for eligibility. 
6.2 
Inclusion Criteria 
1. Male or female ≥ 1 years of age and 65 years  at Visit Yombo Dispensary. 
2. Weight 10 kg and above. 
3. Body temperature ≥37.5°C or history of fever in the last 24 hours; 
4. Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia. 
5. Written informed consent (and assent when applicable) obtained from subject or subject’s 
legal representative and ability for subject to comply with the requirements of the study. 
6. Normal QTc Interval in an ECG, between 360 – 440 milliseconds in men and 370 - 460 
in women. 
6.3 
Exclusion Criteria 
1. Symptoms/signs of severe malaria or danger signs 
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the 
study. 

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3. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
4. Known allergy to study medications 
5. Hb <8 g/dl 
6. Reported antimalarial intake within last 2 weeks 
7. On regular medication, which may interfere with antimalarial pharmacokinetics and 
blood transfusion within last 90 days. (see Section 7.1 below) 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy for Uncomplicated P. falciparum malaria is allowed except for treatments noted 
in the exclusion criteria described above.  
Patients with fever ≥38.0°C will be treated with paracetamol or acetaminophen according to 
national treatment guidelines. Parents or guardians will be instructed in the use of tepid sponging 
for children under 5 years of age.  Prior treatment with antimalarial drugs  will not be considered 
an exclusion criterion; however, during follow-up, if infections other than malaria require the 
administration of medicines with antimalarial activity, the patient will be withdrawn from the 
study. Patients given tetracycline as an eye ointment will not be excluded. Patients will be 
withdrawn from the study in the case of self-medication or if an antimalarial drug or an antibiotic 
with antimalarial activity is administered by a third party. 
Adverse events requiring treatment can be treated according to local practice in Tanzania. If there 
is 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 medicine, the name of the medicine, 
the dosage and the date and time of administration must be recorded on the case report form. The 
use of herbal remedies during the study should be avoided, and participants should be encouraged 
to return to the study site for treatment if they feel unwell. If any herbal remedies are taken during 
the study, this should be captured on the case report form, under ‘study medication administration’. 
 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered 
a protocol violation. 
 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;  

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 pentamidine.  
 * Tetracycline eye ointments can be used.   
 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Computer generated randomization using Microsoft Excel (Ms Excel). This will be done in blocks 
of 10, stratified by sex will be done and treatment allocation will be kept in sealed envelopes. Up 
to 280 eligible patients will be randomly assigned to 3 days  or 6 days + PQ treatment groups in a 
1:1 ratio using a Ms-Excel computer-generated randomization scheme developed by the study data 
management provider.  The investigator will complete a randomization worksheet at Visit 1. 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will be known only 
to investigators, research staff, but NOT patients. The following study procedures will be in place 
to ensure single-blind administration of study treatments.   
1. Access to the randomization code will be strictly controlled.   
2. A taste-matching agent for the placebo. 
3. Packaging and labeling of test and control treatments will be identical to maintain the blind.  
During the study, the blind may be broken only in emergencies when knowledge of the patient’s 
treatment group is necessary for further patient management. When possible, the Investigator 
should discuss the emergency with the Medical Monitor prior to un-blinding.   
8.3 
Formulation of Test and Control Products 
During the study, there will be two test drugs and two test instruments used as listed below; 
1. Artemether-lumefantrine (20/120mg) (Coartem®, Novartis)  or any other pre-qualified 
ALU by WHO according to Tanzanian national treatment guidelines for uncomplicated P. 
falciparum malaria 
2. For patients allocated to the prolonged treatment course, a single 0.25 mg/kg primaquine 
dose (Primaquine phosphate, Sanofi). Primaquine will be prepared and administered in an 
aqueous solution [6]. To preserve the accuracy of lower weight-based doses, all primaquine 
doses will be administered in aqueous solution and measured using a sterile syringe. 
 
 
8.3.1 
Formulation of Test Product 
Primaquine phosphate, a synthetic compound manufactured by Sanofi with potent antimalarial 
activity. Each tablet contains 26.3 mg of Primaquine phosphate (equivalent to 15 mg of 
primaquine base). The dosage is customarily expressed in terms of the base. See Table 1. for the 
formulation of primaquine phosphate. 

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Table 1: Formulation and Measured pH of primaquine phosphate 
 
Primaquine phosphate 
Active 
Ingredient, 
mg/mL 
8-[(4-Amino-1-methylbutyl) amino]-6-methoxyquinoline phosphate 15 
Other ingredient, mg/mL Carnauba Wax, Hydroxypropyl Methylcellulose, Lactose, Magnesium 
Stearate, Microcrystalline Cellulose, Polyethylene Glycol 400, 
Polysorbate 80, Pregelatinized Starch, Red Ferric Oxide , Talc, Titanium 
Dioxide  
 
8.3.2 
Formulation of Control Product  
A placebo solution (0.9% saline).  
8.3.3 
Packaging and Labeling 
Study drug is supplied in blister packs containing 14 single use tablets each pack.  The blister 
packs will be packaged in boxes of 100 packs enclosed. Each box will have a total of 1400 tablets 
contained. 
Each box of study drug will be labeled with the required TFDA warning statement, the protocol 
number, a treatment number, the name of the sponsors, and directions for patient use and storage.   
8.4 
Supply of Study Drug at the Site 
The sponsor will ship study drug to the investigational site.  The initial study drug shipment will 
be shipped after site activation (i.e., all required regulatory documentation has been received by 
the Sponsor and a contract has been executed). Subsequent study drug shipments will be made 
after site request for resupply. 
8.4.1 
Dosage/Dosage Regimen 
 Artemether-lumefantrine (AL) 
Enrolled patients will be treated with oral tablets of artemether-lumefantrine (WHO pre-qualified 
formulation) according to body weight and Tanzanian national treatment guidelines for 
uncomplicated P. falciparum malaria, as follows: One tablet to those weighing 5-14kg; two tablets 
to children with 15-24 kg or three tables to children with 25 – 34kg and 4 tablets to those 
participants above 35 kg.  
Adverse events are generally mild, most commonly gastrointestinal (vomiting and diarrhea) and 
hematologic (anemia and eosinophilia). The full course of treatment for all study patients consists 
of 6-doses given twice daily, at 0, 8, 24, 36, 48, 60 with the dose being given as directly observed 
by a health worker, and the second dose should strictly be given after 8 hours.  
But in the intervention arm, extended from 3 to 6 days. In the control arm, patients will be receiving 
oral placebo after completion of the standard 3 days-six dose regimen. For practical purposes, and 
to comply with standard practice, a simpler dosage regimen is recommended in order to improve 

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compliance; subsequent doses could be given twice daily (morning-evening) in the second and 
third days of treatment until completion of the doses [16].   
A fatty snack (biscuits) will be administered together with all artemether-lumefantrine doses to 
optimise absorption. Participants will be observed for 30 minutes after each drug dose. Treatment 
will be re-administered in cases of vomiting. If the patient vomited within the 30 minutes, full 
treatment dose of antimalarial will be repeated and observed for additional 30 minutes. If vomiting 
occurs again, patient will be excluded and rescue drug will be administered. 
 
 
Figure 1: Dosage of AL per weight and age 
 
Primaquine 
For patients allocated to the prolonged treatment course, a single 0.25 mg/kg primaquine dose 
(Primaquine phosphate, Sanofi) will be administered concomitantly with the last (i.e. twelfth) 
artemether-lumefantrine dose. Primaquine will be prepared and administered in an aqueous 
solution as previously described [6].  
To preserve the accuracy of lower weight-based doses, all primaquine doses will be administered 
in aqueous solution and measured using a sterile syringe. The primaquine dose will be given based 
on weight bands. All doses including placebo will be mixed with glucose-based syrup that masks 
the color and taste of primaquine. All treatments will be directly observed.  
A snack with approximately 5g of fat will be administered prior to both AL and primaquine 
administration to optimize absorption of AL and minimize gastrointestinal side effects with 
primaquine. All treatment doses will be directly observed by a study nurse.  
Primaquine is absorbed rapidly and peak concentrations are reached in approximately 2 hours. It 
has a half-life of 6 hours and is metabolized in the liver. The metabolically inert principle 
metabolite (carboxy-primaquine) reaches peak concentrations within 6 hours of administration. 
The active metabolite has not yet been identified. The kinetics of primaquine are affected by 
malaria (acute infection reduces oral clearance of primaquine), by food (increase primaquine bio-
availability), or by other antimalarial (quinine induces a higher area under the curve (AUC) of the 
carboxy metabolite).  
 
Table 2. Primaquine dose administration based on weight bands. 
Weight (Kg) 
Cc (15mg tab in 5mls) (Average) 
mg/day 
Tablets (15mg per tab) 

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10-14 
0.83-1.16 (0.98) 
2.50-3.50 
 
15-19 
1.25-1.58 (1.42) 
3.75-4.75 
1/4 
20-24 
1.66-2.00 (1.83) 
5.00-6.00 
 
25-29 
2.08-2.42 (2.25) 
6.25-7.25 
 
30-34 
2.50-2.83 (2.67) 
7.50-8.50 
1/2 
35-39 
2.92-3.25 (3.09) 
8.75-9.75 
 
40-44 
3.33-3.66 (3.49) 
10.00-11.00 
 
45-49 
3.75-4.08 (3.92) 
11.25-12.25 
3/4 
50-54 
4.17-4.50 (4.34) 
12.50-13.50 
 
55-59 
4.58-4.92 (4.75) 
13.75-14.75 
 
60-64 
5.00-5.30 (5.15) 
15.00-16.00 
1 
65-69 
5.40-5.75 (5.58) 
16.25-17.25 
 
70-74 
5.83-6.17 (6.00) 
17.50-18.50 
 
75-79 
6.25-6.58 (6.42) 
18.75-19.75 
1 and 1/4 
80-84 
6.67-7.00 (6.82) 
20.00-21.00 
 
≥85 
7.08         (7.10) 
21.25 
 
8.4.2 
Dispensing 
The Study clinician/nurse is the one responsible for dispensing all the study medications. 
8.4.3 
Storage 
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 to 86ºF). 
If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below this range, this 
should be reported to the Sponsor or designee and captured as a deviation.. 
8.4.4 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff.  The number of study drug 
dispensed and returned by the subject will be recorded on the Investigational Drug Accountability 
Record.  The study monitor will verify these documents throughout the course of the study. 
8.5 
Measures of Treatment Compliance 
All the drug administration will be under Directly Observed Therapy by the study staff. Whom 
will document all the given medication in the CRF. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of events representing the required testing procedures to be performed for the duration 
of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent must be signed and dated 
by the subject or subject’s legal representative.  If appropriate, assent must also be obtained prior 
to conducting any study-related activities. 

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9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Baseline/Screening 
and at Study Days and at early termination when applicable.  Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, address) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at Screening. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a sub-investigator 
who is a physician at Visit 1.    Qualified staff (MD, NP, RN, and PA) may complete the 
abbreviated physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting for 
5 minutes on all Study Days. 
9.1.6 
ECG 
Electrocardiography will be performed by a qualified physician. All study participants’ cardiac 
profile will be examined by an ECG before enrolment and also will be taken 4-5 hours after the 
last dose. This is for the assessment of prolongation of QTc interval, should be less than 440ms 
form men and 460ms  for women. 
9.1.7 
Pregnancy screening 
This will be done to women of child bearing age (12-50 yrs) whom have reported to not seen 
their menstrual period bleeding more than one normal cycle. 
9.1.8 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to study 
drug will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements  
9.2.1 
Blood Collection Procedures: 
Finger prick: The skin will be cleaned and sterilized using an alcohol wipe. A sterile disposable 
lancet will be used for the procedure.  Blood will be collected into sample collection slides, tubes 

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and filter papers will be labelled with the subject’s study ID, date and time of collection. 
Hemostasis will be achieved and a bandage placed on. Symptomatic control will be provided as 
needed. 
 
Venipuncture: A tourniquet will be applied to the arm and the skin cleaned with alcohol. A sterile 
disposable venipuncture needle will be used and blood collected into appropriate vacutainers. After 
removal of the needle, hemostasis will be achieved and a bandage placed on the site. Symptomatic 
control will be provided as needed. Vacutainers will be labelled with the subject’s study ID, date 
and time of collection. Blood will then be processed for the appropriate assays.  
9.2.2 Microscopy 
Conventional Microscopy 
A malaria rapid diagnostic test (mRDT) will be collected for quick screening. Thick and thin blood 
films for parasite counts and species identification should also be obtained and examined at 
screening on day 0 to confirm adherence to the inclusion and exclusion criteria. Thick blood films 
will also be examined on day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35 and 42. Also on any other day if the 
patient returns spontaneously and parasitological reassessment is required.  
During day 0, parasite clearance will be assessed at eight hours intervals to elucidate the mean 
parasite clearance time. Filter paper for molecular genotyping will be collected for each sample of 
blood that will be taken. Specimens will be labelled anonymously with a unique study ID, day of 
follow-up and date. 
 
A fresh Giemsa stain dilution will be prepared at least once a day and possibly more often, 
depending on the number of slides to be processed. Giemsa-stained thick and thin blood films will 
be examined at a magnification of 1000 to identify the parasite species and to determine the 
parasite density. 
 
Two blood slides with thick and thin smears per patient will be obtained at screening. One slide 
will then be stained rapidly (10% Giemsa for 10–15 min) for initial screening, while the second 
slide will be retained. If the patient is subsequently enrolled, the second slide will be stained more 
carefully (e.g. 2.5–3% Giemsa for 45–60 min), and slower staining will also be used for all slides 
obtained at follow-up visits. The study number of the patient, the date and the day of follow-up 
will be recorded either on the frosted edge of the slide or on the glass with a permanent glass pen. 
 
The thick blood smear for initial screening will be used to count the numbers of asexual parasites 
and white blood cells in a limited number of microscopic fields. 
The second blood smear will be used to calculate the parasite density, by counting the number of 
asexual parasites per 200 White Blood Cells (WBCs) with a hand tally counter. Once a field has 
been started, it must be counted to completion; the final number of WBCs will therefore rarely be 
exactly 200. If more than 500 parasites have been counted before 200 WBCs 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 WBCs counted and then multiplying by assumed 
WBCs of 8000 per µl. 
 

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Parasite density (per µl) = 
number of parasites counted  (8000) 
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 10 per 200 WBCs in follow-up smears, counting 
will be done against at least 500 WBCs (i.e. to completion of the field in which the 500th WBC 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 noted, but this information 
will not contribute to basic evaluation. 
 
In addition, 100 fields of the second-thick film 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. 
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. 
 
All the microscopy slides will be stored at MUHAS for long term storage. 
 
Mobile Microscopy MOMIC 
 
The aim of this study is to assess the clinical feasibility of a mobile mini-microscope for providing 
remote, image-based aid to diagnostics in fever patients in Tanzania. In this pilot study, we will 
evaluate the prototype for a miniaturized, high-resolution microscope developed by our research 
group. We will combine the mini microscope with remote image analysis of malaria parasites and 
blood cells, into a diagnostic method for the fever patient.  
 
We have developed technology for computer vision analysis of P. falciparum, and quantification 
of white and red blood cells in blood smear images, captured with the mini microscope and 
uploaded to our webmicroscopy platform (http://www.webmicroscope.net) [17], [18]. The 
webmicroscope platform is adapted to perform image analysis remotely, to run several computer 
vision analyses simultaneously and rapidly return results over mobile wireless networks to the 
health professional at the point-of-care (POC)  
 
Specific aims 
 
The specific aims and objectives of the proof-of-concept field study are to test the feasibility of 
the mini microscope and to assess the diagnostic accuracy of the method. The study will be 
performed in patients presenting with fever during screening and conventional blood smear 
microscopy (above) will serve as a gold standard.  
 

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1. 
Primary objectives: Diagnostic accuracy (sensitivity, specificity, positive and negative 
predictive value) for malaria in fever patients.  
 
2. 
Secondary objectives:  
 
a. 
Determining percentage parasitemia from the blood smears of those patients who were 
considered to have a malaria infection. 
 
b. 
Sample evaluation time and ease-of-use  
 
Two hundred and eighty (280) consecutive patients eligible for a malaria rapid test screening will 
be included into the study. The malaria rapid test will be assessed according to a standard protocol 
from a finger-prick capillary blood sample. From the same finger prick two additional blood drops 
for two thin smears will be taken on separate glass slides, two for DAPI staining. 
 
The thin blood smear samples will be analyzed with conventional microscopy at the point-of-care 
(Primary Health Care Center, Yombo, Bagamoyo District, Tanzania). 
 
The blood films will be stored after fixing on site by an experienced microscopist (recruited for 
the study). The slides will be analyzed at a later date. With the aid of the mini microscope, the 
analysis of the collected blood slides will be performed. The result i.e. the diagnosis, and if malaria 
is detected also the parasite count, will be compared to the corresponding results of the routinely 
analyzed sample.  
 
Before analysis with the mini microscope, any personal identification information will be replaced 
with internal bar codes and the label area of the slides covered. Body temperature, symptoms, and 
prescription of drugs will be recorded in the case record form (CRF). On the CRF, the 
corresponding unique study ID number, which appears on the blood smear slides, will be 
documented. 
9.2.3 Loop Mediated Isothermal Amplification (LAMP) 
In order to check for malaria clearance on day 3 LAMP procedure will be used. LAMP is a highly 
efficient and less costly method that amplifies P. falciparum DNA allowing researchers to detect 
malaria [19]. The mechanism that LAMP works includes DNA amplification using primers 
designed to bind the parasite’s DNA, amplifying the DNA in a circular fashion under isothermal 
conditions, forming a cauliflower-like DNA sequence in a globe, which can easily be detected due 
to its cloudiness or fluorescence. This technique fits well to be used in a clinical setting where 
there is no access to expensive instruments such as PCR machines. Additionally, the design of the 
procedure (with the amplification taking in a tube) reduces the chance of contamination, and can 
be done at the time blood samples have been taken, ensuring accuracy and less contamination of 
the samples collected [20]. This tool has been used for detections of asymptomatic  malaria patients 
in low transmission setting, and its specificity and sensitivity has shown to be comparable to PCR 
as gold standard [21].  
 
The parasites DNA will be extracted from blood using (400 mM NaCl, 40 mM Tris pH 6.5, 0.4% 
SDS), heating at 95 degrees for 5mins. The clear supernant will be transferred into dilution tube 

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with 150microL of sterile water ready for lamp amplification using Loopamp TM MALARIA 
Pan/Pf detection kit .  30 μl of Positive Control, negative control and samples will be added into a 
reaction tube and mixed thoroughly. Thereafter the parasites DNA will be amplified by setting the 
temperature at 65°C for 40 minutes. To terminate amplification process, samples in the reaction 
tubes will be heated at 85°C for 5 minutes. To detect for parasite presence, UV light will be 
illuminated under each reaction tube, whereby green light will be observed for positive controls 
and samples; and no light will be illuminated for the negative controls and samples. 
9.2.4 
Haemoglobin 
As baseline investigation during screening, approximately 20µl of blood in Hemocue cuvettes will 
be collected for the haematological measurements. This will provide haemoglobin measures in 
addition to other haematological parameters, some of which will be used for patient management. 
This will be also taken at Day 7. 
9.2.5 
Urinalysis 
Urine sample will be obtained at two points, screening and day 7. Patients will also be asked to 
observe the color of their urine, and whenever they observe a change they will be advised to collect 
it in a white container, and then the observed color change will be gauged against the Hillmen 
color chart. A color change of ≥5 scores represents hemolysis. 
9.2.6 
Blood Chemistry Profile 
Blood will be obtained on day 0 and sent to each site’s clinical chemistry lab for determination of 
serum sodium, potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, 
total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), albumin and LD. A total of 
about 2ml of venous blood will be required.  
9.3 
Research Laboratory Measurements 
9.3.1 
Molecular Genotyping 
Four Dried Blood Spots (DBS), each containing approximately 60 microliter of blood, will be 
prepared. Blood samples will be collected on PerkinElmer 226 filter paper, and DNA extraction 
done by either Chelex-100 or QIAamp DNA minikit. P. falciparum will be detected using a highly 
sensitive real time based quantitative PCR targeting the cytochrome b gene [22]. Pfs25 female 
specific and P230p male specific transcripts will be used to detect and quantify male and female 
gametocytes using previously described protocols [23], [24]. Genotyping of SNPs in pfmdr1 and 
pfcrt will be done by PCR-RLFP based methods [25], [26], and sequencing of especially pfcrt 
positions 70-77. Analysis of pfmdr1 gene copy numbers will be done by a comparative ∆∆Cq 
method after Tag Man RT multiple qPCR [27]. Sequencing of  Kelch13 (858 bp portion covering 
almost all of the six propeller domains),will be done as previously described, and 3D7 used as 
reference in numbering of nucleotide and amino acid positions Haplotype diversity (h) calculated 
as h = {n/n-1} {1-Σ pi2}where n=nr infections sampled and pi =frequency of ith haplotype in a 
group  [27] 
A special emphasis will be put on characterization of parasite sub-populations that remain PCR 
detectable on day 5 and 7. These parasites will be subjected to multi targeted deep sequencing in 

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a collaborative project with Prof Juliano, University of North Carolina, using recently described 
methods [5]. PCR analysis of msp2, msp1 and glurp will be done in order to distinguish between 
recrudescence and reinfections.  
 
The backup DBS will be stored at Karolinska Institutet in Sweden for long-term storage 
from 10 years 
9.3.2 
Pharmacokinetic Measurements 
Procedures during sample collection: A standard history will be taken and clinical examination 
performed. A Dried Blood Spots (DBS) of about 200 μL will be taken before treatment for plasma 
drug assay using the Whatman 903 Protein Saver Card filter papers then two hours after the first 
dose and two hours after the last dose. Each child will be given artemether-lumefantrine (Coartem, 
Novartis Pharma, Switzerland) at the standard dose according to the Standard Treatment Guideline 
in Tanzania. This dose will be repeated at 8, 24, 36, 48, 60, for control arm, and at 8, 24, 36, 48, 
60, 72, 84, 96, 108, 120, and 132 hours. All doses will be given under direct observation with a 
fatty snack (equivalent if 2gm of fat). Further six DBS samples will be taken from randomly 
selected time-points in the following schedule: 4hrs/12hrs (before second dose), 16hrs/ 24hrs 
(before third dose), 36hrs (before fourth dose), 40hrs/ 48hrs (before fifth dose), 52hrs/ 60hrs 
(before sixth dose), 64hrs and 72hrs (before seventh dose), and then before first doses on Days 4 
(ninth dose at 96hrs), 5hrs (eleventh dose at 120hrs), and 5hrs (twelfth and last dose at 123hrs). 
  
An additional 3 mL venous sample will be taken at one randomly selected time-point in parallel 
with a DBS for assay validation. For collection of DBS, the fingertip/heel/earlobe will be cleaned 
with alcohol. A spring-loaded lancet will be used to express a blood droplet which will be applied 
to the filter paper. At each time-point, 2-5 blood spots will be collected from the single sampling 
site. The DBS will be air dried (for >1 h), placed into a gas impermeable plastic bag with desiccant 
and stored in a laboratory freezer at -80oC until analysis. Blood for determination of serum 
concentrations of Lumefantrine will be done at Prof. Tim Davis laboratory in Australia using 
established method.   
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  An unexpected 
AE is one of a type not identified in nature, severity, or frequency in the current Investigator’s 
Brochure or of greater severity or frequency than expected based on the information in the 
Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates 
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 

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AE Severity 
Table below should be used to grade severity.  It should be pointed out that the term “severe” is a 
measure of intensity and that a severe AE is not necessarily serious. 
Table 3.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 4. 
 
Table 4.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
10.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 

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 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
10.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug).  The 
collection period for all SAEs will begin after informed consent is obtained and end after 
procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the MUHAS Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs 
to the IRB/IEC.   
 
 
10.3 Medical Monitoring 
Dr. Nahya Salim should be contacted directly at these numbers to report medical concerns 
or questions regarding safety. 
Phone: 0713 250074 
Email: nahyasalim@hotmail.com 
   
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
11.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  The following is a list of 
possible reasons for study treatment discontinuation:  
1. Subject is not compliant with study procedures 
2. Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment  
3. Subject withdrawal of consent (or assent) 
4. Protocol violation requiring discontinuation of study treatment 
5. Lost to follow-up 
6. Sponsor request for early termination of study 
7. Positive pregnancy test (females) 

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If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents.  
11.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents.  As noted above, subjects who discontinue study treatment early (i.e., 
they withdraw prior to Visit 12) should have an early discontinuation visit. Subjects who withdraw 
after Visit 12 but prior to Visit 18 should be encouraged to come in for a final visit (and the 
procedures to be followed would include those for their next scheduled visit).   
11.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will not be replaced.   
 
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following: 
1. Failure to meet inclusion/exclusion criteria 
2. Use of a prohibited concomitant medication 
3. Non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor 
representative and the Investigator. A copy of the form will be filed in the site’s regulatory binder 
and in the Sponsor’s files. 

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13 DATA SAFETY MONITORING  
The Muhimbili University of Health and Allied Sciences (MUHAS) Data Safety Monitoring Board 
(DSMB) will establish a Data Monitoring Committee (DMC) to review data relating to safety and 
efficacy, to conduct and review interim analyses, and to ensure the continued scientific validity 
and merit of the study, according to the MUHAS Data Safety Monitoring Board Operations 
Manual and a DMC Charter to be established for this protocol. There will be three interim 
review(s) conducted by the DMC for the purpose of monitoring study conduct and assessing 
patient safety. Further details regarding the timing and content of the interim reviews is included 
in the statistical section below. 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications to 
the analysis plan described below.   
14.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the study 
drug (the Intention to Treat -ITT Population) will be included in the Intention to Treat analysis.  
All eligible patients who have completed the study with all the follow up and received treatment 
medication will be the Per Protocol Population and included in the Per Protocol Analysis. 
14.2 Patients Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening and Eligibility 
Assessment 
Excluded   
   Not meeting inclusion criteria  
   Declined to participate  
Allocated to control Arm   
 Receive ALU for 3 days + Placebo for 3 
Days 
Allocated to intervention arm 
 Receive allocated ALU for 6 Days + Low 
dose Primaquine (0.25mg/kg) on last ALU 
treatment 
Allocation 
Randomization 
Enrollment 

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14.3 Primary Analysis plan 
Data will be double entered into a password protected SPSS V. 20 database. Data will be cleaned 
by visual inspection for outliers. Preliminary univariate and bivariate analyses will be carried out 
to estimate the effects of lumefantrine level, age, and parasitemia and host polymorphisms. 
Descriptive statistics such as mean, standard deviation and percentages will be reported in the 
univariate analysis according to the type of the data and using ANOVA statistical output will be 
obtained. Comparison of fever to parasite clearance among treatment arms will be done using 
Kaplan-Meiyer’s Curves and the Logistic Regression Model. Both adjusted and unadjusted 
analysis by confounding factors will be implemented. Interaction terms will be used to assess effect 
measure modification. P< 0.05 will be considered significant.  
14.4 Analysis of Secondary Endpoints 
Safety and tolerability data will be summarized by treatment group.  Adverse event rates will be 
coded by body system and MedDra classification term.  Adverse events will be tabulated by 
treatment group and will include the number of patients for whom the event occurred, the rate of 
occurrence, and the severity and relationship to study drug.   
14.5 Interim Analysis 
When approximately 50% of patients have completed the study through Visit 10, an interim 
analysis for safety will be conducted by an independent data monitoring committee. Serious 
adverse events will be monitored by the committee on an ongoing basis throughout the study. 
14.6 Sample Size and Randomization 
The sample size was calculated based on an assumed clinically meaningful difference between 
the arms in PCR positivity rate of 15% on day 6 (20% after standard 3-day artemether-
lumefantrine treatment and 5% in the interventional arm). To be able to show this difference with 
80% power at 0.05 significance level, 116 patients are needed in each arm. To allow for 20% 
attrition, a total of 140 patients will be included in each arm.  
Safety completed 42 days of follow up  
(Per Protocol Population analysis) 
Efficacy completed 28 days of follow up 
Efficacy completed 28 days of follow up 
Safety completed 42 days of follow up 
(Per Protocol Population analysis) 
Analysis 
Follow-Up 
Lost to follow-up
Lost to follow-up 
Lost to follow-up 
Lost to follow-up 

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N = size of group  
 
 
 
p = response rate of standard treatment group   
d = difference between the two treatment groups 
δ= the clinically acceptable margin  
 
β= probability of Type II error 
α= probability of Type I error 
 
 
z = test statistic of assuming normal 
population  
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel at the site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific paper CRF when the information corresponding to that visit is available.  
Subjects will not be identified by name in the study database or on any study documents to be 
collected by the Sponsor (or designee), but will be identified by a site number, subject number and 
initials or a barcode. 
If a correction is made on a CRF, the study staff member will line through the incorrect data, write 
in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study. 
15.2 Data Management Procedures 
The data will be entered into a validated SPSS database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock will 
occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting NIMR and TFDA guidelines for the handling and analysis of data for clinical 
trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. The study database will 

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be updated in accordance with the resolved queries.  All changes to the study database will be 
documented. 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. 
Databases are backed up by the database administrator in conjunction with any updates or changes 
to the database.  At critical junctures of the protocol (e.g., production of interim reports and final 
reports), data for analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigator will make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., NIMR and TFDA) inspectors 
upon request.  A file for each subject must be maintained that includes the signed Informed 
Consent, Assent Form and copies of all source documentation related to that subject.  The 
Investigator will ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of 10 years following completion of the study. 
The study documents will be stored at MUHAS. There may be other circumstances for which the 
Sponsor is required to maintain study records and, therefore, the Sponsor should be contacted prior 
to removing study records for any reason. 
15.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor. By signing this protocol, 
the Investigator grants permission to the Sponsor (or designee), and appropriate regulatory 
authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject initials 
will identify all study subjects on CRFs and other documentation submitted to the Sponsor. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers, Institutional Review Boards, and Obligations of Clinical Investigators. 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the NIMR and TFDA.  
The Investigator must also comply with all applicable privacy regulations. 

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16.1 Protocol Amendments 
Any amendment to the protocol will be written by the Investigator. Protocol amendments cannot 
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRBs are notified 
within five working days. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating 
center prior to study initiation, including NIMR and TFDA. Ethical clearance from MUHAS has 
been sought and granted. The procedures for ethical review stipulated by the Swedish law on 
ethical review in medical research have been followed, and approval from the Regional Ethics 
Review Board, Stockholm, has been granted (Dnr: 2016/2286-32).  Serious adverse experiences 
regardless of causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as 
to the progress of the study.  The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the informed 
consent form will be in the possession of the Investigator before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the Investigator to the Sponsor 
prior to the shipment of study supplies to the site.  This approval must refer to the study by exact 
protocol title and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely 
the safety of the patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed. 
16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP.The 
Investigator will prepare the informed consent and assent form, and provide the documents to the 
Sponsor or designee for approval prior to submission to the IRB/IEC.  The consent form generated 
by the Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC.  The 
written consent document will embody the elements of informed consent as described in the 
International Conference on Harmonisation and will also comply with local regulations. The 

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Investigator will send an IRB/IEC-approved copy of the Informed Consent Form to the Sponsor 
for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to entering 
the subject into the trial.  Information should be given in both oral and written form and subjects 
(or their legal representatives) must be given ample opportunity to inquire about details of the 
study.  If appropriate and required by the local IRB/IEC, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF), a legal representative 
may sign for the subject.   A copy of the signed consent form (and assent) will be given to the 
subject or legal representative of the subject and the original will be maintained with the subject’s 
records. 
 
 
16.4 Publications  
This is a PhD Study. The preparation and submittal for publication of manuscripts containing the 
study results shall be in accordance with a process determined by mutual written agreement among 
the study Sponsor and participating institutions. The publication or presentation of any study 
results shall comply with all applicable privacy laws. 
 
  
17 BUDGET 
 
No 
Category 
Item 
Specification 
Quantity 
Unit Cost 
Total Cost  
1 
Chemicals/ 
consumables 
AL tablets 
p/12 
120 
2,000 
                    
240,000  
p/24 
120 
2,000 
                    
240,000  
Primaquine 
tablets 
  
100 
2550 
                    
255,000  
Paracetamol 
tablets 
p/1000 
1 
12,000 
                     
12,000  
Amoxy caps/tabs 
 Doses 
50 
2,500 
                    
125,000  
Quinine Tablets 
Doses 
50 
4000 
                    
200,000  
Giemsa stain 
Liter 
1 
10,000 
                     
10,000  
Immersion oil 
Tubes 
5 
5000 
                     
25,000  
Methanol 
 Liter 
1 
10,000 
                     
10,000  

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Blood slides 
p/72 pks 
50 
4000 
                    
200,000  
Filter papers 
Pcs 
10 
20,000 
                    
200,000  
Slide boxes 
Pcs 
30 
6,000 
                    
180,000  
Plastic bags 
p/100 
30 
12,000 
                    
360,000  
Descicants 
  
3,000 
33 
                     
99,000  
Blood lancet 
p/100 
40 
6,000 
                    
240,000  
Cotton wool 
 Pcs 
4 
11,000 
                     
44,000  
Cotton gauze 
Pcs 
2 
15,000 
                     
30,000  
Cuvettes 
p/50 
44 
5,000 
                    
220,000  
Syringes 
p/1000 
1 
20,000 
                     
20,000  
Gloves 
p/50 pcs 
100 
11,500 
                
1,150,000  
Stopwatch 
  
2 
25,000 
                     
50,000  
Digital 
thermometre 
Pcs 
4 
7,000 
                     
28,000  
Bed nets 
pcs 
10 
8,000 
                     
80,000  
Bed sheets 
pcs 
20 
5,000 
                    
100,000  
Flat files 
  
280 
1,000 
                    
240,000  
Screening books 
pcs 
2 
4000 
                     
8,000  
Envelopes 
  
280 
100 
                     
24,000  
  
  
Fuel 
liters 
200 
2200 
                    
440,000  
  
Sub total 
  
  
  
  
                
4,830,000  
No. 
Category 
Item 
Specification 
Quantity 
Unit cost(Tsh) 
  
2 
Field work and 
allowances 
Per diem for PhD 
student 
1 
180 
60,000 
                
10,800,000  

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Per diem for the 
supervisor 
1 
20 
80,000 
                
1,600,000  
Per diem for the 
driver 
1 
90 
60,000 
                
5,400,000  
Research 
assistants  
2 Nurses 
4 
100,000 
            
5,360,000  
2 Clinical 
officer  
150,000 
2 
Technicians 
400,000 
Meal for the 
participants and 
their parents/ 
guardians 
Maximum 
280 subjects 
and 120 
relatives 
3 
8,000 
                
6,720,000  
Transport per 
visit 
Maximam 
280 
participants 
16 
5,000 
              
22,400,000  
Training 
6 Research 
assistances+ 
1 Trainer 
2 
20,000 
                    
280,000  
  
Sub-total 
  
  
  
  
           
46,725,000  
  
Grand Total 
  
  
  
  
              
57,135,000  
 
17.1 Budget Justification 
The project work is under the bilateral (Tanzania-Sweden) Malaria sub-project supported by the 
Swedish Development Agency (Sida). An estimated Tshs 57,135,000 /= will be required to carry 
out this study. The reagents will be used for fixing and staining of blood slides and analysis of 
lumefantrine plasma concentration. Primaquine is a drugs under investigation, and artemether-
lumefantrine will be used as a control whereas, Quinine as rescue drug and Amoxicillin and 
Paracetamol will be used to treat other accompanying morbidities. Blood slides and filter papers 
will be used to collect blood samples whereas slide boxes and plastic bags will be used to store 
slides and filter paper respectively after the sample is taken. The patients may be admitted/ retained 
for up to 12 hours after initial dose; therefore, they will need bed nets and sheets, and food. In 
addition, patients will be refunded for their transport costs for every visit.  
The PhD student will be staying at the study site for the whole time of patient’s enrolment and 
treatment to ensure that the protocol and standard operating procedures are followed. The per 
diems required are Tshs. 60,000 per day whereas a total of 180 days will be spent at the site. To 
ensure adherence to protocol and provide guidance on the conduct of the research the Supervisor 
will have to visit the study sites at least twice a month, and will need Tshs 80,000 per day and he 
will go to the field for a total of 20 days in a period of 5 months. A project car will be used 
throughout this study to ease transportation of samples and the visits at the study site. The project 
driver will be required at all times during the visits at the sites, therefore the driver will require the 
allowance for 90 days. 

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Since continuous collection of blood samples will be required, the study will recruit six research 
assistants (2 Nurses, 2 Clinical Officers and 2 Laboratory technicians). The clinical officers will 
be screening the patients with fever or history of fever, the technicians will be taking blood 
samples, staining and reading of blood slides and other tests as required. The nurses will be 
administering the medications and taking care of the wards and issues related to food for 
patients. The researcher (PhD student) will be the overseer of all activities in site. The study will 
be conducted during the high malaria transmission season in the area from June to October, thus 
it will be preferable to pay the research assistances per month. The clinical officers will be paid 
Tshs. 150, 000 per month each and nurses will be paid Tshs 100, 000 per month each, whereas 
the technicians will be paid Tshs. 400,000 per month each. 
 
17.2 Work plan 
Item/Task 
Duration 
of Task  
1 mo. = 30 
days 
.75 
mo=22.5 
.5 mo=15 
days 
.235 mo=7 
days 
.2 mo=6 
days 
.05 mo=2 
days 
(can be 
changed) 
Days 
(=C*30) 
Start Date 
Finish 
Date 
Predecessor 
Task 
FS=task indicated 
in this column must 
finish prior to start 
of current task line 
 
SS=tasks can both 
start on the same 
day and run in 
parallel (can be 
changed) 
  
Award Notification to 
First Subject Enrolled 
Totals: 
  
260 
15-May-16 
29-Jan-17 
  
1 
Notification of SIDA- 
Award Approval 
Received 
  
0 
15-May-16 15-May-16 
NA 
2 
Protocol Development to 
Final Draft  
(Includes protocol development 
and vetting through SIDA and 
MUHAS. Time presented is an 
average based on experience. 
Can be longer or shorter based 
on status of protocol at award.) 
2 
60 
15-May-16 
14-Jul-16 
1 FS 
3 
Submit final draft 
protocol and consent 
document to MUHAS 
Reviewers for review and 
comment; incorporate 
revisions 
0.05 
2 
14-Jul-16 
15-Jul-16 
2 FS 
4 
MUHAS reviewers 
Review of Final Draft 
0.5 
15 
15-Jul-16 
30-Jul-16 
3 FS 

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5 
Oversight Senate 
Committee Review of 
Protocol 
0.5 
15 
30-Jul-16 
14-Aug-16 
4 FS 
6 
Protocol & Consent 
Document Finalization  
(Includes review, comment and 
recommendations by 
IRB/NIMR.) 
2 
60 
14-Aug-16 
13-Oct-16 
5 FS 
7 
Submission & Approval 
of Protocol & Consent 
Documents to necessary 
to Uppsala University for 
admission  
(Assumes single site with one 
IRB.) 
1.5 
45 
13-Oct-16 
27-Nov-16 
6 FS 
8 
Preparation and 
submission of IND (if 
applicable)  
(Minimum of 30 days must 
elapse between submission of 
IND and beginning of 
enrollment. IRB may request 
documentation of IND approval 
prior to issuing final IRB 
approval.) 
2 
60 
14-Aug-16 
13-Oct-16 
6 SS 
9 
Data Management & 
Safety Management 
Tasks for Site Activation 
(This time includes creation of 
source documents, CRFs, 
designing and implementing a 
database, (EDC or a paper 
study) training on the data 
system, setting up safety 
reporting (SAEs), and all 
associated Plans.) 
2.25 
68 
27-Oct-16 
3-Jan-17 
7 SS +14 days 
10 
Site Staff Preparation 
(Time includes writing a 
Manual of Procedures, 
assessing SOPs, training staff 
on protocol, specimen 
collection, processing, storage 
and shipping, study time and 
events tables, full protocol 
training identification of site 
staff for study roles.) 
3 
90 
13-Oct-16 
11-Jan-17 
7 SS 
11 
Site Facility Preparedness 
(Includes collection of 
necessary supplies, assuring 
physical facilities meet privacy 
and security standards as well 
as any labs meeting 
requirements per protocol, for 
example: appropriate specimen 
processing equipment, freezers, 
centrifuges etc.) 
1.5 
45 
13-Oct-16 
27-Nov-16 
7 SS 

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12 
Study Product Ready on 
Site 
(Time includes identification of 
study product supplier, 
calculating amount of study 
product needed, ordering study 
product, shipment prior to Site 
Initiation Visit, QC of received 
product, development of 
process for study product 
distribution to patients.) 
3 
90 
13-Oct-16 
11-Jan-17 
6 FS 
13 Site Initiation Visit 
0.05 
2 
11-Jan-17 
13-Jan-17 
6FS, 7FS, 
8FS, 9FS, 
10FS, 12FS 
14 
Site Activation Checklist 
Completed  
(Includes time for completion 
of checklist, approval, and 
signature by NIDCR.) 
0.5 
15 
13-Jan-17 
28-Jan-17 
9 FS 
15 Site is Activated 
0.05 
2 
28-Jan-17 
29-Jan-17 
10 FS 
16 
Data Collection ( Patients 
enrollment, filling CRF, 
Follow up, Specimen 
collection and storage) 
5 
150 
29-Jan-17 
28-Jun-17 
11 FS 
17 
Data Processing ( Data 
entry and Data cleaning 
and analysis of 
preliminary data to get 
initial finding and 
preparing samples for 
shipment to Karolinska) 
4 
120 
28-Jun-17 
26-Oct-17 
12 FS 
18 
Lab works ( Processing 
the blood samples and 
running analysis as per 
protocol, Attending short 
courses and seminars) 
3 
90 
26-Oct-17 
24-Jan-18 
13 FS 
19 
Preparing Manuscripts for 
publication, and 
contacting Journals for 
publishing requirements 
3 
90 
24-Jan-18 
24-Apr-18 
14 SS 
20 
Publishing the Papers, 
Attending Short courses, 
More lab/field works 
9 
270 
24-Apr-18 
19-Jan-19 
15 SS 
 
17.3 Investigator Responsibilities  
 

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By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet standard guidelines. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records and to make those records available for inspection 
with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports) 
9. Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements 
 
18 BIBLIOGRAPHY 
[1] 
C. Sisowath et al., “In vivo selection of Plasmodium falciparum pfmdr1 86N coding 
alleles by artemether-lumefantrine (Coartem).,” J. Infect. Dis., vol. 191, no. 6, pp. 1014–7, 
Mar. 2005. 
[2] 
A. Mårtensson et al., “Efficacy of artesunate plus amodiaquine versus that of artemether-
lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum 
malaria in Zanzibar, Tanzania.,” Clin. Infect. Dis., vol. 41, no. 8, pp. 1079–86, Oct. 2005. 
[3] 
M. Malmberg et al., “Temporal trends of molecular markers associated with artemether-
lumefantrine tolerance/resistance in Bagamoyo district, Tanzania,” Malar. J., vol. 12, no. 
1, p. 103, 2013. 
[4] 
R. Mwaiswelo, B. Ngasala, I. Jovel, W. Xu, and M. Malmberg, “Occurrence of day 3 
submicroscopic Plasmodium falciparum parasitemia before and after implementation of 
artemether-lumefantrine treatment policy in Tanzania .,” Dar Es Salaam, 2016. 
[5] 
N. Mideo et al., “A deep sequencing tool for partitioning clearance rates following 
antimalarial treatment in polyclonal infections,” Evol. Med. Public Heal., vol. 2016, no. 1, 
pp. 21–36, 2016. 
[6] 
R. Mwaiswelo et al., “Safety of a single low-dose of primaquine in addition to standard 

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artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium 
falciparum malaria in Tanzania.,” Malar. J., vol. 15, p. 316, 2016. 
[7] 
WHO, “WHO World Malaria Report 2015,” Geneva, Switzerland, 2015. 
[8] 
WHO, WHO guidelines for the treatment of malaria 2015, 3rd Editio. Geneva, 
Switzerland, 2015. 
[9] 
A. M. Dondorp et al., “Dondorp Artemisinin Resistance in Plasmodium falciparum 
Malaria,” NJ New Engl. J. Med. Churchill Hosp. N.J.W. N Engl J Med, vol. 3615361, no. 
30, pp. 455–67455, 2009. 
[10] F. Ariey et al., “A molecular marker of artemisinin-resistant Plasmodium falciparum 
malaria.,” Nature, vol. 505, no. 7481, pp. 50–5, Jan. 2014. 
[11] B. Witkowski et al., “Novel phenotypic assays for the detection of artemisinin-resistant 
Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response 
studies.,” Lancet. Infect. Dis., vol. 13, no. 12, pp. 1043–9, Dec. 2013. 
[12] J. Straimer et al., “K13-propeller mutations confer artemisinin resistance in Plasmodium 
falciparum clinical isolates,” Science (80-. )., vol. 2624, no. 1985, pp. 428–431, Jan. 2014. 
[13] M. Malmberg et al., “Plasmodium falciparum drug resistance phenotype as assessed by 
patient antimalarial drug levels and its association with pfmdr1 polymorphisms.,” J. 
Infect. Dis., vol. 207, no. 5, pp. 842–7, Mar. 2013. 
[14] National Bureau of Standard, “2012 Population and Housing Census Population 
Distribution by Administrative areas,” 2013. 
[15] Bagamoyo District Council, “Bagamoyo District Health Profile,” Bagamoyo, 2012. 
[16] NMCP, “PRESIDENT ’ S MALARIA INITIATIVE Tanzania Malaria Operational Plan 
FY 2015,” pp. 1–45, 2013. 
[17] E. Linder et al., “Web-Based Virtual Microscopy for Parasitology: A Novel Tool for 
Education and Quality Assurance.” 
[18] M. Lundin et al., “A European network for virtual microscopy—design, implementation 
and evaluation of performance,” Virchows Arch., vol. 454, no. 4, pp. 421–429, Apr. 2009. 
[19] B. Aydin-Schmidt et al., “Loop mediated isothermal amplification (LAMP) accurately 
detects malaria DNA from filter paper blood samples of low density parasitaemias.,” PLoS 
One, vol. 9, no. 8, p. e103905, 2014. 
[20] J. Cook et al., “Loop-mediated isothermal amplification (LAMP) for point-of-care 
detection of asymptomatic low-density malaria parasite carriers in Zanzibar,” Malar. J., 
vol. 14, no. 1, p. 43, 2015. 
[21] B. Aydin-Schmidt et al., “Field Evaluation of a High Throughput Loop Mediated 
Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections 
in Zanzibar,” PLoS One, vol. 12, no. 1, p. e0169037, 2017. 
[22] W. Xu et al., “SYBR Green real-time PCR-RFLP assay targeting the plasmodium 
cytochrome B gene--a highly sensitive molecular tool for malaria parasite detection and 
species determination.,” PLoS One, vol. 10, no. 3, p. e0120210, 2015. 

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[23] G. Mlambo, Y. Vasquez, R. LeBlanc, D. Sullivan, and N. Kumar, “A filter paper method 
for the detection of Plasmodium falciparum gametocytes by reverse transcription 
polymerase chain reaction.,” Am. J. Trop. Med. Hyg., vol. 78, no. 1, pp. 114–6, Jan. 2008. 
[24] P. Schneider et al., “Quantification of female and male Plasmodium falciparum 
gametocytes by reverse transcriptase quantitative PCR,” 2015. 
[25] G. Fröberg et al., “Decreased prevalence of Plasmodium falciparum resistance markers to 
amodiaquine despite its wide scale use as ACT partner drug in Zanzibar,” Malar. J., vol. 
11, no. 1, p. 321, 2012. 
[26] M. I. Veiga, P. E. Ferreira, A. Björkman, and J. P. Gil, “Multiplex PCR–RFLP methods 
for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum,” Mol. Cell. Probes, vol. 
20, no. 2, pp. 100–104, 2006. 
[27] R. N. Price et al., “Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 
gene copy number.,” Lancet (London, England), vol. 364, no. 9432, pp. 438–47, 2004. 
 
 
 
 
 
 
19 APPENDIX I. SCHEDULE OF EVENTS DURING STUDY VISITS 
 

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20 APPENDIX II: INFORMED CONSENT  
20.1 English Version  
Muhimbili University of Health and Allied Sciences (MUHAS) 
Karolinska Institute (KI) 
Uppsala University 
Consent to Participate in a Research Study 
Adult and Parental/guardian permission for a Minor Child to Participate in a Research 
Study  
________________________________________________________________________ 
 
Protocol No. 01.05.2017/04 
Consent Form Version Date: Version 4.0 dated 4th July 2017 
 
Title of Study: Aiming at prolonging the therapeutic life span of artemisinin-based 
combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo 
District, Tanzania - new strategies with old tools. 
 
Protocol Version 4.0, dated 4th July 2017 
 
Principal Investigator: Dr. Lwidiko Edward Mhamilawa (Tanzania) 
Principal Investigator Phone number: +255 712 865 206 
Principal Investigator Email Address: lwidikoedward@gmail.com 
Co-Investigators: Dr. Billy Ngasala, MUHAS; Prof. Anders Bjorkman (KI) Prof. Andreas 
Martenson (Uppsala) 
 
Study Sponsors: Swedish International Development Cooperation Agency(SIDA) and 
Swedish Research Council.  
 
Study Contact telephone number:  +255 712 865 206 
_________________________________________________________________ 
 
This informed consent form has two parts: 
I. Information sheet (to share information about the study with you) 
 
II. Certificate of consent (for signatures if you agree your child to take part in the study).  
You will be given a copy of the full informed consent form 

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Part I: Information sheet 
My name …………………………, and I work for.................................. We are doing a study on the 
treatment of malaria. Malaria is a dangerous disease; however, it can be treated. The purpose of this 
study is to determine the effects of prolonging the therapeutic life span of artemisinin-based 
combination therapies when is combined with a single lower-dose primaquine, another antimalarial 
drug which is capable of killing mature P. falciparum gametocytes; the combination can stop 
transmission of the disease. We have screened your blood/ blood of your child and we have 
determined that you have been infected with malaria parasites. Thus, we are inviting all patients with 
uncomplicated malaria aged 1 year and above living in this area to take part in this study. 
 
a. Introduction to the Study 
I am going to give you information and invite you to consent for yourself or your child to participate 
in this study. There will be other 280 participants in total of this research study. Before you decide 
whether you want yourself or your child to participate, you can talk to anyone you feel comfortable 
with. There may be some words that you do not understand. Please ask me to stop as we go through 
the information, and I will take time to explain. If you have questions later, you can ask me, the study 
doctor or the staff. Your decision to have yourself/your child participate in this study is entirely 
voluntary. If you choose not to consent, all the services you/your child receives at this clinic will 
continue as usual. Even if you agree now but decide to change your mind and withdraw later, the 
services you/your child receives at the clinic will continue.  
Your participation or that of your child can be terminated without the need for consent from you 
when you violate the study protocol agreements or when the study staff determine it is for your own 
good not to continue participating in the study.  
 
b. Inclusion and Exclusion criterion 
 
In order to participate in the study, you can be male or female with more than 1 years of age but 
below 65 years at Visit Yombo Dispensary. Minimum weight is 10 kg. You or your child 
must present with a body temperature of more than 37.5°C or history of fever in the last 24 
hours; Microscopy determined asexual P. falciparum mono-infection regardless of 
parasitemia. We will also asses the condition of your heart if there are no conditions that may 
prevent you from using study drugs. 
If you/ your child has any of the following, or develop them during the study, we will have 
to withdraw you from the study. Symptoms/signs of severe malaria or danger signs as 
deemed by study staff. If you are Pregnant or breastfeeding, or have allergy to study 
medications. You/ your child is not expected to take any medication without prior 
consultation with study clinician, if you/your child have taken anti-malarial within last two 
weeks you will not be eligible to the study. Moreover, if you have hemoglobin level of less 
than 8 g/dl you cannot continue with the study. You are not expected to be on regular 
medication, which may interfere with antimalarial pharmacokinetics and blood transfusion 
within last 90 days. 
c. About the Study Medication and Dosage 

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We will use two types of medication in our research study, Artemether Lumefantrine (AL) and 
Primaquine. AL is the first-line treatment for uncomplicated malaria in Tanzania. It is registered and 
licensed for use in Tanzania. There are reports of AL resistance from South-East Asia which could 
spread to Africa. Additionally, there are areas of low malaria transmission in the country where 
malaria elimination programs by using primaquine can be implemented. Furthermore, WHO 
emphasizes on assessing the safety and efficacy of lower doses of primaquine and where it is accepted 
to be used for the above mentioned purposes in combination with artemether-lumefantrine.  
Primaquine however is not registered for routine use in Tanzania, hence clearance for use in human 
has been sought from TFDA, and Insurance cover from the National insurance corporation of 
Tanzania (NIC) in case of study related injuries.  Many countries including Tanzania are fighting 
hard to control and eventually eliminate malaria. Primaquine given as a single dose in addition to 
ACTs such as AL is said to be potent in killing the transmissible malaria parasites, the gametocytes, 
thus aid in elimination efforts. Nonetheless, this medicine has side effects including hemolysis which 
can be fatal to those with G6PD deficiency. Otherwise, its side effects includes: nausea, vomiting, 
epigastric distress and abdominal pain. It is advised to take food before medication to avoid most of 
the side effects. Similarly, acute hemolytic anemia due to Primaquine is a dose dependent 
phenomenon, thus to avoid this a lower dose of 0.25 mg/kg which is recommended by WHO will be 
used.  Conversely, AL is known to be very effective, but you should know that may have some minor 
side-effects: weakness, headache, nausea, vomiting, abdominal pain, diarrhea and itching. These 
symptoms are usually transient and of mild or moderate intensity.  
 
Artemether-lumefantrine is usually given at six doses spread twice a day over three days. For the 
purpose of this study, there will be two treatment arms, one will receive standard 3 days regimen, and 
the other one will receive extended treatment for 6 days. You/your child will receive artemether-
lumefantrine twice a day for three days or six days depending on which arm of the study you will be 
randomly assigned to. In addition to that, for those of you who will be in the primaquine arm will 
receive a single low-dose (0.25mg/kg) of primaquine together with the last dose of AL on the sixth 
day of AL. Food will be taken prior to all medications to alleviate primaquine gastrointestinal side 
effects and to improve absorption of AL. 
 
If we find that the medicine you have received is not able to cure the malaria infection that you are 
infected with, we will instead give you what is called ‘rescue medicine’. The rescue medicine is called 
quinine and is given orally at a dose of 10mg/kg body weight thrice daily to complete a total of 21 
doses in 7 days. You should also know that this medicine has some minor side-effects: such as 
tinnitus, muffled hearing, sometimes vertigo or dizziness. In case you/your child develop signs of 
severe malaria infection we will provide in-patient care and treat you/your child with quinine given 
directly into your blood using a drip. 
 
 
 
d. Follow up days and blood sample collection 

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During the follow-up, a small amount of blood of about 6mls total (teaspoon full) will be taken from 
your finger, 8 hourly on day 0, followed by 12 hourly on days 1, 2, 3, 4 and 5, and thereafter once 
daily on days 6, 7, 14, 21, 28, 35, 42 and on any day of recurrent illness. You/your child may 
experience a bit of pain or fear when the finger is pricked or during the venous phlebotomy. The pain 
should disappear within 1 day. The blood will be dropped onto a slide or a small piece of paper. The 
blood samples will be used to study malaria parasites in your blood, the level of drug concentration 
and to determine the level of your blood (Hb), nothing else will be done with the blood. 
The study period for each patient in this study is 42 days. During that time, you/your child will have 
to come to the health facility for 1 hour, which in total will be 19 visits including today’s visit. At 
each visit, you will be asked a few questions about your health condition, including if you/your child 
have/has developed any new symptoms since last visit and if you were taking any other medicines 
than the study medication. In addition, you will also undergo a brief physical examination by study 
clinician at every visit.  
 
e. More information about the Study administration 
As previously mentioned the medicine can have some unwanted or unexpected effects that we are 
not currently aware of; however, we will follow you/your child closely and keep track of these effects, 
if they arise, and of any other problems. We will give you a telephone number to call if you notice 
anything out of the ordinary or if you have concerns or questions, please see below. You can also 
come to this health facility at any time and ask to see....................................................  (give name of 
nurse, doctor). If you/your child experience side-effects, we may use some other medicines, free of 
charge, which will help to reduce the symptoms or reactions, or we may stop the medicine. If this is 
necessary we will discuss it together. You will always be consulted before we move to the next step. 
 
The blood samples on the filter papers will be transported to Sweden because the labs in Tanzania do 
not have the capacity to process the analysis needed. They will be stored for about 10 years as it is a 
policy for studies like this. By signing this consent, you authorize the transportation and storage of 
the blood samples taken for use and purpose of this study.  
 
Today, we will take few drops of blood for testing. We will also take your picture/of your child which 
will aid us during follow-up. If you decide that you/your child will participate in this study, any 
illnesses related to malaria or to the malaria treatment will be treated at no charge to you. Your 
participation will help us to know whether the medicine is working as envisaged, and this will benefit 
the society and future generations. Accommodation and food will be provided to you, should you 
decide to stay here after first visit and as you are waiting for the next 8 hourly dose and in case of 
children then to the child and one parent/guardian. In addition, travel expenses will be reimbursed for 
every visit according to local transport rates. 
 
 
f. Confidentiality Section   
We will not share the identity of participants in the study with anyone. The information that we collect 
from this study will be kept confidential.  There is a possibility that we will share the information 

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with the study monitors, sponsors, ethics committees from TFDA and NIMR.  Any information 
collected will have a number on it instead of names. Only the study team members will know what 
the number is it about. 
We will share the knowledge that we get from this study with you before it is made available to the 
public. Confidential information will not be shared. There will be small meetings in the community 
where members of the study team will inform you about the results of the study, and these meetings 
will be announced in advance. Afterwards, we will publish the results and make them available so 
that other interested people may learn from our study. 
This proposal has been reviewed and approved by the institutional ethical committee of the 
Muhimbili University of Health and Allied Sciences, Tanzania Food and Drug Authority and 
Tanzania National Institute for Medical Research. The committees have carefully assessed the study 
in advance to make sure that study participants are protected from any harm. If you wish to find more 
about the study approval, you may contact the Director of research and publication +255 22 2152489, 
Muhimbili University, National Institute for medical research +255 22 2121400 or Tanzania Food 
and Drug Authority +255 22 2452108. Or you can contact the Principle Investigator at Lwidiko Edward 
Mhamilawa, 0712865206.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part II: Certificate of consent 
I have been invited to participate/have my child participate in a study of a medicine used to treat 
malaria. I have read the above information/or it has been read to me. I have had the opportunity to 

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ask questions, and any questions that I have asked have been answered to my satisfaction. I consent 
voluntarily to participate/my child’s participation in this study. 
Name of participant: ______________________________        
Name of parent or guardian: ________________________ 
Signature of parent or guardian: ______________________           
Date: __ ___ _____ (dd/mm/yy) 
Witness’ signature: (A witness’ signature and the thumbprint of the participant’s parent or guardian 
are required only if the parent or guardian is illiterate. In this case, a literate witness must sign. If 
possible, this person should be selected by the participant’s parent or guardian and should have no 
connection with the study team). 
I have witnessed the accurate reading of the consent form to the potential participant’s parent or 
guardian, who has had the opportunity to ask questions. I confirm that the participant’s parent or 
guardian has given consent freely. 
Name of witness: _______________________: Signature of witness: ________________ 
Thumbprint of parent/guardian_______________Date:___________________________ 
 
 
 
Investigator’s signature: 
I have accurately read or witnessed the accurate reading of the consent form to the potential 
participant’s parent or guardian, who has had the opportunity to ask questions. I confirm that the 
participant’s parent or guardian has given consent freely. 
Name of investigator: _________________________________________________ 
Signature of investigator: ________________Date: _________________________ 
A copy of this informed consent form has been provided to participant’s parent or guardian _____ 
(initials of the principal investigator/assistant). 
 
 
 
 
 
 
 
 
 
 
 
 
 

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20.2 Swahili version 
Muhimbili University of Health and Allied Sciences (MUHAS) 
Karolinska Institute (KI) 
Uppsala University 
Fomu ya Ridhaa ya kushiriki kwenye Mradi wa Utafiti 
Kwa ajili ya Watu wazima na Wazazi/ Walezi ili kutoa ridhaa ya Mtoto/ mwenyewe 
kushiriki kwenye mradi wa utafiti  
___________________________________________________ 
Protocol No. 01.05.2017/04 
Toleo na Tarehe ya Fomu ya Ridhaa: Namba ya Toleo 4.0 Tarehe 4 Julai  2017 
 
Jina la Mradi wa utafiti: Kulenga katika kuongeza muda wa tiba ya dawa mseto ya 
artemisia katika kipindi cha usugu wa vimelea malaria Plasmodium falciparum kwa dawa, 
wilaya ya Bagamoyo, Tanzania – mikakati mipya kwa kutumia zana zilizopo 
 
Toleo la Andiko 4.0, Tarehe 4 Julai 2017 
Mtafiti Mkuu: Dr. Lwidiko Edward Mhamilawa (Tanzania) 
Namba ya simu: +255 712 865 206 
Barua Pepe: lwidikoedward@gmail.com 
 
Watafiti washiriki: Dr. Billy Ngasala, MUHAS; Prof. Anders Bjorkman (KI) Prof. Andreas 
Martenson (Uppsala) 
 
Wafadhili: Swedish International Development Cooperation Agency(SIDA) and Swedish 
Research Council.  
Mawasiliano ya Mradi:  +255 712 865 206 
_________________________________________________________________ 
Fomu ya maelezo ya ridhaa kwa Watu wazima na  wazazi/walezi waliokuja na watoto wao 
kituoni. 
Fomu hii ya maombi ya ridhaa ina sehemu mbili:  
I. Fomu ya maelezo (itakupasha taarifa za utafiti) 
II. Uthibirisho wa kukubali (utaweka saini yako iwapo utakubali ushiriki wa mwanao) na 
utapewa nakala ya taarifa hii kwa ajili ya kumbukumbu. 
Sehemu ya I. Fomu ya maelezo 
Mimi naitwa........................................, na ninafanya kazi ………............ Tunafanya utafiti 
kuhusu matibabu ya malaria. Malaria ni ugonjwa hatari;  hata hivyo, ni ugonjwa unaotibika 

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kwa dawa. Lengo la utafiti huu ni  kuchunguza faida za kuongeza muda wa tiba ya dawa 
mseto ya Artemisia pamoja na dozi ndogo ya Primaquine kwa kuangamiza vimelea vya 
malaria katika kipindi cha usugu wa vimelea wa malaria kwa dawa na kuzuia maambukizi 
ya ugonjwa huo. Tumechunguza damu ya mtoto wako na tumegundua ameambukizwa 
vimelea vya ugonjwa wa malaria. Huwa tunawaalika wagonjwa wote wenye malaria isiyo 
kali, wenye umri zaidi ya mwaka mmoja wanaoishi maeneo haya, kushiriki kwenye mradi 
huu. 
a. Utangulizi kuhusu mradi huu wa utafiti 
Kwa hivyo, nitakupa taarifa zinazohusu utafiti wetu huu unaofanyika hapa na kukuomba 
wewe / mwanao ashiriki. Kabla hujaamua ushiriki wako/ wa mwanao ama la, unapewa uhuru 
wa kupata ushauri kutoka kwa mshauri yeyote ili utoe mashaka kuhusu utafiti huu. Pengine 
kutatokea baadhi ya maneno hujayaelewa, tafadhali usisite kunirudisha kwenye taarifa hiyo 
ili nikufafanulie kwa kina. Kama utakuwa na swali lolote usisite kumuuliza mganga au 
mhudumu wa afya kituoni hapa.  
Ushiriki wako / wa mwanao kwenye utafiti huu ni wa hiyari. Kutakuwa na washiriki wengine 
280 kwenye mradi huu wa utafiti wanaoishi maeneo haya. Iwapo utaamua asishiriki, hakuna 
huduma yeyote atakayonyimwa kituoni hapa. Hata ukiamua kushiriki kwa sasa basi unaweza 
kubadili maamuzi yako baadae, huduma na msaada wa matibabu anayopewa itaendelea kama 
kawaida. Ushiriki wako/ mwanao unaweza kusitishwa wakati wowote bila kuhitaji ridhaa 
yako kama utakiuka makubaliano ya ushiriki ama wafanyakazi wa mradi wataona ni salama 
kwako/ kwa mwanao kusimamishwa ushiriki kwenye mradi.  
b. Vigezo vya ushiriki au kutolewa kwenye mradi. 
Ili ushiriki kwenye mradi unaweza kuwa wa kiume au wa kike, mwenye umri zaidi ya mwaka 
mmoja lakini chini ya miaka 65, wanaokuja kuhudumiwa zahanati ya Yombo. Uzito wa chini 
kushiriki ni Kg 10. Wewe/ mwanao lazima awe na Homa (joto mwili la digrii 37.5) ama 
historia ya kuwa na homa ndani ya masaa 24 yaliyopita. Vipimo vya darubini lazima viwe 
vimeonesha vimelea vya malaria aina ya P. falciparum. Pia tutakufanyia vipimo moyo wako 
kujua kama hakuna shida itakayojitokeza ukishiriki kwenye mradi.  
Kama wewe/mwanao mna hali zifuatazo ama zikijitokeza wakati wa mradi, itatulazimu 
kusimamisha ushiriki. 1. Kupata dalili za malaria kali ama dalili za hatari, kama wafanyakazi 
wa mradi watakavyotambua. 2. Kama una ujauzito ama 3. Unanyonyesha au 4. Dawa za 
mradi zinakudhuru. Wewe/mwanao hategemewi kutumia matibabu mengine yoyote kipindi 
cha mradi bila kuwasiliana na dakitari wa mradi, na kama wewe au mwanao mmetumia dawa 
za malaria ndani ya wiki mbili, hautakidhi vigezo vya ushiriki. Zaidi ya hapo , wingi wa 
damu ni lazima uwe zaidi ya gramu 8 kwa desilita. Na kusiwe na matumizi ya dawa za muda 
mrefu ambazo zinaweza ingiliana na dawa za mradi kwenye ufanyaji kazi mwilini. Ndani ya 
siku 90 zilizopita inatakiwa kusiwe kumefanyika zoezi la kuongezewa damu.  
 
c. Taarifa kuhusu dawa zinazotumika katika mradi huu na unywaji wa dozi 
 
Tutatumia dawa aina mbili kwenye utafiti wetu, Dawa mseto ya Artemisia na dawa ya 
Primaquine. Dawa mseto ya Artemisia ni dawa ya awali ya matibabu ya malaria isiyo kali 
na imesajiliwa kwa matumizi ya tiba Tanzania. Kuna ripoti za Usugu wa Dawa mseto ya 

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Artemisia kutoka Kusini-Mashariki mwa Asia ambayo inaweza kuenea hadi Afrika. Pia kuna 
maeneo yenye kiwango kidogo cha maambukizi ya malaria ambapo miradi ya kutokomeza 
malaria kwa tutumia primaquine inaweza kufanyika. Shirika la afya duniani (WHO) 
linasisitiza upimaji wa usalama na uwezo tiba wa dozi ndogo ya dawa ya primaquine na kule 
iliko kubalika itumike kwa kazi tajwa hapo juu kwa kuunganishwa na dawa ya mseto ya 
Artemisia. Nchi nyingi ikiwemo Tanzania, zina pambana vikali ku mudu na hatimaye ku 
tokomeza malaria. Primaquine ikitolewa kama dozi moja ndogo pamoja na dawa mseto ya 
Artemisia kama vile AL, inasemekana kuwa na uwezo wa kuua vimelea ambukizi vya 
malaria, hivyo kusaidia kwenye jitihada za kutokomeza malaria.  
Primaquine hata hivyo haijasajiliwa kwa matumizi ya tiba ya malaria Tanzania, hivyo kibali 
kimeombwa kutoka Mamlaka ya chakula na dawa (TFDA) na bima imekatwa kutoka Shirika 
la bima la Taifa (NIC).  Hata hivyo dawa hii ina madhara ambata ikiwemo kuvunjika kwa 
chembe nyekundu hai za damu ambayo huweza kuua kwa watu wenye upungufu wa 
kimengenya cha G6PD. Madhara ambata mengine ni kichefuchefu, kutapika, na maumivu 
ya tumbo. Inashauriwa kula chakula kabla ya dawa ili kuepuka madhara haya ambata. Vivyo 
hivyo, upungufu wa damu unaotokana na primaquine ni hali inayotegemea kiwango cha 
dawa utakachopata, hivyo ku kwepa hilo, kiwango kidogo zaidi cha mg 0.25 kwa kg ambayo 
inapendekezwa na shirika la afya duniani (WHO) itatumika. Kwa upande mwingine AL 
inafahamika kuwa na ubora sana kwenye tiba, ila ni muhimu ujue kuwa ina madhara ambata 
kidogo: uchovu, maumivu ya kichwa, kichefuchefu kutapika, kuwashwa , maumivu ya 
tumbo na kuhara. Dalili hizi ni za mpito na za uzito mdogo ama hafifu.  
Dawa mseto ya artemisia hutolewa kwa dozi sita zilizotawanywa marambili kwa siku kwa 
siku tatu.  Katika tafiti hii, kutakuwa na makundi mawili yatakayopokea dawa kwa idadi 
tofauti za siku, kundi moja siku tatu mfululizo, kundi la pili siku sita mfululizo kutegemeana 
na kundi utakalopangiwa/atakalo pangiwa mtoto wako kwa bahati nasibu. Zaidi ya hayo, 
kama atakuwa kundi la siku sita za kunywa dawa ya mseto, atapewa dozi moja ya Primaquine 
ambayo itaambatana na dozi ya mwisho ya mseto. Kitu cha kula kitapatikana kabla ya dawa 
zote kupunguza madhara ambata ya tumboni ya primaquine na pia kuboresha unyonywaji 
wa dawa mseto mwilini.  
Iwapo tutagundua dawa hizi zimeshindwa kuua vimelea vya malaria vilivyo kwenye damu 
yake, tutampa dawa nyingine tunayoiita ‘dawa ya kunusuru’ ambayo ni quinine na inatolewa 
kwa kunywa 10mg/kg moja ya mwili na zinanywewa mara tatu kwa siku hadi utimize dozi 
21 kwa muda wa siku 7. Iwapo utapata dalili za malaria kali tutamlaza na kumtibu kwa dawa 
ya quinine ambayo tutaitia moja kwa moja kwenye damu kupitia mrija (drip). 
 
 
 
d. Siku za kuja kituoni na kutoa vipimo vya damu 
Wagonjwa wote tutakaowashirikisha kwenye utafiti huu wataombwa kurudi tena kituoni 
siku ya 1, 2, 3, 4, 5, 6, 7, 14, 21,28, 35 na 42 tangu siku waliposajiliwa, lakini unashauriwa 
kurudi/ kumleta mwanao wakati wowote ukihisi ana homa ambayo haijapoa. Kila siku 
mtakayokuja, kutatolewa damu kidogo isiyozidi mls 6 kwa ujumla (kijiko kidogo cha chai) 
itakayochukuliwa kutoka kwenye kidole chake/chako au mshipa wa damu. Kwa ujumla 

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mwanao atatolewa damu ya kidole kila mara atakapokuja hapa kituoni, ikiwepo leo pia. Kwa 
wastani tano siku ya kwanza na mara tatu kwa siku tano za mwanzo yaani siku ya 1,2,3,4, 
na 5. Baada ya hapo atatolewa mara moja kwa siku siku ya 6,7,14,21.28,35,42.  Kutolewa 
damu kidoleni au kwenye mshipa wa damu  kunaweza kusababisha maumivu kidogo. 
Maumivu haya ni ya muda mfupi tu na huweza kupotea ndani ya siku moja. Damu 
itakayotolewa itawekwa kwenye kigae na kwenye kipande cha karatasi ndogo tu. Damu 
itakayowekwa kwenye kigae itachunguzwa kuangalia ubora wa dawa ya kuua vimelea vya 
malaria na hivyo kuondoa uwezekano wa vimelea hivyo kurudi tena kwenye damu yake. 
Utafiti huu utafanywa kituoni kwa kila siku mgonjwa atakayopaswa kuja. Damu 
itakayochukuliwa kwenye kipande cha karatasi itatumika kuchunguza maumbile ya vimelea 
vya malaria. Kwa vile usomwaji huo utafanyika baada ya utafiti kumalizika majibu ya damu 
hizi hayatotumika kutoa mbadala wa matibabu wala hayatachunguza matibabu 
anayofanyiwa mwanao. Ukitoa uchunguzi ulioelezwa hapo juu pamoja na kuhifadhiwa 
chembe za damu kwenye kipande cha karatasi kwa ajili ya uchunguzi wa dawa kwa majaribio 
ya baadaye, damu yake haitotumika kuchunguza jambo jingine.   
Muda wa kushiriki utafiti huu ni siku 42. Katika muda huu, tutakuomba uwe unakuja na 
mwanao hapa kituoni kwa zile siku tutakazokupangia, ambapo pamoja na siku ya mwanzo 
utakuja nae kwa jumla ni safari 19. Kila safari atakayokuja hapa mtatumia takribani muda 
wa saa 1 kwanzia kesho, ila kwa siku ya leo mtakaa kwa takribani masaa 12. Kila safari 
atakayokuja, ataulizwa maswali kidogo kuhusu afya yake, tutataka kufahamu maendeleo 
yake iwapo amepata dalili nyengine za homa tangu safari iliyopita na pia tutakuwa 
tunakuuliza iwapo umempa dawa nyingine yeyote zaidi ya ile tuliyompa. Atachunguzwa 
afya yake na mganga hapa kituoni kwa kila safari utakayokuja naye. 
e. Taarifa za ziada kuhusu uongozi wa Mradi 
Kama nilivyokueleza awali dawa tutakayotumia imekuwa inasababisha baadhi ya matokeo 
yasiyohitajika au yanaweza yakatokea mengine ambayo hatuyafahamu; hata hivyo, tutakuwa 
karibu nawe kufahamu na kulipatia ufumbuzi tokeo lolote litakalotokea, iwapo litatokea, 
pamoja na tatizo jengine la kiafya. Tutakupa nambari ya simu ambayo utaweza kupiga kama 
umegundua  wewe/ mtoto ana tatizo lolote au kama una swali lolote, angalia simu zilizopo 
hapo chini. Unaweza pia kuja kituoni hapa wakati wowote kuuliza au kuonana 
na.................................................... (jina la Mtabibu au muuguzi). Iwapo umetokewa na 
tatizo lolote lisilo la kawaida baada ya kutumia dawa hii tutakupa matibabu ya ziada, bila ya 
malipo, dawa ambazo zitasaidia kuondoa tatizo ulilonalo, au tunaweza kukushauri asiendelee 
na kutumia dawa hizi. Iwapo kuna umuhimu sana tutajadiliana pamoja nawe. Siku zote 
utashauriwa kuhusu hatua inayofuata.  
Sampuli za damu kwenye vi karatasi zitapelekwa nje ya nchi, Sweden kwa ajili ya kufanyiwa 
uchunguzi zaidi kwasababu maabara za Tanzania hazina uwezo wa kufanya vipimo 
vinavyohitajika kwenye mradi huu. Sampuli hizo zitatunzwa kwa muda wa miaka kumi 
kama ilivo katika sera za utafiti. Kwa kusaini ridhaa hii unatoa pia ruhusa ya usafirishwaji 
wa sampuli zako/ za mwanao za damu kwenda nje ya nchi na pia kuhifadhiwa kwa matumizi 
ya mradi huu.  
 
Faida za ushiriki wako/ wa mwanao 

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Ushiriki wako/ mwanao kwenye utafiti huu utasaidia kufahamu ufanisi wa dawa hizi katika 
kupambana na ugonjwa, na hii ni kwa faida ya jamii yetu pamoja na kizazi kijacho. Malazi 
na chakula vitatolewa hapa kituoni kwa mtoto na mzazi/mlezi mmoja kama utabaki kituoni 
kusubiri dozi na kipimo cha baada ya masaa nane ya awali kama unatoka mbali. Gharama za 
usafiri zitatolewa kwa kuja/ kumleta mtoto kituoni siku alizopangiwa kuendana na nauli 
halali za hapa. 
f. Usiri wa taarifa zako/ za mwanao 
Tunakuhakikishia hatutampa utambulisho wa mwanao mtu yeyote asiye husika na utafiti 
huu. Taarifa zote tunazochukua kwa wagonjwa wetu hapa tutaziweka kuwa ni siri kubwa. 
Kuna uwezekano tukawapa tarifa  zako/za mwanao wakaguzi wa mradi, wafadhili ama 
kamati za maadili za TFDA na NIMR.  Taarifa yeyote tutayochukua kutoka kwa mwanao 
tutaitambua kwa nambari atakayopewa badala ya jina lake. Ni baadhi ya wataalamu 
wanoshiriki utafiti huu ndio watakaofahamu taarifa zake.  
Tutakupatieni matokeo ya utafiti huu pamoja na elimu tuliyoipata kabla hatujazitangaza 
hadharani.  Tutaitisha mikutano kwenye jamii ili kuwapa wananchi matokeo ya utafiti wetu, 
na mikutano hiyo itatolewa taarifa mapema. Baada ya hapo, tutachapisha matokeo ya utafiti 
huu kwenye majarida ya kisayansi ili watu wasome na waelimike kutokana na utafiti wetu. 
Rasimu ya utafiti huu imepitiwa na kuhakikiwa na Baraza la maadili ya utafiti la Chuo Kikuu 
cha Afya na sayansi shirikishi Muhimbili. Baraza limechunguza kwa kina rasimu ya utafiti 
huu ili kuhakikisha kuwa wagonjwa watakaoshiriki wanalindwa na hawataathiriwa. Iwapo 
unataka kuhakikisha unaweza Kupiga simu kwa Kurugenzi ya Utafiti na Uchapishaji, 
Muhimbili +255 22 2152489, Muhimbili University, National Institute for medical research 
+255 22 2121400 au Tanzania Food and Drug Authority +255 22 2452108. Ama kumpigia 
simu Mtafiti kiongozi Lwidiko Edward Mhamilawa, kwenye simu nambari 0712865206. 
Iwapo una swali lolote kuhusu utafiti huu au kwa njia yeyote unataka kuwasiliana na 
wahusika wa utafiti huu unakaribishwa kufanya hivyo na unaweza kutumia namba hizi 
zifuatazo: 
 
Bw/Bi____________________________________________Namba__________________ 
 
 
 
 
Sehemu ya II. Ithibati ya ridhaa  
Mimi ______________________________nimeshauriwa ushiriki wa mtoto wangu kwenye 
utafiti wa kupima ufanisi wa dawa ya mseto ya malaria ikichanganywa na dozi ndogo ya 
Primaquine. 
Nimesoma/nimesomewa taarifa hizo hapo juu. Nilipewa nafasi ya kuuliza swali lolote, na 
yale maswali niliyouliza nimejibiwa na nimeridhika na majibu niliyopewa. Kwa hiari yangu 
nakubali mimi/ mwanangu ashiriki utafiti huu.  

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Jina mtoto (mgonjwa): _________________________________________ 
Jina la mzazi/mlezi:____________________________________________ 
Sahihi ya mzazi/mlezi____________________Tarehe____________________________ 
 
Sahihi ya shahidi: (Shahidi wa mshiriki na alama ya dole gumba la mshiriki itahitajika tu 
iwapo mzazi/mlezi wa mshiriki hafahamu kusoma na kuandika. Iwapo itatokea hivyo, 
shahidi wa mshiriki lazima aweke saini yake. Iwapo itawezekana, shahidi wa mshiriki 
ateuliwe na mshiriki mwenyewe na asiwe miongoni mwa watafiti).  
Nimemsomea taarifa hizi mzazi/mlezi wa mshiriki mtarajiwa kikamilifu, na alipata nafasi ya 
kuuliza maswali. Nakubali kwamba mzazi/mlezi wa mtoto ametoa ridhaa yake kushiriki na 
hakulazimishwa.  
Jina la shahidi______________________________ 
Sahihi ya shahidi___________________ 
Alama ya dole gumba la mzazi/mlezi______________ 
Tarehe __________________  
Saini ya mtafiti: ___________________ 
 
Nimemsomea taarifa hizi mzazi/mlezi wa mshiriki mtarajiwa kikamilifu, na alipata nafasi ya 
kuuliza maswali. Nakubali mzazi/mlezi ametowa ridhaa ya mwanawe kushiriki katika utafiti 
huu, na hakulazimishwa.  
 
Andika jina la mtafiti:_____________________ 
Saini ya mtafiti:______________Tarehe__________________ 
 
Nakala ya fomu hii ya ombi la ridhaa amepewa mzazi/mlezi wa mshiriki _____ (weka 
herufi za majina ya Mtafiti mkuu au msaidizi wa mtafiti mkuu). 
 
 
 
‘ 
 
 
 
 
 
 

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21 APPENDIX III: INFORMED ASSENT FORM  
21.1 English Version  
Muhimbili University of Health and Allied Sciences (MUHAS) 
Karolinska Institute (KI) 
Uppsala University 
Assent to Participate in a Research Study 
Minor subjects (7-12 yrs)  
________________________________________________________________________  
 
Protocol No. 01.05.2017/04 
Assent Form Version Date: Version 4.0 dated 4th July 2017 
 
Title of Study: Aiming at prolonging the therapeutic life span of artemisinin-based 
combination therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo 
District, Tanzania - new strategies with old tools. 
 
Protocol Version 4.0, dated 4th July 2017 
 
Principal Investigator: Dr. Lwidiko Edward Mhamilawa (Tanzania) 
Principal Investigator Phone number: +255 712 865 206 
Principal Investigator Email Address: lwidikoedward@gmail.com  
Co-Investigators: Dr. Billy Ngasala, MUHAS; Prof. Anders Bjorkman (KI) Prof. Andreas 
Martenson (Uppsala) 
 
Study Sponsors: Swedish International Development Cooperation Agency(SIDA) and 
Swedish Research Council.  
 
Study Contact telephone number:  +255 712 865 206 
The people named above are doing a research study. 
_________________________________________________________________ 
These are some things we want you to know about research studies:  
Your parent needs to give permission for you to be in this study. You do not have to be in 
this study if you don’t want to, even if your parent has already given permission.  
You may stop being in the study at any time. If you decide to stop, no one will be angry or 
upset with you.  Your doctors will still continue to take good care of you. 

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Sometimes good things happen to people who take part in studies, and sometimes things 
happen that they may not like. We will tell you more about these things below. 
Why are they doing this research study? 
The reason for doing this research is to learn more about malaria disease where you live.  
Malaria can cause bad illnesses, mainly in babies and young children. 
The information in this study will help us understand why some medicines are not working 
very well to help malaria. Also we are trying to find out if someone takes malaria medicine 
longer than it is normal, will it help to kill the malaria causing organisms better. 
Why are you being asked to be in this research study?  
You are being asked to be in the study because you have malaria.  
How many people will take part in this study?  
If you decide to be in this study, you will be one of about 280 other people, children and 
adults in this research study. The study is being done here in Yombo, Tanzania.  
What will happen during this study?  
If you wish to be in this study, this is what will happen:  
- You may have to stay in the hospital for the day today, so the doctors can treat the malaria. 
While you are in the hospital, you will be given the regular treatment for malaria. For this 
study, you will have blood taken from a vein in your arm, and some other days on you finger. 
This will be done today, and then twice each day you are in the hospital for about seven days. 
The blood will be tested to check the amount of malaria in your blood, and if you are unwell 
because of anemia (low blood level).  
-Your parent or guardian (the person who takes care of you) will also be asked questions 
about your health and your household.  
-Today you will also be given medicine to treat your malaria, and a person on the study team 
will stay with you for 30 minutes after you get the medicine to see how you feel. You will 
also come tomorrow and day after tomorrow for six days to take some malaria medication.  
-After coming to the hospital for 7 days taking medication and blood test, you will stay home 
for seven days, and then you will come to the clinic with your parent for another visit. At this 
visit we will ask your parent or guardian some questions about your health. You will also 
have several drops of blood taken by pricking your finger with a needle. The blood will be 
tested to see if the medicine is working to make your malaria better.  
-There will be 5 other visits to the clinic like the one above. You will be in the study for 42 
days.   

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Who will be told the things we learn about you in this study?  
Information learned from this study will be kept private. The study doctor will talk about the 
study with your parent/guardian, but will not talk about it with anyone else except the people 
working on the study. If the study doctor needs to talk to anyone else about you, he will ask 
you and your parent or guardian if it is OK.  
What are the good things that might happen?  
The information from the study will help us to better understand malaria disease in your 
country. This will give us important information on how best to protect people at risk against 
malaria.  
What are the bad things that might happen?  
Sometimes things happen to people in research studies that may make them feel bad. These 
are called “risks.” When having your blood taken, you might feel slight pain where the needle 
goes into the skin. There is a small chance of getting sick from drawing blood.  
Not all of these things may happen to you. None of them may happen or things may happen 
that the researchers don’t know about. You should report any problems to the researcher.  
What if you or your parents don’t want you to be in this study?  
You may decide not to take part in the study at any time, without giving a reason.  
Nobody will force you to take part in the study.  
Will you get any money or gifts for being in this research study?  
You will receive food for the time when you will stay at the hospital for the day if you take 
part in this study.  
Who should you ask if you have any questions?  
If you have questions you should ask the people listed on the first page of this form. If you 
have other questions, complaints or concerns about your rights while you are in this research 
study you may contact the Muhimbili University of Health and allied sciences Institutional 
Review Board at+255 22 2121400 or Tanzania Food and Drug Authority +255 22 2452108. 
Or you can contact the Principle Investigator at Lwidiko Edward 0712865206.  
 
 
If you sign your name below, it means that you agree to take part in this research study. 
 

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____________________________________________________ 
Sign your name here if you want to be in the study  
 
__________________
_ 
Date 
 
_____________________________________________________
_ 
Print your name here if you want to be in the study 
  
 
 
 
_____________________________________________________
_ 
Signature of Research Team Member Obtaining Assent 
 
__________________
_ 
Date 
 
_____________________________________________________
_ 
Printed Name of Research Team Member Obtaining Assent 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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21.2 Swahili  
Muhimbili University of Health and Allied Sciences (MUHAS) 
Karolinska Institute (KI) 
Uppsala University 
Fomu ya Ridhaa ya Kushiriki kwenye mradi wa utafiti  
Vijana wadogo  (Miaka 7-12 )  
________________________________________________________________________ 
 
Protocol No. 01.05.2017/04 
Toleo na Tarehe ya fomu ya ridhaa: Toleo 4.0 Tarehe 4 Julai 2017 
 
Jina la Mradi wa utafiti: Kulenga katika kuongeza muda wa tiba ya dawa mseto ya 
artemisia katika kipindi cha usugu wa vimelea malaria Plasmodium falciparum kwa dawa, 
wilaya ya Bagamoyo, Tanzania – mikakati mipya kwa kutumia zana zilizopo 
 
Toleo la Andiko 4.0, Tarehe 4 Julai 2017 
Mtafiti Mkuu: Dr. Lwidiko Edward Mhamilawa (Tanzania) 
Namba ya simu: +255 712 865 206 
Barua Pepe: lwidikoedward@gmail.com 
 
Watafiti washiriki: Dr. Billy Ngasala, MUHAS; Prof. Anders Bjorkman (KI) Prof. Andreas 
Martenson (Uppsala) 
 
Wafadhili: Swedish International Development Cooperation Agency(SIDA) and Swedish 
Research Council.  
Mawasiliano ya Mradi:  +255 712 865 206 
Watu waliotajwa hapo juu wanafanya huu mradi wa utafiti kuhusu malaria 
_________________________________________________________________ 
 
 
Kuna vitu tunataka wewe ujue kuhusu mardi huu wa utafiti:  

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Wazazi wako wanahitaji kutoa ruhusa ya wewe kushiriki kwenye mradi huu. Sio lazima 
wewe ushiriki kwenye mradi, kama hutaki, hata kama wazazi wako wametoa ridhaa, 
hautalazimishwa. 
Unaweza kuacha kushiriki mradi huu muda wowote. Kama ukiamua kuacha kushiriki hakuna 
mtu ambaye atakasirika ama kukusikitikia. Dakitari wako ataendelea kukuhudumia kama 
kawaida. 
Wakati mwengine mambo mazuri hutokea kwa watu wanaoshiriki mradi, na wakati 
mwingine vinaweza kutokea vitu usivyo vipenda. Tutakuambia kuhusu vitu hivi haoa chini.  
Kwanini wanafanya mradi huu wa utafiti?  
Sababu ya kufanya utafiti huu nu kujifunza kuhusu ugonjwa wa malaria kwenye maeneo 
unayo ishi. Malaria inaweza kusababisha kuumwa sana , hasa kwa vichanga na watoto 
wadogo. 
Taarifa katika utafiti huu utatusaidia kuelewa kwanini baadhi ya dawa hazifanyi kazi 
sawasawa kusaidia kutibu malaria. Tunataka kujua pia kama mgonjwa akinywa dawa mseto 
ya malaria kwa siku nyingi zaidi ya kawaida  kama itasaidia kuuwa wadudu wa malaria vizuri 
zaidi. 
Kwanini wewe unaombwa kushiriki kwenye mradi huu wa utafiti?  
Unaombwa kushiriki kwasababu umepimwa na kukutwa na wadudu wa malaria. 
Watu wangapi watashiriki kwenye mradi huu wa utafiti?  
Kama ukikubali kushiriki kwenye mradi huu, utakuwa mmoja kati ya watu 280 wengine, 
watoto na wakubwa. Mradi huu utafanyika hapa Yombo, Tanzania. 
Nini kitatokea kwenye mradi huu?  
Ukukubali kushiriki kwenye mradi, hivi vitatokea, 
-Unaweza kuhitajika kukaa hospitalini siku nzima leo, ili dakitari wako akutibu malaria. 
Wakati upo hospitali utapewa vidonge vya malaria. Kwa mradi huu, itabidi utoe damu 
kidogo kwaajili ya vipimo kutoka kwenye mshipaya damu ama kidole chako, mara mbili 
kwa siku kwa siku saba za mwanzo. Damu hio itafanyiwa vipimo vya wadudu wa malaria, 
pia itapimwa wingi wa damu ambayo ikipungua unaumwa.  
-Wazazi wako au walezi wataulizwa maswali kuhusu wewe na afya yako na nyumbani. 
-Leo pia utapewa dawa za malaria, na mhudumu wa mradi atakuwa nawe kwa dakika 30 
baada ya dawa kuangalia unaendeleaje na kama hauta tapika. Pia utakuja kesho na kesho 
kutwa hadi siku ya sita kunywa dawa. 

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-Baada ya kuja hapa kwa siku 7 kunywa dawa na kutoa vipimo, utakaa nyumbani kwa siku 
7 halafu utakuja tena hapa hospitali kwaajili ya vipimo.Kila mara ukija tutamuuliza mzazi 
wako/mlezi kuhusu afya yako. Pia tuthitaji kutoa marone kadhaa  ya damu (3-6) kwa sindano. 
Damu yako itapimwa kuangalia hali yako inaendeleaje ili upone vema.  
-Baada ya hapo, utakuja tena mara 5 kama vile hapo juu. Utashiriki kwenye mradi huu kwa 
siku 42. 
Nani mwingine ataambiwa vitu ambavyo tutagundua kuhusu wewe kwenye utafiti?  
Taarifa tutakazo zigundua kuhusu wewe na mradi zitakuwa siri. Dakitari wa mradi 
atazungumza na mzazi wako/mlezi lakini hata zungumza na mtu mwingine yeyote ukiacha 
wafanyakazi wa mradi. Kama dakitari wako atahitaji kuzungumza na mtu mwingine kuhusu 
wewe, atakuomba ruhusa wewe na pia mzazi wako kama ni sawa.  
Vitu gani vizuri vinaweza kutokea? 
Matokeo ya utafiti yatatusaidia kuelewa vizuri malaria nchini kwako. Hii itatupa taarifa 
muhimu namna nzuri ya kulinda watu na malaria. 
Vitu gani vibaya vinaweza kutokea?  
Wakati mwingine vitu vinatokea kwenye mradi ambavyo vinasikitisha. Hivi vinaitwa 
“vihatarishi”. Wakati wa kutoa damu, unaweza kusikia maumivu wakati wa kuchoma 
sindano, na kuna hatari kidogo ya kuumwa wakati wa kutoa damu. 
Sio vyote hivi vinaweza kutokea kwako. Inawezakana hata moja kisitokee kwako, ama 
vikatoke vitu ambavyo hata watafiti hawajui vizuri. Lazima uripoti tatizo lolote unalolisikia 
kwa watafiti. 
Vipi kama mzazi wako hataki ushiriki kwenye mradi huu? 
Unaweza kuamua kuacha kushiriki kwenye mradi huu muda wowote, bila kuwa na sababu 
yoyote. Hakuna mtu atakae kulazimisha kubaki. 
Je nitapata pesa yoyote ama zawadi kwa kushiriki kwenye mradi?  
Utapata chakula wakati ukiwa umebaki hospitali na ukipata matibabu na kutoa vipimo vya 
mradi. 
 
Uzungumze na nani kama una maswali?  
Kama una maswali yoyote kuhusu mradi, waulize watu walioko kwenye karatasi hii 
mwanzoni.  

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Kama  una maswali, manunguniko, hofu na malalamiko kuhusu haki zako wakati wa mradi, 
unaweza kuwasiliana na Muhimbili University of Health and allied sciences Institutional 
Review Board at+255 22 2121400 or Tanzania Food and Drug Authority +255 22 2452108. 
Ama kumpigia simu Mtafiti kiongozi Lwidiko Edward Mhamilawa, kwenye simu nambari 
0712865206 
 
Ukiweka sahihi yako hapa inamaanisha unakubali kushiriki kwenye mradi huu. 
 
 
_____________________________________________________
_ 
Weka sahihi yako hapa kama unataka kushiriki kwenye mradi 
 
__________________
_ 
Tarehe 
 
_____________________________________________________
_ 
Andika jina lako hapa kama unataka kushiriki kwenye mradi 
  
 
 
 
_____________________________________________________
_ 
Sahihi ya Mtafiti anaeomba ruhusa kwako  
 
__________________
_ 
Tarehe 
 
_____________________________________________________
_ 
Jina la Mtafiti anaeomba ruhusa kwako 
  
 
 
 
 
 
 
 
 
 
 

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22 APPENDIX IV: CASE RECORD FORM (CRF):  
Aiming at prolonging the therapeutic life span of artemisinin-based combination therapies in 
an era of imminent Plasmodium falciparum resistance in Bagamoyo District, Tanzania - new 
strategies with old tools.                                                          
Patient study No. 
 
 
 
Inclusion (Y/N) All must be YES!               
Exclusion (Y/N) All must be NO! 
P. falciparum density 2000-200 000/l 
 
Danger signs/signs of severe malaria 
 
Age 1+   65 yrs 
 
Other disease than malaria as cause of fever 
 
Weight  10 kg 
 
Serious underlying disease 
 
Fever/history of fever within 24 h 
 
History of allergy to Coartem (AL) 
 
Screening Haemoglobin ≥ 8 g/dl 
 
Treated with any other antimalarial drug < 14 
days 
 
Able to ingest tablets orally   
 
Consent from parent/guardian  
 
ECG – QTc interval more than 440ms for 
men or more than 460ms for women 
 
Willing and able to come for follow-up 
 
Pregnant, breastfeeding, or unwilling to 
practice birth control during participation. 
 
Informed consent attached 
 
 
Demography 
Date of birth (dd. mm. yy)  
Sex (M/F) 
Age (months) 
Weight (Kg) 
Does the Patient meet all Inclusion Criteria  
YES                          NO 
Treatment ARMS 
Control arm: AL tablets assigned as per protocol  
(indicate number of tablets per dose) + Placebo 
Intervention Arm: Prolonged AL + Primaquine arm 
0.25mg/kg  (indicate number of tablets per dose) 
 
 
Investigators name: 
Signature 
Date 
Confidential information: 
Patient full name: 
 
Phone Number  and location of house: 
 
 

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Patient ID No: 
 
 
 
Treatment Arm: 
Parent/guardian’s full name: 
 
 
 
TREATMENT ASSESSMENT   
 
 
 
                                                                  
Days of visit 
Day 0 
Day 0 
Day 0 
Day 0 
Day 1 
Day 1 
Day 1 
Day 2 
 Time of study (Hours) 
0 
2 
4 
8 
24 
36 
40 
48 
Date (dd. mm. yy) 
 
 
 
 
 
 
 
 
Patient seen (Y/N) 
 
 
 
 
 
 
 
 
1. Lab. Parameters 
 
 
 
 
 
 
 
 
P. falciparum, asexual forms (parasites/l)  B/S 
 
 
 
 
 
 
 
 
P. falciparum, asexual forms(parasites/l) MOMIC 
 
 
 
 
 
 
 
 
Gametocytes/1000 WBC 
 
 
 
 
 
 
 
 
Temperature (◦C) 
 
 
 
 
 
 
 
 
ECG – QTc Interval 
 
 
 
 
 
 
 
 
Hemoglobin (g/dl) 
 
 
 
 
 
 
 
 
Urine Analysis for Hematuria 
 
 
 
 
 
 
 
 
 
2. Symptoms: Y= Present N=Absent 
 
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
 
 
Weakness 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
Others (specify) 
 
 
 
 
 
 
 
 
Symptoms/signs of Severe malaria (Y/N) 
 
 
 
 
 
 
 
 
Adverse event (Y/N): If yes, fill AEF  
 
 
 
 
 
 
 
 
Serious Adverse Event (Y/N): If yes Fill the SAEF 
 
 
 
 
 
 
 
 
3. Samples Collection 
 
 
 
 
 
 
 
 
DBS for PCR -60ul   (Y/N) 
 
 
 
 
 
 
 
 
Capillary blood for LAMP- 30ul (Y/N) 
 
 
 
 
 
 
 
 
Venous Blood for Pharmacokinetics -2 mls (Y/N) 
 
 
 
 
 
 
 
 
Venous blood for Biochemistry- 2 mls (Y/N) 
 
 
 
 
 
 
 
 
DBS for antimalarial PK- 60ul (Y/N) 
 
 
 
 
 
 
 
 
Concomitant drugs (Y/N) 
 
 
 
 
 
 
 
 

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4. Signature of clinician 
 
 
 
 
 
 
 
 
 
TREATMENT ASSESSMENT                                                                                      
Days of visit 
Day 
2 
Day2 
Day 
3 
Day 
3 
Day 
3 
Day 
4 
Day4 
Day 
4 
Day 
5 
Day 
5 
Time of study (Hours) 
52 
60 
72 
84 
88 
96 
100 
108 
120 
132 
Date (dd. mm. yy) 
 
 
 
 
 
 
 
 
 
 
Patient seen (Y/N) 
 
 
 
 
 
 
 
 
 
 
1. Lab. Parametres 
 
 
 
 
 
 
 
 
 
P. falciparum, asexual forms (/l) B/S 
 
 
 
 
 
 
 
 
 
 
Gametocytes/1000 WBC 
 
 
 
 
 
 
 
 
 
 
Temperature (◦C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG – QTc Interval 
 
 
 
 
 
 
 
 
 
 
Hemoglobin (g/dl) 
 
 
 
 
 
 
 
 
 
 
Urine Analysis for haematuria 
 
 
 
 
 
 
 
 
 
 
2. Symptoms: Y= Present 
N=Absent 
 
 
 
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
 
 
 
 
Weakness 
 
 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
 
Others (specify) 
 
 
 
 
 
 
 
 
 
 
Symptoms/signs of Severe malaria (Y/N) 
 
 
 
 
 
 
 
 
 
 
Adverse event (Y/N): If yes, fill AEF  
 
 
 
 
 
 
 
 
 
 
Serious A. Event(Y/N):If yes Fill SAEForm 
 
 
 
 
 
 
 
 
 
 
3. Samples Collection 
 
 
 
 
 
 
 
 
 
DBS for PCR -60ul   (Y/N) 
 
 
 
 
 
 
 
 
 
 
Capillary blood for LAMP- 30ul (Y/N) 
 
 
 
 
 
 
 
 
 
 
Venous Blood for PK -2 mls (Y/N) 
 
 
 
 
 
 
 
 
 
 
Venous blood for Biochemistry-2mls (Y/N) 
 
 
 
 
 
 
 
 
 
 
DBS for antimalarial PK- 60ul (Y/N) 
 
 
 
 
 
 
 
 
 
 
Patient ID No: 
 
 
 
Treatment Arm: 

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Concomitant drugs (Y/N) 
 
 
 
 
 
 
 
 
 
 
4. Signature of clinician 
 
 
 
 
 
 
 
 
 
 
TREATMENT ASSESSMENT                                                                                     
Days of visit 
Day5 
Day 
5 
Day 
6 
Day 
7 
Day 
14 
Day 
21 
Day 
28 
Day35 
Day 
42 
Any 
Day 
Time of study (Hours) 
134 
136 
144 
168 
336 
504 
672 
840 
1008 
 
Date (dd. mm. yy) 
 
 
 
 
 
 
 
 
 
 
Patient seen (Y/N) 
 
 
 
 
 
 
 
 
 
 
1. Lab. Parameters 
 
 
 
 
 
 
 
 
 
P. falciparum, asexual forms (parasites/l) 
 
 
 
 
 
 
 
 
 
 
Gametocytes/1000 WBC 
 
 
 
 
 
 
 
 
 
 
Temperature (◦C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG – QTc Interval 
 
 
 
 
 
 
 
 
 
 
Hemoglobin (g/dl) 
 
 
 
 
 
 
 
 
 
 
Urine Analysis for haematuria 
 
 
 
 
 
 
 
 
 
 
2. Symptoms: Y= Present 
N=Absent 
 
 
 
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
 
 
 
 
Weakness 
 
 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
 
Others (specify) 
 
 
 
 
 
 
 
 
 
 
Symptoms/signs of Severe malaria (Y/N) 
 
 
 
 
 
 
 
 
 
 
Adverse event (Y/N): If yes, fill AEF  
 
 
 
 
 
 
 
 
 
 
Serious A.Event(Y/N): If yes Fill the SAEF 
 
 
 
 
 
 
 
 
 
 
3. Samples Collection 
 
 
 
 
 
 
 
 
 
DBS for PCR -60ul   (Y/N) 
 
 
 
 
 
 
 
 
 
 
Capillary blood for LAMP- 30ul (Y/N) 
 
 
 
 
 
 
 
 
 
 
Venous Blood for PK -2 mls (Y/N) 
 
 
 
 
 
 
 
 
 
 
Venous blood for Biochemistry-2mls (Y/N) 
 
 
 
 
 
 
 
 
 
 
Patient ID No: 
 
 
 
Treatment Arm: 

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DBS for antimalarial PK- 60ul (Y/N) 
 
 
 
 
 
 
 
 
 
 
Concomitant drugs (Y/N) 
 
 
 
 
 
 
 
 
 
 
4. Signature of clinician 
 
 
 
 
 
 
 
 
 
TREATMENT SUMMARY                                                                                      
Patient study No. 
 
 
 
Completed treatment as per protocol (Y/N/Not Known) 
 
Consumption of any other antimalarial drug (Y/N) 
 
Outcome Day 14 
YES 
NO 
Outcome Day 42 
YES 
NO 
Completed follow up D14 
 
 
Completed follow up D42 
 
 
Adequate Clinical and 
Parasitological Response 
 
 
Adequate Clinical and 
Parasitological Response 
 
 
Early Treatment Failure 
 
 
  
 
 
Late Clinical Failure 
 
 
Clinical Failure D15-42 
 
 
Late Parasitological  
Failure 
 
 
Parasitological Failure D15-
42 
 
 
 
Severe malaria (Y/N)  If Yes fill below 
 
Date of severe malaria 
 
Rescue treatment given (Y/N) 
 
Hospitalization needed   (Y/N) 
 
Survived (Y/N/Not Known) 
 
 
Withdrawal from study (Y/N) If yes fill below 
 
Date of withdrawal (dd. mm. yy) 
 
Reason for withdrawal: 
Severe malaria (Y/N) 
 
Treatment failure (Y/N) 
 
Guardians request (Y/N) 
 
Lost to follow up (Y/N) 
 
Other reason (please state) 
 
 
ADMINISTRATION OF TREATMENT                                                                  
Dose 
Date 
Time 
No. of tablets/mg 
Acronym of Drug intake  
Sign. (study 
nurse/Dr) 
Day 0 (0 hrs) 
 
 
 
 
 
 
 
 Day 0 (8hrs) 
 
 
 
 
 
 
 

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Day 1 morning 
 
 
 
 
 
 
 
Day 1 evening 
 
 
 
 
 
 
 
Day 2 morning 
 
 
 
 
 
 
 
Day 2 evening 
 
 
 
 
 
 
 
Dose 
Date 
Time 
No. of tablets/mg 
Acronym of Drug intake  
Sign. (study 
nurse/Dr) 
Day 3 morning 
 
 
 
 
 
 
 
Day 3 evening 
 
 
 
 
 
 
 
Day 4 morning 
 
 
 
 
 
 
 
Day 4 evening 
 
 
 
 
 
 
 
Day 5 morning 
 
 
 
 
 
 
 
Day 5 evening 
 
 
 
 
 
 
 
 
Vomiting within 30 minutes after any drug administration (Y/N), if yes indicate after which dose 
 
Replacement dose given (Y/N), if yes state after which dose 
 
 
Study treatment permanently withdrawn (Y/N), if yes specify reasons 
 
 
Any severe adverse event requiring treatment withdrawal (Y/N) 
 
 
 
 

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23 APENDIX IV: SERIOUS ADVERSE EVENT REPORT FORM:  
STUDY -Aiming at prolonging the therapeutic life span of artemisinin-based combination 
therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, 
Tanzania - new strategies with old tools 
Serious adverse event report form 
Health center name:       
Visit Type; Initial        Follow up       
District:       
Patient identity number:          
Region:       
Date of visit (dd-mm-yy):       
 
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 
 
Serious adverse event  
Type of event: 
 Death 
 
 Life-threatening  
 Hospitalization or prolongation of hospitalization 
 Permanent disability 
 
 
Describe the serious adverse event (include all relevant laboratory results): 
      Reaction/ Event Start date (dd-mm-yy) 
      Reaction /Event End date (dd-mm-yy) 
      
Describe how the reaction was treated: 
      
      
 
Serious adverse event report form (page 2) 

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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:                    
 
 

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24 APENDIX V: ADVERSE EVENT FORM 
STUDY -Aiming at prolonging the therapeutic life span of artemisinin-based combination 
therapies in an era of imminent Plasmodium falciparum resistance in Bagamoyo District, 
Tanzania - new strategies with old tools 
                                                                                                
Patient study No. 
 
 
 
Date 
 1st AE (dd. mm. yy) 
 2nd AE (dd. mm. yy) 
Day in Study 
of 1st  AE 
 of 2nd AE 
Describe AE  (symptoms, signs, 
diagnosis and treatment & action) 
 
 
 
Date start/end 
 
 
Intensity 
[Tick ONE] 
OR 
Urine color chart: Hillmen Grade 
[____] 
Mild 
 
Mild 
 
Moderate 
 
Moderate 
 
Severe 
 
Severe 
 
Very Severe 
 
Very Severe 
 
Unknown 
 
Unknown 
 
Drug-event relationship 
[Tick ONE] 
None 
 
None 
 
Unlikely 
 
Unlikely 
 
Possible 
 
Possible 
 
Probable 
 
Probable 
 
Definite 
 
Definite 
 
Unknown 
 
Unknown 
 
Outcome  
[Check ONE] 
Complete recovery 
 
Complete recovery 
 
Still present 
 
Still present 
 
Sequelae 
 
Sequelae 
 
Death 
 
Death 
 
Unknown 
 
Unknown 
 
Action taken 
[Tick all  applicable] 
None 
 
None 
 
Study treatment stopped 
 
Study treatment stopped 
 
Hospitalization required 
 
Hospitalization required 
 

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Concomitant drug therapy 
 
Concomitant therapy 
 
24.1.1 Appendix Vb  
Data Collection Form for Safety Assessment 
INSTRUCTIONS:  
Complete this form for all cases of confirmed, uncomplicated P. falciparum malaria that have been treated with PQ. 
1. Today’s Date (dd/mm/yy) _ _ / _ _ / _ _  
2. Family Name |__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__| 
3. First (Given) Name |__|__|__|__|__|__|__|__|__|__|__|__|  
4. Nationality: ☐ Tanzania  Other (specify): __________________________ 
5. Is Tanzania your country of residence? ☐ Yes ☐ No     6. Age: |__|__| ☐ yrs ☐ mths  7. Sex ☐ M ☐ F 
8. Mobile No. 1 |__|__|__|__|__|__|__|__|__|__|__|__| 9. Mobile No. 2 |__|__|__|__|__|__|__|__|__|__|__|__|  
10. Pregnant: ☐ Y (Trimester |__|)  ☐ N ☐ Uncertain   ☐ N/A 
 
11. Weight: _ _ _. _ kg 
 
12. Does this patient have a family history of hemolysis (severe anemia)? ☐ Yes ☐ No  ☐ Uncertain   
If yes, was it in response to: ☐ Medication ☐Food ☐ Infection ☐ Other 
13. Does this patient have a family history of G6PD deficiency? ☐ Yes ☐ No  ☐ Uncertain   
14. Has this patient ever had a blood transfusion? ☐ Yes ☐ No   
15. Diagnostic test type: ☐RDT 
☐ Microscopy 
☐Both 
16. Diagnosis:  ☐Pf     ☐ Pv     ☐ Mixed     ☐Other (specify): __________________________   
17. Antimalarial Prescribed (check all given):  
☐AL   ☐Oral QN   ☐IV QN   ☐IM QN   ☐SP/Fandisar   ☐CQ   ☐Other (specify): __________________☐Unknown  
18. Primaquine dose prescribed and # of days: 
Daily dose: ☐15mg   ☐45mg   ☐Other (specify):  __________________________ mg/dose 
For how many days:  ☐1 day   ☐14 days   ☐1x weekly for 8 weeks     ☐Other (specify): 
__________________________ 
19. Day 0:   ☐Hemoglobin:  _ _ _ . _ g/dl  
20.  Blood Spot: ☐Taken     ☐Not taken   (INSTRUCTIONS: Add Barcode No. to blood spot if taken.) 
24.1.1.1  
 
Patient Information Card 
Family Name |__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__| 
First (Given) Name |__|__|__|__|__|__|__|__|__|__|__|__|  
Patient Instructions 
You have received treatment for malaria.  Please return if you do not improve or notice new problems. Please check the 
color of your urine (by passing urine into a white or clear container) while taking malaria medications.  If you notice dark 
to very dark yellow-orange urine or experience nausea, vomiting, stomach or back pain, please return to the health facility 
with this card or call the following mobile number:  |__|__|__|__|__|__|__|__|__|__|__|__| 
------------------------------------------------------------------------perforation-------------------------------------------------------------
--------- 
 
 
Maelekezo kwa mgonjwa                                       
Umepata matibabu ya malaria. Tafadhali rudi hapa kituoni kama hutapata nafuu ama utapata tatizo. Tafadhari chunguza 
rangi ya mkojo (kwa kukojoa kwenye chupa angavu) wakati ukitumia dawa za malaria. Ukiona mkojo wa njano iliyoiva 
Barcode/Unique ID 
Barcode/Unique ID 

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ama njano ya machungwa iliyoiva sana, ama ukipata kichefuchefu, kutapika, maumivu ya tumbo au mgongo, tafadhali 
rudi hapa kituoni na kadi hii ama piga simu kwa namba hizi:  |__|__|__|__|__|__|__|__|__|__|__|__|  
------------------------------------------------------------------------perforation-------------------------------------------------------------
--------- 
 

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Provider Instructions  
Health Facility Name: ____________________________  
Contact No. |__|__|__|__|__|__|__|__|__|__|__|__| 
Should the patient return with signs or symptoms of commonly reported adverse events associated with Primaquine, please complete a patient encounter form. If patient presents to 
a different health facility from the health facility where original treatment was provided, please contact the treating facility 
Patient Encounter Forms 
Patient Encounter 1 
 
1. Date of return visit (dd/mm/yy) _ _ / _ _ / _ _   
2. Is this a scheduled day 7 visit? ☐Yes   ☐No   
3. ☐Hemoglobin: _ _ _ . _ g/dl    
4. # of PQ taken per day: _______________________ 5. # of days PQ tablets taken: _____________________  
6. Did the patient experience an adverse event since being treated with PQ? ☐Yes    ☐No   
If yes, complete adverse event report. Otherwise, leave blank.  
 
 
 
 
 
Type of AE 
(check all that 
apply) 
Onset Date 
Severity Grade 
(check one) 
Actions Taken? 
(specify below if 
needed) 
Is AE related to 
PQ? 
(check one) 
Date Resolved  
Outcome of AE (check one) 
Serious 
AE?   
☐ Rash 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
 ☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Nausea 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization  
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite  
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
Barcode/Unique ID 

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☐ Vomiting 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion  
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Anemia 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Dark Urine 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Diarrhea 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Other 
(describe): 
____________
__________ 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 

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☐ Other 
(describe): 
____________
__________ 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
☐ Other 
(describe): 
____________
__________ 
_ _ / _ _ / _ _ 
☐ Mild 
☐ Moderate 
☐ Severe 
☐ Life-threatening 
 
☐ None 
☐ Stopped PQ 
☐ Prescribed drug  
☐ Blood Transfusion 
☐ Hospitalization 
☐ Other** 
☐ Unrelated 
☐ Unlikely 
☐ Possible 
☐ Probable 
☐ Definite 
_ _ / _ _ / _ _ 
or ongoing ☐ 
☐ Recovered/resolved 
☐ Recovered/resolved with sequelae 
☐ Recovering/resolving 
☐ Not recovered/not resolved 
☐ Fatal  
☐ Unknown 
☐ No 
☐ Yes* 
* Yes should be answered when the adverse event results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. 
 
Definitions  
Severity – Mild (easily tolerated; no or minimal interference with daily activities); Moderate (low level of inconvenience; greater than minimal interference with daily activities); 
Severe (interrupts normal daily activities; usually incapacitating); Life-threatening (life-threatening consequences; urgent intervention indicated); Fatal (death) 
 
**Other information (actions taken): _______________________________________________________________________________________________________ 
_______________________________________________________________________________________________________ 
 
OPTION 1: 
7. Did the patient take any other drugs along with PQ at the time of treatment or in the two-week period prior to the onset of the event? If yes, please specify the following:  
Name of 
Drug 
Dose  
Unit 
Frequency 
(number of 
times per 
day) 
Route 
Date Started 
(dd/mm/yy) 
Date Stopped 
(dd/mm/yy) 
Or 
Continuing? 
Indication 
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ drops   ☐ 
other:_____ 
☐ tsp        ☐ don’t know 
 
☐ oral     ☐ 
topical 
☐ IM       ☐ 
rectal 
☐ IV         
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
 

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☐ tablet/capsule 
☐ other:________ 
☐ don’t know 
If AL is given, complete information above. Include all other concomitant medicines below.  
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ drops   ☐ 
other:_____ 
☐ tsp        ☐ don’t know 
☐ tablet/capsule 
 
☐ oral     ☐ 
topical 
☐ IM       ☐ 
rectal 
☐ IV         
☐ other:________ 
☐ don’t know 
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
 
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ drops   ☐ 
other:_____ 
☐ tsp        ☐ don’t know 
☐ tablet/capsule 
 
☐ oral     ☐ 
topical 
☐ IM       ☐ 
rectal 
☐ IV         
☐ other:________ 
☐ don’t know 
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
 
  
8. Did the patient take any traditional medicines along with PQ at the time of treatment or in the two-week period prior to the onset of the event? If yes, give details if known: 
_______________________________________________________________________________________________________ 
_______________________________________________________________________________________________________ 
INSTRUCTIONS: If patient presents with additional adverse events, attach and complete another form.   
 

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Version Date: 04th July 2017  
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24.1.3 Appendix Vb 
Fomu ya kukusanyia taarifa za usalama wa dawa 
Maelekezo:  
Jaza fomu hii kwa wagonjwa wote waliothibitishwa kuwa na malaria kawaida itokanayo na waliotibiwa na Primaquine. 
1. Tarehe ya leo (sk/mz/mk) _ _ / _ _ / _ _  
2. Jina la familia |__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__| 
3. Jina la kwanza |__|__|__|__|__|__|__|__|__|__|__|__|  
 
4. Utaifa: ☐ Tanzania.  Mwingineo (Taja): __________________________ 
5. Je Tanzania ni nchi yako ya ukazi? ☐ Ndiyo ☐ Hapana  6. Umri: |__|__| ☐ miaka ☐ miezi  7. Jinsia ☐Kiume ☐Kike 
8. Namba ya simu ya mkononi. 1 |__|__|__|__|__|__|__|__|__|__|__|__| 9. Namba nyingine. 2 
|__|__|__|__|__|__|__|__|__|__|__|__|  
10. Mjamzito: ☐ N (Trimester |__|)  ☐ H ☐ Haijulikani   ☐ N/A 
 
11. Uzito: _ _ _. _ kg 
 
12. Je mgonjwa anahistoria ya kupungukiwa damu (kupungukiwa damu sana)? ☐ Ndiyo ☐ Hapana  ☐ Haijulikani   
Kama ndiyo, ilisababishwa na: ☐Dawa ☐Chakula ☐ Maambukizi ☐ Mengineyo 
13. Je mgonjwa ana historia ya familia kuwa na upungufu wa kimengénya kiitwacho G6PD? ☐ Ndiyo ☐Hapana ☐ 
Haijulikani   
14. Je mgonjwa amewahi kuwekewa damu? ☐ Ndiyo ☐Hapana   
15. Aina ya kipimo: ☐RDT ☐Darubini 
☐Vyote 
16. Majibu:  ☐Pf     ☐ Pv     ☐ Mchanganyiko     ☐Mengineyo (Taja): __________________________   
17. Dawa ya malaria iliyotolwa (Tiki zote zilizotolewa):  
☐AL   ☐Oral QN   ☐IV QN   ☐IM QN   ☐SP/Fandisar   ☐CQ   ☐Nyinginezo (Taja): 
__________________☐Haifahamiki  
18. Dozi ya Primaquine iliyotolewa na idadi ya siku: 
      Dozi ya siku: ☐15mg   ☐45mg   ☐Nyinginezo (Taja):  __________________________ mg/dozi 
      Kwa siku ngapi:  ☐ siku 1 ☐ siku 14   ☐mara 1 kwa wiki kwa wiki 8  ☐Mengineyo (Taja): 
_________________________ 
19. Siku 0:   ☐Uwingi wa damu:  _ _ _ . _ g/dl  
20. Damu kwenye karatasi: ☐Imechukuliwa ☐Haijachukuliwa (Maelekezo:Weka namba ya mgonjwa kama damu 
imechukuliwa kwenye kikaratasi) 
 
 
 
Kadi ya maelekezo kwa mgonjwa 
Jina la mgonjwa |__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__| 
Jina la kwanza   |__|__|__|__|__|__|__|__|__|__|__|__|  
------------------------------------------------------------------------mkato-------------------------------------------------------------------
--- 
Maelekezo kwa mgonjwa                                       
Umepata matibabu ya malaria. Tafadhali rudi hapa kituoni kama hutapata nafuu ama utapata tatizo. Tafadhari chunguza 
rangi ya mkojo (kwa kukojoa kwenye chupa angavu) wakati ukitumia dawa za malaria. Ukiona mkojo wa njano iliyoiva 
ama njano ya machungwa iliyoiva sana, ama ukipata kichefuchefu, kutapika, maumivu ya tumbo au mgongo, tafadhali 
rudi hapa kituoni na kadi hii ama piga simu kwa namba hizi:  |__|__|__|__|__|__|__|__|__|__|__|__|  
------------------------------------------------------------------------mkato-------------------------------------------------------------------
--- 
 
 
 
Namba ya mgonjwa 
Namba ya mgonjwa 

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Maelekezo kwa mtoa huduma 
Jina la zahanati: ____________________________ 
 
Namba ya simu. 
|__|__|__|__|__|__|__|__|__|__|__|__| 
Ikitokea mgonjwa akarudi na dalili za madhara ya kawaida yatokanayo na matumizi ya Primaquine, tafadhali jaza fomu 
ya mgonjwa. Kama mgonjwa ataenda hospitali nyingine tofauti na hospitali ambako alipewa matibabu ya kwanza, 
tafadhali wasiliana na hiyo hospitali.  
 
 
 
Fomu ya mgonjwa aliyepata madhara 
Fomu ya mgonjwa aliyedhurika 1 
 
1. Tarehe ya kurudi (sk/mz/mk) _ _ / _ _ / _ _  
 
2. Hii ni siku ya 7 uliyopangiwa? ☐Ndiyo   ☐Hapana   
3. ☐Uwingi wa damu: _ _ _ . _ g/dl    
4. Idadi ya vidonge vilivyomezwa kwa siku: _____________ 5. Idadi ya siku PQ imenywewa: _____________________  
6. Mgonjwa alipata madhara tangu alipokuwa akitibiwa kwa PQ? ☐Ndiyo    ☐Hapana  
Kama ni ndiyo, jaza fomu yaripoti ya madhara makubwa. 
 
Aina ya 
madhara (Tiki 
inayohusika) 
Siku 
yalipoanza 
Kiwango 
(Tiki moja) 
Hatua iliyochukuliwa? 
(Elezea) 
Madhara 
yanahusiana na PQ? 
(Tiki moja) 
Tarehe 
yalipokwisha  
Matokeo ya madhara (Tiki moja) 
Serious 
AE?   
☐ Upele 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavu 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐ 
Kichefuchefu 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavu 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐ Kutapika 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavu 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐ Anemia 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavu 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
Namba ya mgonjwa 

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Version Date: 04th July 2017  
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☐ Mkojo 
mweusi 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavu 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐ Kuharisha 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavulae 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐Mengineyo 
(Elezea):  
_____________
_________ 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavulae 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐Mengineyo 
(Elezea):_____
_____________
____ 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea  ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavulae 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
☐Mengineyo 
(Elezea): 
_____________
_________ 
_ _ / _ _ / _ _ 
☐ Kidogo 
☐ Wastani 
☐ Mbaya 
☐ Yanatishia 
uhai 
 
☐ Hakuna 
☐ PQ Imesitishwa 
☐ Amepewa dawa  
☐ Kaongezwa damu 
☐ Kalazwa 
☐ Mengineyo** 
☐ Hamna uhusiano 
☐ Nadra 
☐ Yawezekana 
☐Hakika 
_ _ / _ _ / _ _ 
au inaendelea ☐ 
☐ Amepona/amepata nafuu 
☐ Amepona na kubaki na 
ulemavulae 
☐Anapata nafuu 
☐ Hajapona/hajapata nafuu 
☐ Hali ni mbaya  
☐ Haifahamiki 
☐ No 
☐ Yes* 
* Iwe ndiyo endapo madhara yamepelekea kifo, inatishia uhai, inahitajika kulazwa au kuongeza muda wa kulazwa, 
inapelekea kuendelea au kupata ulemavu/kupoteza uwezo, au madhara ya kuzaliwa nayo. 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol No 01.05.2017 
Confidential 
 
Version 4: 
Version Date: 04th July 2017  
Page 91 of 92 
 
 
7. Mgonjwa alikunywa dawa wakati akitumia PQ au ndani ya wiki mbili kabla ya kutokea kwa madhara? Kama ndiyo, tafadhari elezea yafuatayo:  
Jina la dawa 
Dozi  
Kipimo 
Frequency 
(number of 
times per day) 
Njia 
Tarehe ya 
kuanza 
(sk/mz/mk) 
Tarehe ya kusitisha 
(sk/mz/mk) 
 
Indication 
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ matone ☐ 
Mengine:_____ 
☐ K/chai        ☐ 
Sifahamu 
☐ Kidonge/tembe 
 
☐ Mdomo     ☐ 
Kupaka 
☐ IM       ☐ Haja 
kubwa 
☐ IV         
☐ Nyingine:________ 
☐ Sifahamu 
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
If AL is given, complete information above. Include all other concomitant medicines below.  
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ matone☐ 
Mengine:_____ 
☐ K/chai        ☐ 
Sifahamu 
☐ Kidonge/tembe 
 
☐ Mdomo     ☐ 
Kupaka 
☐ IM       ☐ Haja 
kubwa 
☐ IV         
☐ Nyingine:________ 
☐ Sifahamu 
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
 
 
☐ mg        ☐ g 
☐ ml         ☐ mcg 
☐ matone☐ 
Mengine:_____ 
☐ K/chai        ☐ 
Sifahamu 
☐ Kidonge/tembe 
 
☐ Mdomo     ☐ 
Kupaka 
☐ IM       ☐ Haja 
kubwa 
☐ IV         
☐ Nyingine:________ 
☐ Sifahamu 
_ _ / _ _ / _ _ 
 
_ _ / _ _ / _ _ 
 
☐ 
  
8. Je, mgonjwa alitumia dawa zozote za asili pamoja na PQ wakati wa matibabu au ndani ya wiki mbili kabla ya kutokea kwa madhara? Kama ndiyo, elezea: 
_______________________________________________________________________________________________________ 
_______________________________________________________________________________________________________ 
Maelekezo: Kama mgonjwa atapata madhara zaidi, ambatanisha na jaza fomu nyingine.    
 

Protocol No 01.05.2017 
Confidential 
 
Version 4: 
Version Date: 04th July 2017  
Page 92 of 92 
 
 
 
24.1.4 Procedure for investigation of suspected hemolysis 
 
24.1.5 Procedure for management of hemolysis