Community Based Safety Study of 2-drug (Diethylcarbamazine and Albendazole) Versus 3-drug (Ivermectin, Diethylcarbamazine and Albendazole) Therapy for Lymphatic Filariasis
Phase: NA
Conditions: Lymphatic Filariasis
Sponsor: Washington University School of Medicine

DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 1 of 90 
“Community Based Safety Study of 2-drug (Diethylcarbamazine and Albendazole) 
versus 3-drug (Ivermectin, Diethylcarbamazine and Albendazole) Therapy for 
Lymphatic Filariasis in Papua New Guinea” 
Protocol Identifier: DOLF_IDA_Papua New Guinea 
Type: Community Based Mass Drug Administration 
DOLF Project Principal Investigators: Gary Weil, MD, Washington University, USA and 
Christopher King, MD, PhD, MPH, Case Western Reserve University, USA 
Study Site Principal Investigators: Leanne Robinson, PhD, MPH and William Pomat, PhD, 
Papua New Guinea Institute for Medical Research, Papua New Guinea 
 
Initial Protocol: v1.0 22 April 2016 
Amendment 1:  v2.0 19 May 2016 
Amendment 2:  v2.1 05 July 2017 
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 2 of 90 
INVESTIGATOR AGREEMENT 
“Community Based Safety Study of 2-drug (Diethylcarbamazine and Albendazole) 
versus 3-drug (Ivermectin, Diethylcarbamazine and Albendazole) Therapy for 
Lymphatic Filariasis in Papua New Guinea” 
DOLF_IDA_Papua New Guinea: v2.1  05 July 2017 
I have read the protocol, including the appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described.  I will conduct this study as 
outlined and make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel, participating in the study under my supervision copies of the 
protocol and access to all study related information provided by the DOLF project. I will discuss 
with them to ensure they are full informed about the study drug(s) and the study procedures. 
Principle Investigator: ___________________________________________    
 
                        Name/Title  (Print/Type) 
 
Signed:  
Date: 
 
NOTE:  Both the Project PI and local PI should have signed investigator agreements on file.   
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 3 of 90 
Co-Investigators: 
 
Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA 
James Kazura, MD  
Ronald Blanton, MD 
Daniel J Tisch, PhD 
 
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA 
Gary Weil, MD 
 
PNG Institute for Medical Research 
Moses Laman, MBBS, PhD 
Livingstone Tavul, MSc 
 
PNG National Department of Health 
Sibauk Bieb, MBBS 
Lucy John, MBBS 
Leo Makita Principal advisor, Malaria and Vector-Borne Diseases 
Mary Yohogu, NTD Program manager 
 
World Health Organisation (WHO) WPRO 
James Wangi, MPH, MBBS, MBBE 
 
Team Roster  
 
Principal Investigators 
1.1.1  
1.1.2 Christopher L King, MD, PhD 
Center for Global Health and Diseases 
Biomedical Research Building 
2109 Adelbert Rd. 
Case Western Reserve University School of Medicine 
Cleveland, OH, 44106-4983 
Tel 216-368-4817, email: cxk21@case.edu 
 
Leanne Robinson, PhD, MPH  
Papua New Guinea Institute of Medical Research (PNG IMR) 
Madang, PNG 
Tel 675-422-2909, email: robinson@wehi.EDU.AU 
 
William Pomat, PhD  
PNG IMR 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 4 of 90 
Goroka, PNG 
Tel 675-532-2800, email: william.pomat@pngimr.org.pg 
 
1.1.3 Investigators 
PNG IMR 
Madang, PNG 
Tel 675-852-2909  
 
Moses Laman, MBBS, PhD email: drmlaman@yahoo.com  
Livingstone Tavul, MSc email: ltteruah1@gmail.com 
 
Center for Global Health and Diseases 
Biomedical Research Building 
2109 Adelbert Rd. 
Case Western Reserve University School of Medicine 
Cleveland, OH, 44106-4983 
1.1.4  
1.1.5 James W Kazura, MD 
Tel 216-368-4810; email jxk14@case.edu 
1.1.6 Ronald E Blanton, MD 
Tel 216-368-4814; email reb6@case.edu 
 
Daniel J Tisch, MPH, PhD  email: dxt37@case.edu    
 
PNG National Department of Health 
 
Sibauk Beib, MBBS  email: svbeib@gmail.com 
Lucy John, MBBS email: Lucy_John@health.gov.pg 
Leo Makita  email: leo.makita@gmail.com 
Mary Yohogu  email: myohogu51@gmail.com 
 
WHO WPRO 
James Wangi, MPH, MBBS, MBBE email: wangij@wpro.who.int/pg 
 
Protocol Statisticians  
Daniel J Tisch, MPH, PhD  
Case Western Reserve University School of Medicine 
Center for Global Health & Diseases, Dept. of Epidemiology and Biostatistics 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 5 of 90 
2109 Adelbert Road, 
Cleveland, OH, USA 44106 
Tel. 216 368 4818 Fax: 216 368 4825 email: dxt37@case.edu  
 
Ken Schechtman, PhD 
Dept. of Internal Medicine and Division of Biostatistics, Washington University School of 
Medicine 
660 South Euclid, St. Louis, MO 63110 
Tel. 314-454-8356; Fax 314-454-5113; email: wshannon@im.wustl.edu 
 
1.1.6.1.1.1.1 Medical Monitor 
Charles H King, MD, MS 
Center for Global Health and Diseases, Case Western Reserve University School of Medicine, 
Cleveland, OH 
 
1.1.6.1.1.1.2 PARTICIPATING SITES  
 
Case Western Reserve University 
IRB approval and oversight provided by University Hospitals Case Medical Center Cleveland, 
OH USA 
 
PNG IMR 
Madang and Maprik, PNG 
IRB approval and oversight provided by PNG IMR, Goroka and the PNG Medical Research 
Advisory Committee (MRAC), Port Moresby 
 
PNG National Department of Health (PNG NDoH) 
Vector Borne Disease Control Program; Lymphatic Filariasis Elimination Program

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 6 of 90 
LAYMAN PROTOCOL SUMMARY 
 
Results from ongoing studies conducted in East Sepik Province, PNG have shown that using 
three drugs together (Ivermectin [IVM], Diethylcarbamazine [DEC] and Albendazole [ALB], i.e., 
“IDA”) is more effective than the current two-drug combination (DEC+ALB) being used in the 
global program to eliminate lymphatic filariasis in PNG.  Lymphatic filariasis (LF) elimination in 
PNG involves annual mass drug administration (MDA) with the current standard two drug 
regimens in LF endemic areas for at least 5 years.  
 
A single dose of the three drugs together, IDA, very quickly cleared all lymphatic filariasis 
“worms” or “microfilariae” (Mf) from the blood of 68 heavily infected individuals with LF in PNG.  
All treated participants remained Mf negative one year after treatment, something that is only 
achieved in ~20 to 30% of individuals treated with the standard two-drug combination in PNG. A 
single dose of the triple drug combination therefore appears to kill or permanently sterilize adult 
worms.  
 
This new treatment could make a huge difference in the global effort to eliminate LF in PNG and 
other LF endemic countries by reducing the number of rounds of Mass Drug Administration 
(MDA) required for elimination. i.e., completely and irrevocably eliminating transmission of LY by 
the local mosquito vectors. The greatest impact of this new treatment may be in areas with high 
infection rates where MDA has not yet been introduced, and also could be very useful areas 
where LF infection persists despite several years of annual MDA with the current 2-drug 
regimens. In PNG, both areas exist and continue to present a challenge to LF elimination 
efforts.  
 
Although all of the individual drugs used in the IDA triple drug combination have been provided 
as MDA to hundreds of millions of people since 2000, there is only limited experience with the 
three drugs used together. Currently a total of 120 participants with heavy LF infections have 
been treated with the triple drug combination in clinical trials in PNG and Cote d’Ivoire. Many of 
the LF infected people given IDA experienced brief side effects that are commonly associated 
with two drug regimens that include DEC+ALB (in PNG and other countries in the Pacific and 
Asia) or IVR+ALB (in various regions of sub-Saharan Africa). Side effects included fever, 
headache, myalgia, and dizziness that usually resolved within 24 to 48 hours.  The frequency of 
adverse events (AE) was higher in triple drug IDA treatment compared to standard two-drug 
treatment.  However, the overall severity of the AEs was similar between IDA and the two drug 
regimens and no serious AE’s requiring hospitalization occurred.  
 
Although there is little doubt that the IDA triple drug combination is more effective than current 
two-drug MDA combinations for LF elimination, more safety data are urgently needed before 
IDA can be rolled out as an MDA regimen for millions of people. The current two-drug MDA 
combination for LF was studied in closely monitored community trials before being endorsed for 
widespread use.  Similar data are now required for the new triple drug IDA combination. The Bill 
& Melinda Gates Foundation is willing to financially support such studies in four countries, 
including PNG.  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 7 of 90 
 
The primary objective of the trial will be to study the safety and tolerability of the triple drug IDA 
combination, by comparing the number and type of adverse events that develop after a single 
treatment of LF infected and uninfected participants with IDA or DEC+ALB (the current standard 
regimen) in LF endemic communities in PNG. Secondary objectives will be to i) compare how 
much more effective the IDA combination is than DEC+ALB in killing microfilariae in community 
settings; and ii) compare community acceptance of MDA with the triple drug IDA compared to 
the two-drug combination of DEC+ALB.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 8 of 90 
TABLE OF CONTENTS 
 
INVESTIGATOR AGREEMENT ...................................................................................... 2 
1.1.1 3 
1.1.2 
Christopher L King, MD, PhD ...................................................................... 3 
1.1.3 
Investigators ................................................................................................ 4 
1.1.4 4 
1.1.5 
James W Kazura, MD ................................................................................. 4 
1.1.6 
Ronald E Blanton, MD ................................................................................. 4 
TABLE OF CONTENTS .................................................................................................. 8 
2 
PROTOCOL SUMMARY ....................................................................................... 13 
3 
BACKGROUND INFORMATION AND RATIONALE ............................................. 16 
3.1 
Country Specific Background ................................................................................ 17 
4 
POTENTIAL RISKS AND BENEFITS.................................................................... 19 
4.1 
Risks of Blood Draw.............................................................................................. 19 
4.2 
Risks of Study Drugs ............................................................................................ 19 
4.3 
Potential Participant and Community Benefit ........................................................ 19 
4.4 
Study Participation and Cost ................................................................................. 20 
4.5 
Compensation for Injury ........................................................................................ 20 
5 
STUDY DESIGN AND OBJECTIVES.................................................................... 21 
5.1 
Study Objectives ................................................................................................... 21 
5.1.1 
Secondary Objectives ............................................................................... 21 
5.2 
Study Design ........................................................................................................ 21 
5.3 
Study Screening and Enrollment ........................................................................... 21 
5.3.1 
Study Site .................................................................................................. 21 
5.4 
Preparatory Activities ............................................................................................ 22 
5.4.1 
Social Mobilization..................................................................................... 22 
5.4.2 
Household Enumeration, Census and Geo-Referencing ........................... 22 
5.5 
Pre-Treatment Assessment Team ........................................................................ 22 
5.6 
Inclusion and Exclusion Criteria ............................................................................ 22 
5.7 
Pregnant Females ................................................................................................ 23 
5.8 
Informed Consent ................................................................................................. 23 
5.9 
Baseline Survey .................................................................................................... 24 
5.10 
Screening for Filarial Antigenemia and Microfilaria ............................................... 24 
5.11 
Assessment of Efficacy of IDA on STH (including Strongyloides by qPCR) .......... 24 
5.12 
Randomization ...................................................................................................... 25 
5.13 
Withdrawal ............................................................................................................ 25 
5.14 
Efficacy and Effectiveness of IDA vs DA ............................................................... 26 
5.15 
Retreatment .......................................................................................................... 26 
5.16 
Guidelines for Stopping the Trial ........................................................................... 26 
5.17 
Triple Drug Regimen Acceptability ........................................................................ 27 
6 
INVESTIGATIONAL PRODUCT ........................................................................... 28 
6.1 
Study Drug Background ........................................................................................ 28 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 9 of 90 
6.1.1 
Product Supply and Storage ...................................................................... 29 
7 
STUDY PROCEDURES/EVALUATIONS/SCHEDULE ......................................... 30 
7.1 
Triple Drug Therapy (IDA) and Two-Drug Therapy (DA) ....................................... 30 
7.2 
Overall Study Schedule ........................................................................................ 30 
8 
SAFETY REPORTING AND SAFETY MONITORING .......................................... 31 
8.1 
Definitions ............................................................................................................. 31 
8.2 
Assessment of Adverse Events ............................................................................ 32 
8.2.1 
Serious Adverse Event (SAE) Assessment and Management ................... 32 
8.3 
Reporting of Pregnancy ........................................................................................ 33 
8.4 
Safety Monitoring by the Oversight Committee ..................................................... 33 
9 
CLINICAL MANAGEMENT OF EVENTS .............................................................. 34 
9.1 
Adverse Event Monitoring and Management ........................................................ 34 
9.1.1 
Mild Localized Symptoms .......................................................................... 34 
9.1.2 
Moderate to Severe Localized Adverse Events ......................................... 34 
9.1.3 
Moderate to Severe Systemic Adverse Events .......................................... 35 
9.2 
Rapid Response Teams for Management of Adverse Events ............................... 35 
10 
STATISTICAL CONSIDERATIONS ...................................................................... 36 
10.1 
Safety ................................................................................................................... 36 
10.2 
Efficacy ................................................................................................................. 36 
10.3 
Enrolling Additional Participants ............................................................................ 36 
11 
DATA HANDLING/RECORD KEEPING/SOURCE DOCUMENTS ....................... 37 
11.1 
Types of Data Collected ........................................................................................ 37 
11.2 
Study Records Retention ...................................................................................... 38 
11.3 
Source Documents ............................................................................................... 38 
12 
RESPONSIBILITIES ............................................................................................. 39 
12.1 
Investigator Responsibilities .................................................................................. 39 
12.1.1 Good Clinical Practice ............................................................................... 39 
12.2 
Institutional Review Board (IRB)/Ethics Committee (EC) ...................................... 39 
12.3 
Informed Consent ................................................................................................. 39 
12.3.1 Informed Consent Training ........................................................................ 39 
12.3.2 Country Specific ICF Information ............................................................... 40 
12.4 
Participant Privacy ................................................................................................ 40 
12.5 
Data Ownership .................................................................................................... 40 
13 
PUBLICATION POLICY ........................................................................................ 42 
14 
LITERATURE REFERENCES .............................................................................. 43 
LIST OF APPENDICES ................................................................................................. 45 
Appendix 1: 
Study Flow Diagram (Country Specific) ........................................... 46 
Appendix 2: 
Participant Enrollment Form [Example] ........................................... 47 
Appendix 3: 
Participant Monitoring Form [Example] ............................................ 50 
Appendix 4: 
Guide To Assigning Adverse Event Severity ................................... 53 
Appendix 5: 
Adverse Event Evaluation and Report Form (AEERF) [Example] .... 56 
Appendix 5a:  
Required Reporting Guideline For Serious Adverse Events ............ 60 
Appendix 6A: 
 Informed Consent Form [Example] ................................................. 64 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 10 of 90 
Appendix 6B: 
 Informed re-Consent Form (V.1, 24 may 2017)Error! Bookmark not defined. 
Appendix 7: 
Treatment Acceptability Study Protocol ........................................... 73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 11 of 90 
LIST OF ABBREVIATIONS 
 
GENERAL PROJECT ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AEERF 
Adverse Event Evaluation and Report Form 
AFC 
Anti-Filariasis Campaign 
Ag 
antigenemia 
ALB 
Albendazole 
CDD 
Community Drug Distributor 
CRF/eCRF 
Case Report Form also referred to as eCRF (electronic case report form) 
DA 
Two Drug Therapy (dyethilcarbamzine and albendazole)  
DEC 
Diethylcarbamazine 
DOLF 
Death for Onchocerciasis and Lymphatic Filariasis 
DOT 
Directly Observed Treatment 
DSMB, DSRB or DMC 
Data and Safety Monitoring Board also called Data Safety Review Board 
or  Data Monitoring Committee 
EC 
Ethics Committee (may also be called IRB or Institutional Review Board) 
EDC 
Electronic Data Capture 
FTS 
Filariasis Test Strip 
GCP 
Good Clinical Practice 
GPELF 
Global Programme to Eliminate Lymphatic Filariasis 
GPS 
Global Positioning System 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDA 
Triple Drug Therapy (Ivermectin, Diethylcarbamazine,and Albendazole) 
IMA 
IMA World Health 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 12 of 90 
IRB 
Institutional Review Board (may also be called EC) 
IVM 
Ivermectin 
LF 
Lymphatic Filariasis 
MDA 
Mass Drug Administration 
MF 
Microfilaria(e) 
Mg 
Milligram 
NTD 
Neglected Tropical Diseases 
NLM 
National Library of Medicine 
PHM 
Public Health Midwife 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
TAS 
Transmission Assessment Surveys 
UNID 
Unique Study Identification Numbers 
UR 
University of Ruhuna 
USAID 
United States Agency for International Development 
WHO 
World Health Organization 
 
COUNTRY SPECIFIC ABBREVIATIONS 
PNGIMR 
Papua New Guinea Institute for Medical Research 
 
 
 
 
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 13 of 90 
2 
PROTOCOL SUMMARY 
Study Title: 
Community Based Safety Study of 2-drug (Diethylcarbamazine and 
Albendazole) versus 3-drug (Ivermectin, Diethylcarbamazine and 
Albendazole) Therapy for Lymphatic Filariasis in Papua New 
Guinea 
Type of Study: 
Mass Drug Administration 
Population: 
IDA/ Triple Drug Arm: participants more than or equal to 5 years of 
age 
DA/ Dual Drug Arm (DA): participants more than or equal to 5 
years of age 
Number of Treated 
Areas: 
Study sites will be communities in Madang Province, Bogia District 
and as alternatives, Dreikiker District, East Sepik Province and 
East New Britian Province 
Duration of Study 
Participation 
Single treatment with daily adverse event follow-up thru Day 7, 
then a long-term follow-up visit at 1 year.   
Study Drugs 
Ivermectin (3 mg tablets)  *not included in two arm treatment 
Diethylcarbamazine (100 mg tablets) 
Albendazole (400 mg tablets) 
Primary Objective: 
Determine the frequency, type, and severity of adverse events 
following triple drug therapy (IVM+DEC+ALB) compared to the 
standard two drug treatment (DEC+ALB) in infected and uninfected 
individuals in a community 
Secondary Objectives: 
 
Compare the efficacy of IDA (3 drug therapy) to DA (2 drug 
therapy) administered in communities for clearance of MF and 
filarial antigenemia (Ag) 
Assess the effect of intensity of filarial infection on the frequency 
and severity of adverse events 
Compare community acceptance of Mass Drug Administration with 
three drug vs two drug therapy  
To examine the impact of IDA vs DA on transmission of LF. 
To evaluate the impact of IDA vs. DA on reduction of scabies and 
other skin infections.  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 14 of 90 
DOLF PROJECT 
This protocol is specific to Papua New Guinea, but results will also 
be included in the larger  DOLF project.  Data will be 
available/reviewed at a country level and at the project level.  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 15 of 90 
STUDY DESIGN 
General Flow Diagram: 
 
DOLF_IDA_Papua New Guinea Study 
ARM 1 
Sample Size: 3000 
Triple Drug 
ARM 2 
Sample Size: 3000 
Two Drug 
NOTE: A Study Flow Diagram specific for Papua New Guinea is provided in Appendix 1.  
Community Teams: 
Consent and Screen 
 
 
Review 
Eligibility 
 
Triple Drug 
(IDA) 
Two Drug 
(DA) 
FTS, MF Survey, Study Drug Administration 
  
Clinical and AE Assessment 
Data Entered into EDC 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 16 of 90 
3 
BACKGROUND INFORMATION AND RATIONALE 
LF is a parasitic worm infection where adult male and adult female worms that have mated in 
the lymph nodes of the human lymphatic system release immature forms (microfilaria or MF) 
that appear in the blood stream at night. These MF are taken up by mosquitoes, after which 
they develop to infective forms over 1-2 weeks that continue the parasite lifecycle when blood 
seeking female mosquitoes again bite a potential human host. Dying adult worms provoke 
disabling and disfiguring obstruction of the lymphatic vessels.  In 2000, the World Health 
Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) 
to eliminate lymphatic filariasis as a public health problem by 2020. To interrupt transmission, 
WHO recommends therapy using combinations of two medicines delivered to entire at-risk 
populations through a strategy known as mass drug administration (MDA). Ivermectin and 
albendazole are administered in areas where onchocerciasis is co-endemic; diethylcarbamazine 
and albendazole are administered in areas where onchocerciasis is not co-endemic. 
Results of a pilot study in Papua New Guinea suggest that triple drug therapy (ivermectin, 
diethylcarbamazine and albendazole) is superior to the currently recommended two-drug 
regimen [11]. A single dose of the triple therapy rapidly achieved complete clearance of 
Wuchereria bancrofti microfilariae from the blood of 12 individuals for at least one year post-
treatment. All six individuals tested at 24 months were still amicrofilaremic, suggesting that the 
triple therapy might permanently sterilizes adult filarial worms. Many people treated in these 
studies experienced transient systemic adverse events commonly associated with 
diethylcarbamazine or ivermectin treatment of filariasis. Adverse events were more frequent 
after the triple therapy than after the usual combination of two drugs. However, no serious 
adverse events were observed. Preliminary results from two larger clinical trials in Papua New 
Guinea and in Cote d’Ivoire (West Africa) are consistent with results from the pilot study. The 
dramatic reduction and sustained clearance of microfilaremia along with the safety profiles seen 
in these studies suggest that the triple drug therapy may be a useful tool for achieving the goal 
of eliminating lymphatic filariasis as a public health problem by 2020.  
Although the studies mentioned above have clearly demonstrated the superiority of the triple 
drug therapy for clearing W. bancrofti microfilariae from the blood, more safety and efficacy data 
are needed before triple therapy can be rolled out on a large scale as a mass drug 
administration regimen in lymphatic filariasis endemic countries. WHO recommends a best 
practice called “cohort event monitoring” for demonstrating safety of new drug regimens for 
public health program use. Establishing safety through such methodology requires pre and post 
treatment assessments from at least 10,000 people treated with the triple therapy across 
multiple settings.  
The inclusion of IVM to an MDA regimen also provides additional public health benefits, since it 
complements the deworming effect of ALB , a global initiative for the control of gastrointestinal 
worm infections (e.g., hookworm, Ascaris, Trichuris, Strongyloides) and eliminates lice and 
scabies mites (4).  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 17 of 90 
3.1 Country Specific Background 
Papua New Guinea (PNG) has some of the most heavily infected populations with lymphatic 
filariasis in world and most areas in PNG have never received any treatment for lymphlatic 
filariasis.  Adverse events (AEs) following MDA are directly related the burden of infection, 
especially the microfilarial levels which are rapidly killed by ivermectin [IVM] and 
diethylcarbamazine [DEC].  The addition of IVM to existing treatment regimen with DEC+ALB 
might be expected to increase AEs, especially in individuals with high MF levels as was 
observed PNG (Thomsen, et al CID, 2016).  Thus studies in PNG will be crucial to establish the 
safety of triple drug therapy in participant with high microfilaria level of the principal human 
filarial parasite W. bancrofti. Results from ongoing studies conducted in East Sepik Province 
have shown that using three drugs together (ivermectin [IVM], diethylcarbamazine [DEC] and 
albendazole [ALB]) is more effective than the current two-drug combination (DEC/ALB) being 
used in the global program to eliminate lymphatic filariasis in Papua New Guinea.  Lymphatic 
filariasis elimination in PNG involves annual mass drug administration (MDA) in lymphatic 
filariasis (LF) endemic areas for at least 5 years.  
A single dose of the three drugs together very quickly cleared all lymphatic filariasis “worms” or 
“microfilariae” (MF) from the blood of 68 heavily infected with LF in PNG.  All but two treated 
participants remained MF negative 1 year after treatment, something that is only achieved in ~ 
20 to 30% of individuals treated with the standard two-drug combination in PNG.  The two MF 
positive individuals at one year had only one MF in 2 mls of blood, a level unlikely to be 
transmissible.  Moreover these individuals lived in a community with exceptionly high 
transmission and it is possible that they may be been re-infected during the course of year 
followup.  A single dose of the triple drug combination therefore appears to kill or permanently 
sterilize adult worms.   In this larger study of triple drug treatment, AEs were slightly higher 
compared to the standard two drug regimen, but this difference was not significantly different. 
There was one severe AE in a participant that received the triple drug regimen, however this 
resolved within 24 hours, did not require hospitalization, and was deemed not be an SAE by 
medical professional evaluating the individual.  
This new treatment could make a huge difference in the global effort to eliminate LF by reducing 
the number of rounds of MDA required for elimination. The greatest impact of this new treatment 
may be in areas with high infection rates where MDA has not yet been introduced, but it also 
could be very useful for areas where LF infection persists despite several years of annual MDA 
with current 2-drug regimens. In PNG, both areas exist and continue to present a challenge to 
LF elimination efforts.  
The WHO, academic experts, and the donor community are excited, because IDA has the 
potential to accelerate LF elimination around the world.  Although the studies cited above have 
clearly demonstrated the superiority of the IDA regimen for clearing W. bancrofti MF, more 
safety and efficacy data are needed before IDA can be rolled out on a large scale. The WHO 
and Bill & Melinda Gates Foundation have accepted the efficacy data, but in order to elevate 
this approach to WHO policy and obtain increased drug company donation, it will be necessary 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 18 of 90 
to obtain evidence of an acceptable AE profile in large multi-center international studies. WHO 
recommends a best practice called “cohort event monitoring” for demonstrating the safety of 
new drug regimens for public health program use (see A Practical Handbook on the 
Pharmacovigilance of Medicines used in the Treatment of Tuberculosis, World Health 
Organization, Geneva, 2012). Establishing the safety of IDA for MDA through such methodology 
requires pre- and post-treatment assessment from at least 10,000 people treated across 
multiple settings. The current two-drug MDA regimens were studied in closely monitored 
community trials in a similar manner before they were endorsed for widespread use by the 
GPELF. This study is designed to obtain data on the safety and effectiveness of IDA therapy in 
the PNG population to guide future use of the therapy for the treatment of LF in PNG and to be 
included in the larger data set from all contributing countries to advance IDA therapy for use in 
elimintating LF wordwide. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 19 of 90 
4 
POTENTIAL RISKS AND BENEFITS 
4.1 Risks of Blood Draw 
Blood collection via finger prick is considered to be minimal risk and little or no discomfort is 
anticipated.  The risk of infection is minimized by the use of standard sterile techniques.  On 
occasion a participant may faint during or after the finger prick.  Study personnel will be alert to 
participant reactions after the blood collection and will provide aid as needed. 
4.2 Risks of Study Drugs 
The combinations of ivermectin plus albendazole or DEC plus albendazole are widely used for 
MDA. There also have been clinical trials of DEC plus Ivermectin and for triple drug therapy that 
show no significant drug interactions [11]. Risks of each drug separately, with some indication of 
how likely these are to occur, are summarized below:  
Diethylcarbamazine (DEC): The most common side effects reported are itching and swelling of 
face, headache, joint pain, unusual tiredness or weakness. These are transient. Less common 
are dizziness, nausea or vomiting. Fever, painful and tender glands in groin, neck and armpits 
or skin rash can occur, and are usually associated with high burdens of infection as judged by 
the level of blood microfilaremia.  
Albendazole (ALB): The most common side effects reported are headache, nausea, stomach 
pain and vomiting and are usually associated with heavy soil-transmitted helminths infections. 
Severe allergic reactions occur rarely, and include rash, hives, itching, difficulty breathing, 
tightness in the chest, swelling of the mouth, face, lips, or tongue, dark urine. Mild elevation in 
liver transaminases can occur, but normalize with cessation of treatment. These AEs are usually 
associated with prolonged ALB therapy.  
Ivermectin (IVM):  The most common side effects reported are diarrhea, dizziness and nausea. 
Rare side effects include rash, hives, itching, difficulty breathing, chest tightness, swelling of the 
mouth, face, lips, or tongue, eye pain, fainting, and fast heartbeat. Mild decrease in leukocyte 
counts, elevated liver function tests, and cardiovascular effects that included tachycardia and 
orthostatic hypotension have been described. Infrequently, treatment can exacerbate bronchial 
asthma. These AEs are usually associated with prolonged therapy. 
4.3 Potential Participant and Community Benefit 
Infected participants, who sign an informed consent, will be treated for the LF infection. LF 
transmission to the community will be reduced by participation in either treatment arm.  A 
broader community benefit may be facilitated by the triple drug regimen as it is believed the 
triple drug regimen has the potential to markedly reduce the number of MDA treatments needed 
to achieve transmission interruption and elimination of LF.  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 20 of 90 
Both regimens provide treatment for intestinal worms, and the triple drug treatment has the 
added benefit of providing an effective treatment for scabies.  
If the triple drug intervention proves successful, the triple therapy is likely to be adopted in many 
LF endemic areas globally. In order to facilitate such an uptake of triple therapy into national 
treatment policies, the study will be performed by Papua New Guinea Institute for Medical 
Research (PNGIMR) in collaboration with National Department of Health responses for the LF 
control program and results from this study will be combined and shared with the World Health 
Organization. 
4.4 Study Participation and Cost  
Participation is voluntary and participants may decline participation without consequences.  
There will be no cost to the individual to participate in the study and they will not be paid for their 
participation.  The study will cover cost associated with laboratory test, study drugs, and clinical 
monitoring. 
4.5 Compensation for Injury 
The study drugs have been widely used for treatment of lymphatic filariasis and it is anticipated 
that injury resulting from treatment will be rare.  In the event that a participant experiences a 
serious adverse event (SAE) attributable to study treatment, the project will help in supporting 
the medical treatment and/or hospitalization required.  
In the event that a participant experiences a Serious Adverse Event attributable to treatment, 
the project will help support medical treatment and hospitalization required. If the participant 
dies as a direct consequences of treatment, then compensation to the family will be provided. It 
is anticipated that any injuries resulting from this study will be rare because the drugs employed 
have been widely used for treatment of lymphatic filariasis with very few serious adverse events. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 21 of 90 
5 STUDY DESIGN AND OBJECTIVES 
5.1 Study Objectives 
To determine the frequency, type and severity of adverse events following triple-drug therapy 
(IVM+DEC+ALB, IDA) compared to the standard two-drug treatment (DEC+ALB, DA) in infected 
and uninfected individuals in a community. 
5.1.1 Secondary Objectives 
1. To compare the efficacy of IDA vs. DA administered in communities for clearance of MF 
and filarial antigenemia (Ag). 
2. To assess the effect of intensity of filarial infection on the frequency and severity of 
adverse events. 
3. To compare community acceptance of MDA with IDA vs. DA. 
4. To examine the impact of IDA vs DA on transmission LF. 
5. To evaluate the impact of IDA vs. DA on reduction scabies and other skin infections.  
5.2 Study Design 
The trial will be an open labelled two-armed study. The two arms are (1) MDA with IDA (triple 
drug therapy) and (2) MDA with the currently used combination of DA (two-drug regimen). An 
overview of the study flow is provided in Appendix 1. 
The primary endpoint will be the rate of AE and SAE among participants. The definitions of mild, 
moderate, severe and serious AE are provided in Appendix 4.  
5.3 Study Screening and Enrollment 
5.3.1 Study Site 
Previous studies have identified the mainland and coastal islands of Northern PNG as the most 
effected by lymphatic filariasis (5-8). The study will be conducted in an area with high 
prevalence of lymphatic filariasis (LF).  We have identified three potential study sites: i) Bogia 
District, Madang Province as the most likely study site where many of the villages average 
between 50 to 60% antigen positivity from a survey conducted in March 2016.  Other potential 
sites are in areas of ii) East Sepik Province (ESP), and/or Sandaun Provinces (SP).  None of 
these sites have previously received MDA. Another potential site is in East New Britian Province 
(ENB).  Some areas within ENB have antigen positive rates as high as 68% based on recent 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 22 of 90 
screening by our study team.  Other areas in ENB have low or neglible LF infection rates and 
some have received MDA. 
5.4 Preparatory Activities 
5.4.1 Social Mobilization 
Prior to the administration of the drugs, intense social mobilization activities will be conducted to 
ensure maximum community participation. This will include development and distribution of key 
messages that will emphasize the acceptance and swallowing of the drugs along with their 
benefits and safety.  
5.4.2 Household Enumeration, Census and Geo-Referencing 
Health workers with the research team and community drug distributors (CDD) will enumerate 
and record the GPS coordinates of each house and compound within the selected study areas 
(PHMs) (House Visit #1, Appendix 1). A census will be performed to collect name, age and sex 
of each household member greater than or equal to 5 years of age. Basic information on house 
structure that might affect mosquito exposure to lymphatic filariasis infection, e.g. type of 
structure, whether screened windows present, existence of a toilet, running water, electricity 
and/or insecticide treated bed nets will also be collected.  
5.5 Pre-Treatment Assessment Team 
The pre-treatment assessment (House visit #2, Appendix 1) team will be composed of people 
with basic medical training able to perform a medical history and a basic physical examination 
(local health workers, physicians, and nursing or medical students), laboratory technicians, and 
community drug distributors involved in previous MDA for LF and known by the local 
community. 
5.6 Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Age ≥ 5 years, for IDA and DA arms (males and females).  
2. Able to provide informed consent or give parental consent for minors to participate in the 
trial  
3. No evidence of severe or systemic co-morbidities except for features of filarial disease  
Exclusion Criteria 
1. Age < 5 years (ivermectin is not approved for use in children less than 5 years of age) 
2. Unable to provide informed consent or give parental consent for minors to participate in 
the trial 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 23 of 90 
3. Pregnant women (DEC, ivermectin and albendazole are not known to be safe for use 
during pregnancy) 
4. Severe chronic illness (chronic renal insufficiency, severe chronic liver disease, or any 
illness that is severe enough to interfere with activities of daily living) 
5. History of previous allergy to MDA drugs 
5.7 Pregnant Females 
Pregnant females will not be eligible to participate in this study because of the unknown effects 
of the drugs and drug combination used in this study.  Females will be asked about the timing of 
the first day of their last menstrual period. Females who report that their last menstrual period 
started 4 weeks or longer before the interview will be excluded from the study. Females who do 
not recall the timing of their last menstrual period will also be excluded. 
5.8 Informed Consent 
A waiver of consent is being requested for the Census and Geo-referencing portion of the study 
prior to receiving formal consent.  The study team will be collecting information about the 
communities and residents.  This portion of the study is not greater than minimal risk and the 
members of the study team who are conducting the Census and Geo-referencing portion of the 
study will explain what they are collecting to village residents.  
Individuals will be evaluated as to whether they meet the inclusion/exclusion criteria, before they 
give informed consent.Before any physical procedures or drug administration occur, signed 
consent will be obtained from participants.  
Adult participants will sign a written, informed consent before the inclusion process (Appendix 
6).  Minors from ages 5 to 7 years do not need to give assent to the study. Respecting the 
cultural practices and norms in PNG, minors between the ages 7 and 12 years will not sign an 
assent form, but their parents will sign consent to allow their participation. This process reflects 
the cultural norms and practices usually employed in studies in PNG, and respect the roles that 
parents and the community have in the informed consent process.   Minors aged 14-17 will sign 
the adult consent form in order to participate.  
In the event that a participant is unable to read or has insufficient level of knowledge to 
comprehend the consent form, another villager with sufficient reading and writing skills will act a 
witness to the consenting process. The witness should not be involved in the implementation of 
the study. Participants who do not speak or read English are neither specifically included nor 
excluded from this study. There are hundreds of languages in Papua New Guinea. A native 
speaking community worker who is knowledgeable about research and the study will translate 
the consent form from English into the local language. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 24 of 90 
5.9 Baseline Survey 
After consenting and prior to evaluation for LF infection and treatment, all individuals will be 
assigned a unique ID and be enrolled using a participant enrollment form (Appendix 3). 
Questions will be asked to each participant about their general health and last menstrual period 
(to establish pregnancy for women of childbearing age). Each individual will be asked if they 
have signs of LF complications (hydrocele, lymphedema, lymphangitis, and lymphadenitis), if 
they took treatment during the previous MDA for LF and if they recently took albendazole, 
diethylcarbamazine, or ivermectin for other conditions. Participants reporting lymphedema will 
be examined to identify the location and grade of the lymphedema.  
 
Impact of IDA versus DA on LF transmission using xeno-monitoring 
 
Mosquito collections will be conucted prior to commencement of community MDA. After 
consultation with community leaders as to those areas of their community where many 
mosquitoes are observed near or within households, light traps will be strategically placed and 
mosquitoes collected for 24 to 48 hours.   Anopheline mosquitos known to transmit lymphatic 
filariasis will be collected from the light traps, pools of 10 to 25 mosquitos made, and DNA 
extracted from the pooled mosquitoes for PCR amplification of W. bancrofti DNA.  The 
proportion of filarial infected mosquitoes will then be determined.   The same xeno-monitoring 
will be conducted in the same villages one year following treatment.   
 
5.10 Screening for Filarial Antigenemia and Microfilaria 
Approximately 75µl of capillary blood from each eligible individual will be collected via finger 
prick to be deposited on the rapid diagnostic test Filariasis Test Strip (FTS, Alere™, WHO 
approved)) for LF antigen detection in the field. Following application of blood for the FTS, a few 
drops of blood will be applied to a filter paper and dried for subsequent serological evaluation of 
LF exposure infection. Participants with positive FTS tests will be visited at night (10 - 12 am) for 
microfilaria testing (60 μl measured volume blood smear- 3 lines, prepared according to the 
project standard operating procedure (SOP)) collected by the finger prick method. 
Study participants will be informed that their blood samples may be shipped to other countries 
like the United States for additional parasitology testing. These samples may be stored for a 
longer time after the intended testing. No HIV or human genetic testing will be performed. 
Universal precautions for individuals collecting and working with blood samples to include 
proper disposal of contaminated materials (test strips, lancets, capillary tubes, blood film slides) 
will be in accordance with the guidelines prescribed by the local health authorities. 
5.11 Assessment of Efficacy of IDA on STH (including Strongyloides by qPCR) 
Expected number of positive individuals per treatment arm: We assume that per treatment 
arm we will collect stool samples from a community of about 1,000 individuals. With a 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 25 of 90 
confidence level of 95% and a confidence interval of 5% we would require testing at least 278 
participants. Assuming a sample size of 300 (~278) and a confidence level of 95% we expect to 
treat at a prevalence of 50% (ie any STH) between 133 and 167 infected individuals and at a 
prevalence of 10% (ie one STH species only) between 20-40 infected individuals. Based on 
previous data from eastern Indonesia and PNG we expect a minimum prevalence of any STH of 
50%.     
Study sites: It is sufficient to select the 300 individuals per treatment arm from one study 
area/village, because a more homogeneous distribution of STH compared to LF can be 
expected. Susceptibility to the drug treatment should not vary within the same region.     
Collection of stool samples: We will follow the DOLF ‘SOP for Stool Collection’.  A 
convenience sampling method will be used without special regard to sex and age, because drug 
efficacy is unlikely to depend on these parameters.  A follow-up stool sample will be collected 2-
4 weeks and one year after treatment from the same individuals that provided the baseline 
sample. We expect a compliance of 90% because of pre-selection of compliant individuals. 
Participants who are FTS positive one year after treatment will also be asked to provide a stool 
sample.   
Assessment of STH eggs: We will use the Kato Katz method before and after treatment, 
because of its sufficient sensitivity in high prevalence areas, its simple performance in the field, 
and the standardized quantitative assessment.  We will follow the DOLF ‘SOP Kato Katz 
Procedure’.  Stool aliquots will be preserved for later examination by qPCR. This will enable us 
to archive STH DNA samples before and after IDA treatment and to test for efficacy of IDA for 
Strongyloides. We will follow the DOLF ‘SOP Stool Sample Management ’ (version 2016). 
Participants will be informed that that the stool samples may be shipped to other countries like 
the United States for qPCR testing. These samples may be stored for a longer time after the 
intended testing. No HIV or human genetic testing will be performed. 
5.12 Randomization 
Communities will be assigned treatment either by randomization or by purposively matching 
communities based on population and prevalence of LF. If the prevalence is homogenous 
across the communities, each site may be randomly assigned to one of the two treatment arms. 
If the prevalence is heterogeneous, communities will be selected into each arm so that the 
population and prevalence between the two treatment arms is similar. 
5.13 Withdrawal 
Participation in this project is completely voluntary, and participants may terminate participation 
at any time.  Also if the well-being of the participant is compromised in any way, based on the 
opinion of the investigator, the participant can also be withdrawn from the study. Even if the 
participant leaves the project early, we will encourage them to contact us at any time within the 
month after treatment to report any possible study-related AEs. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 26 of 90 
All particpants that sign the informed consent and receive study drug will be included in the 
analysis. 
5.14 Efficacy and Effectiveness of IDA vs DA 
One year post MDA, all individuals who were positive for either microfilaremia or filarial 
antigenemia (FTS) during the baseline survey will be tested for filarial antigen using the FTS to 
assess their response to treatment and to compare the efficacy of the two treatment regimens. 
Persons with positive FTS will also be tested for nocturnal microfilaremia by blood smear (finger 
prick). 
We will also collect stool samples from all treated individuals who were positive for helminth or 
LF infections in order to describe the long term effect of both treatment regimens on STH. 
Additionally, for all participants who were positive for filarial antigenemia, 60µl of capillary blood 
will be applied to a filter paper. The dried filter disks will be stored in a cool, dry place until used 
for testing.  Study participants will be informed that their blood on filter paper will be tested for 
stongyloides and potentially for other diseases of public health importance and will be shipped 
to the United States and stored for a longer time after the intended testing. No HIV or genetic 
testing will be performed. 
5.15 Retreatment 
Any individual who tests positive for lymphatic filariasis at 12 months (by microscopy or antigen 
test) will be re-treated with the standard MDA regimen (single dose of DEC with Albendazole). If 
triple drug therapy (IDA) is recommended by the WHO or by national regulatory agencies for 
lymphatic filariasis and if investigators have adequate supply of ivermectin, infected individuals 
may be offered IDA. This practice is meant to ensure that all participants who participated in the 
study may get the most beneficial treatment. Pregnant women will not be eligible for re-
treatment. 
5.16 Guidelines for Stopping the Trial 
There are no pre-specified criteria for terminating the study early. 
Upon review of the data for the trial, the DSMB will make decisions regarding the continuation of 
the trial.  The final decision to stop the trial is left to the recommendation of the DSMB.  If the 
DSMB recommends discontinuation or modification of the study, the Chair of the DSMB will 
meet or talk with the DOLF Project Team at the earliest opportunity to review the basis for the 
recommendation. The study should be stopped if a treatment arm shows a significant increase 
in unacceptable side effects that would include, death, fever, and nausea that persist more than 
a day and would require hospitalization.   

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 27 of 90 
5.17 Triple Drug Regimen Acceptability 
A survey to assess the treatment acceptability in the community is planned to follow the safety 
trial (Appendix 7). The overall aim is to understand the community’s acceptance of the 3-drug 
regimen as well as gain insight into the feasibility of administering this new therapy in the future. 
Part of the investigation will include assessing community member’s perception of the possible 
side effects experienced as a result of the 3-drug therapy compared to the 2-drug therapy, and 
how that might affect future rounds of mass drug administration (MDA) at the community level. 
Community acceptance will be measured using a survey to community members receiving both 
the 2-drug and 3-drug treatments during the safety trial. The survey participants will be identified 
from the roster of individuals enrolled in the safety trial. To complement this survey, a series of 
focus group discussions in the community as well as key informant interviews are proposed with 
community leaders, health personnel and drug distributors in the same communities to assess 
perceptions about the 3-drug versus the 2-drug regimen. The community acceptability study will 
be carried out within one month of the completion of the safety trial. The protocol for the 
acceptability survey is included in Appendix 7 of this protocol. The community questionnaire and 
topic guides will be submitted to the the EC for approval as an amendment prior to 
implementation of the survey. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 28 of 90 
6 INVESTIGATIONAL PRODUCT 
Each of the drugs used in this study is approved for human use and has a prior history of use in 
the treatment of Lymphatic Filariasis.   
6.1 Study Drug Background 
Albendazole (ALB) has been known to cause degenerative alterations in the tegument and 
intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its 
polymerization or assembly into microtubules [12]. The loss of cytoplasmic microtubules leads 
to impaired uptake of glucose by larval and adult stages of the parasite, and depletes glycogen 
stores. Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, 
and the subsequent release of lysosomal enzymes result in decreased production of adenosine 
triphosphate, which is the source of energy required for survival of the helminth. Due to 
diminished energy production, the parasite is immobilized and eventually dies. Adverse events 
are uncommon in persons who are treated with a single dose of albendazole (apart from AEs 
that result from parasite death). Some patients report mild gastrointestinal AEs such as nausea 
after ingesting the tablet. 
Ivermectin (IVM) is an avermectin compound of macrocyclic lactones derived from the 
bacterium Streptomyces avermitilis [13]. The mechanism by which IVM kills LF microfilariae is 
not known with certainty, but the drug interferes with glutamate gated ion channels that can 
affect parasite contractility and release of immunomodulatory molecules by the parasite [13]. 
IVM also has a direct effect on the central nervous system and muscle function of worms as it 
enhances strength of inhibitory neurotransmission pathways.  The main concern with the use of 
IVM in animals and humans is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has 
not been observed in humans given single dose IVM for LF or other parasitic infections [14]. 
IVM has been used to treat millions of people with LF and onchocerciasis. Peak IVM serum 
concentrations are reached approximately 4-5 hours after administration. The half-life of IVM in 
various populations ranges from 12 to 56 hours [15]. There is no evidence of drug: drug 
interaction between ALB and IVM [16]. IVM can cause nausea, dizziness and occasionally 
pruritus, but these are infrequent, transient and usually mild. Serious adverse events have 
occurred in patients with heavy Loa loa infections. 
DEC (diethylcarbamazine citrate) is an anthelminthic drug that is structurally distinct from ALB 
and IVM [17]. DEC inhibits arachidonic acid metabolism by LF, and inducible nitric oxide 
synthase and the cyclooxygenase pathway may be essential for activity in vivo [17]. DEC also 
has anti-inflammatory properties. The mechanisms of action of DEC remain poorly understood. 
Its ability to kill MF and adult worm depends on the host immune responses since the drug has 
little direct activity on parasites in vitro. The drug has potent activity against LF microfilaria. DEC 
has about 50-70% efficacy in killing or sterilization of adult worms [19]. The drug is rapidly 
absorbed from the gastrointestinal tract, has a serum half-life of 12 to 14 hours, and is excreted 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 29 of 90 
in the urine with little modification by liver metabolism. Adverse events from DEC are unusual 
apart from those that result from killing filarial worms.  
6.1.1 Product Supply and Storage 
Only WHO approved drugs will be used in this study. DEC and albendazole will be provided by 
WHO, and a request will be submitted to Merck to provide ivermectin. Alternatively WHO 
approved generic ivermectin may be purchased. 
 
All three study drugs are approved and distributed globally by WHO as part of GPELF. Detailed 
information for each drug is available from the pharmaceutical manufacturer. All products should 
be maintained between18-25 °C.  
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 30 of 90 
7 
STUDY PROCEDURES/EVALUATIONS/SCHEDULE 
7.1 Triple Drug Therapy (IDA) and Two-Drug Therapy (DA)  
The triple-drug combination will consist of a single dose of ivermectin (200 µg /kg), DEC 
(6mg/kg) and albendazole (flat dose of 400 mg). The two-drug combination will consist of a 
single dose of DEC (6mg/kg) and albendazole (flat dose of 400 mg). Study personnel will 
directly observe oral administration of drugs. Drugs will be given after the informed consent has 
been obtained. The study population will be encouraged to eat before swallowing the medicine 
(without chewing the tablets) with a glass of water. Vomited doses will be replaced. Drug 
administration will be supervised (directly observed treatment or DOT) to ensure that all enrolled 
individuals swallow the drugs. There will be one supervisor per study team. 
Universal precautions for individuals collecting and working with blood samples to include 
proper disposal of contaminated materials (test strips, lancets, capillary tubes, blood film slides) 
will be in accordance with the guidelines prescribed by the local health authorities.  
7.2 Overall Study Schedule 
A flow diagram illustrating the study events schedule is presented in Appendix 1.  
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 31 of 90 
8 SAFETY REPORTING AND SAFETY MONITORING 
The post-treatment assessment team will be composed of individuals with basic medical training 
who are able to perform a medical history and a basic physical examination (Physicians, local 
health workers, nursing and/or medical students). Physicians from the area will be available to 
assist in the evaluation and management of adverse events. 
8.1 Definitions 
Adverse Event (AE)  
Any untoward medical occurrence in a clinical investigation participant who has received a study 
product intervention and that does not necessarily have to have a causal relationship with the 
study product. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a study medicinal product, whether or not considered related to the study medicinal 
product. 
An AE does not include: 
 
Medical or surgical procedures (e.g. surgery, tooth extraction, transfusion). The 
condition that leads to the procedure  is an adverse event 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
prior to the screening visit that do not worsen 
 Serious Adverse Event (SAE)  
An SAE is any adverse event that results in any of the following outcomes: 
 
Death; 
 
Life-threatening (immediate risk of death); 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
Persistent or significant disability or incapacity; 
 
Congenital anomaly/birth defect; 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 32 of 90 
Unexpected 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Package Insert). 
Expedited Safety Report  
Documentation in appropriate form and format summarizing an SAE that meets expedited 
safety reporting criteria, submitted within the required reporting time frame of applicable 
regulatory authorities and/or IRBs/IECs of participating countries. 
8.2 Assessment of Adverse Events 
Adverse event monitoring will be performed approximately 24 and 48 hours following drug 
administration (late afternoon and evenings following treatment, house visit #3 and 4, Appendix 
1). All dosed participants will be followed for adverse events through Day 7. 
Evaluations will be documented on pre-printed Patient Monitoring forms (Appendix 3) using the 
scoring instructions for AEs (Appendix 4) or entered directly into an electronic form using tablet 
computers.  
Most adverse events after mass drug administration are associated with killing of MF and are 
seen in the first 12-24h following treatment. However, occasional adverse events related to 
adult worm death may be delayed by several days.  
To capture these adverse events and to assure that any systemic adverse events that occurred 
earlier have resolved, study personnel will also visit study villages daily on days 3 through 7 
after treatment (passive AE monitoring). Individuals with AEs that interfere with activities of daily 
living (grade 2 or higher) will have more detailed assessments that will include a brief physical 
examination (including measurement of temperature, blood pressure and pulse).  
8.2.1 Serious Adverse Event (SAE) Assessment and Management 
Study participants with definite or suspected serious AEs (any event ≥ grade 3) will be referred 
to a physician or appropriate health care professional for evaluation. These evaluations will be 
documented with special adverse event evaluation forms (Appendix 5), following the instructions 
(Appendix 5a).  
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable to 
one or more of the study drugs, and is unexpected based on the Company Core Safety 
Information.   
The investigator should notify the Institutional Review Board (IRB) or Ethics Committee (EC) as 
soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 33 of 90 
8.3 Reporting of Pregnancy  
Pregnancy is an exclusion criteria for this study. Although not AEs, pregnancies are reportable 
events. The pregnancy outcome (e.g., any premature terminations, elective or therapeutic, and 
any spontaneous abortions or stillbirths, as well as the health status of the mother and child 
including date of delivery and infant’s gender and weight) should be reported. Any pregnant 
woman inadvertently dosed who has a miscarriage or spontaneous abortion within the week of 
follow-up will be reported as an SAE. 
8.4 Safety Monitoring by the Oversight Committee 
A Data Safety Monitoring Board consisting of 4 experts (including 3 physicians) knowledgeable 
in neglected tropical diseases will be in place to monitor the safety data per country and across 
countries participating in the DOLF project. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 34 of 90 
9 
CLINICAL MANAGEMENT OF EVENTS 
Individuals who have basic medical training (physicians and/or nursing or medical students) are 
who are able to complete and pass a training course will be responsible for the initial adverse 
event evaluations.  
In the case of mild symptomatic reactions local health workers/study personnel will provide 
antipyretics/analgesics and anti-allergic agents at the time of follow-up. It is anticipated that the 
majority of adverse events will resolve within a day or two and will not require treatment.  In the 
initial adverse event monitoring if any of the following are noted a physician will be notified to 
evaluate the participant for a potential serious adverse event: 
 
Participant reports they are unable to participate in their normal daily activities 
 
Participant has or reports a temperature >39ºC 
 
Participant has or reports a significant drop in blood pressure 
 
Participant has other significant objective findings that should be referred to a physician 
All grade 3, 4 or 5 events or overnight hospitalization will require completion of the Adverse 
Event Evaluation and Report Form (Appendix 5). The physician will provide any required 
immediate treatment and facilitate admission into the hospital or health centre as deemed 
appropriate. 
9.1 Adverse Event Monitoring and Management 
Adverse Event monitoring and management will follow or exceed WHO guidelines.  Participants 
will be visited on the two days following treatment by study personnel with medical training.  
Formal assessment of adverse events (with a standard form) will take place on days 1 and 2 
and later if symptoms persist or start late.   
Study personnel will use the toxicity table (Appendix 4) to score adverse events for severity. 
Serious adverse events will be followed until resolution. Study personnel will visit each study 
area daily for 7 days following MDA treatment to manage any adverse events as follows:   
9.1.1 Mild Localized Symptoms 
Participants who develop painful lymphadenopathy, scrotal pain or painful swelling or nodules 
along lymphatic vessels will be treated with acetaminophen or ibuprofen. 
9.1.2 Moderate to Severe Localized Adverse Events 
Participants with more severe local adverse effects (Grade 3, Appendix 4) like acute swelling or 
severe scrotal pain that is not relieved by acetaminophen will be transported by study personnel 
to the medical facility identified for the study for evaluation by one of the physicians or other 
qualified medical personnel involved in the study. If appropriate, participants will be transferred 
(after stabilization) to the Departmental Hospital. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 35 of 90 
9.1.3 Moderate to Severe Systemic Adverse Events 
Participants with more severe systemic adverse effects (fever over 39°C > 72 hours, other 
adverse events ≥ grade 3, syncope, jaundice, or any condition that might require hospitalization) 
will be transported by study personnel for physician or other qualified medical personnel for 
evaluation at the medical facility identified for the study. If appropriate, participants will be 
transferred (after stabilization) to a local hospital. 
9.2 Rapid Response Teams for Management of Adverse Events 
Medical teams will be located at strategic places close to the study sites. Participants, and 
persons involved in the study (inclusion process and AE monitoring) will be informed about the 
location and phone numbers of these teams so that they can report directly to these teams if 
necessary. These teams will be in position from the day of drug administration until the 
completion of operations. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 36 of 90 
10 STATISTICAL CONSIDERATIONS 
All participants receiving study drug will be included in both the safety and efficacy analysis 
10.1 Safety  
The sample size of 3000 participants per arm in Papua New Guinea will contribute to the total 
sample size for the project. The WHO requires a total of 10,000 participants to detect a SAE 
rate of 0.1% for each of the treatment regimens and recruitment in other countries (e.g., India, 
Indonesia, Haiti, and Sri Lanka) is planned to contribute to the overall sample size required. It is 
well known that systemic AEs are related to killing of MF and that the severity of AEs is related 
to MF counts. Since MF rates in the study area are relatively low, the study will not be powered 
to compare rates of SAEs between MDA regimens.  
The primary endpoint for safety studies will be the rates of SAEs that occur in infected and in 
uninfected participants within the first 7 days post MDA. Total AEs will be a secondary endpoint 
for the study.  
10.2 Efficacy 
Assuming an MF-prevalence of 1% in the study population at baseline, the survey is expected 
to detect at least 30 MF positive participants in each arm. A minimum of 21 (70%) of these MF-
positive participants in each arm will be retested at 12 months post-treatment for antigenemia 
and microfilaremia. This sample size is adequate to demonstrate superiority of the IDA regimen 
(assumptions: 90% reduction in MF prevalence after IDA and 60% reduction after DA, 80% 
power for detecting an effect size of 30%). The primary endpoint for efficacy will be complete 
clearance of MF 12 months post MDA. Clearance of filarial antigenemia at 12 months will be a 
secondary endpoint for the efficacy analysis. 
10.3 Enrolling Additional Participants 
It is possible that recruitment in other countries may be less than anticipated. In this case the 
number of participants enrolled in this study may need to be increased to make up for the loss in 
another country. The number of additional people enrolled will be no more than is necessary to 
reach the total of 10,000 participants treated with IDA. In this situation the pricinple investigators 
will seek an amendment from the ethics review committees for the expanded enrollment. 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 37 of 90 
11 DATA HANDLING/RECORD KEEPING/SOURCE DOCUMENTS 
Data will be collected using a tablet based system, pre-loaded with study templates.  Field 
teams will be trained in the use of the instruments and data will be uploaded as entries are 
completed. 
11.1 Types of Data Collected 
Enrollment Data will include (Appendix 2): 
 
Site Identification 
 
Participant Identifier 
 
Informed Consent Date 
 
Demographic Information 
 
Pregnancy/last menstrual period 
 
Medical History 
 
Presence of hydrocele and lymphedema 
 
Bed Net and Window Screen Use 
 
History of prior MDA tratement 
 
Pre-treatment adverse event assessment 
 
Limited Physical Exam 
Laboratory Results   
 
FTS (filarial antigen test)  
 
FTS score 
 
MF slide (including MF count) 
Participant Monitoring Forms (24 & 48 hour post treatment): 
 
Adverse Event Assessment 
 
Physical Examination, as appropriate 
Adverse Event Evaluation and Report (Appendix 5) 
 
Participant Identification 
 
MDA Treatment 
 
Concomitant Medication taken at the time of the MDA 
 
AE Description,  
 
Start and Stop Date 
 
Outcome 
 
SAE Evaluation and causality to MDA (definite, probable, possible, or unrelated) 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 38 of 90 
11.2 Study Records Retention  
Study documents will be retained for a minimum of three (3) years after the last participant has 
completed the study.  These documents will be retained for a longer period, however, if required 
by local regulations. No record will be destroyed without the written consent of DOLF. 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9, regulatory and institutional requirements for the protection 
of confidentiality of particpants. Each site participating in this study will permit authorized 
representatives of the sponsor and regulatory agencies to examine (and when required by 
applicable law, copy) clinical records for the purposes of clinical site monitoring, quality 
assurance reviews, audits, and evaluation of the study safety and progress.  
11.3 Source Documents 
This study will use both paper and electronic source and this may vary by location due to local 
availability.  All sites will be provided with hard copy data collection forms derived from the 
eCRFs.  If data is first entered on paper the study staff will enter the data into the electronic 
capture system. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 39 of 90 
12 
RESPONSIBILITIES 
12.1 Investigator Responsibilities 
12.1.1 Good Clinical Practice 
The investigator will ensure that the basic principles of Good Clinical Practice are followed along 
with the appropriate laws and regulations of the country in which the research is conducted.  
12.2 Institutional Review Board (IRB)/Ethics Committee (EC) 
The protocol and any accompanying material to be provided to the participants such as the 
informed consent will be submitted to the EC for review and approval.  Approval from the 
committee must be obtained before starting the study and should be documented in 
correspondence to the investigator. 
Any modifications to the protocol after receipt of the IRB or EC approval must be submitted to 
the committee for approval prior to implementation. 
12.3 Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each individual 
participating in the study after adequate explanation of the aims, methods, objectives and 
potential risk of any study related procedures.  The investigator must use an IRB/EC approved 
informed consent.  The investigators will accept either signed (cursive) or printed signatures or a 
witnessed mark in the case of illiterate study participants on the consent form.   
Only the principal investigators or study staff authorized to obtain consent will consent 
participants for this study.  Only individuals who have signed the consent form and meet 
eligibility criteria will be enrolled in the study.  
Entry into the study and participation will be strictly voluntary.  It will be made clear that refusal 
to participate or a decision to withdraw can occur at any time throughout the course of the study 
and will not influence their rights or the care they receive at local health facilities. Potential 
participants will be told that all of their health information will be confidential and that records will 
be coded without personal identifiers before they are shared with statisticians or project 
scientists outside of the village/region/country. They will also be told that no monetary or other 
gains are offered in exchange for participation apart from compensation for time and 
reimbursement of travel expenses as described above. 
12.3.1  Informed Consent Training 
Each step of the study will be explained in detail to the local study personnel. The basic 
principles of informed consent process, documentation of informed consent, protection of 
participants’ rights, confidentiality, and handling of data will be covered in these training 
sessions. Study personnel will be monitored by the on-site project coordinatoron a regular basis 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 40 of 90 
to ensure compliance with the principles of informed consent. The investigators and study 
personnel who will obtain consent from study participants will also receive training in the 
informed consent process and good clinical practices (GCP). 
12.3.2 Country Specific ICF Information  
Professionals, PIs and site project coordinators will conduct on-site training sessions for study 
staff who will be collecting study information, specimens, and/obtaining consent from 
participants in the study. The study will be explained in detail to the local study staff. The basic 
principles of informed consent process, documentation of informed consent, protection of 
participants’ rights, confidentiality, and handling of data will be covered in these training 
sessions. All training sessions will be documented, and study staff monitored by the on-site 
project coordinator on a regular basis to ensure compliance with the principles of informed 
consent. The Principal Investigator will provide training and readings materials on human 
participant regulations with an emphasis on informed consent. If the field staff in PNG has 
difficulty with the use of modern technology (computers, mouse, etc.) the Principal Investigators 
and/or professional staff will provide the specified training (as outlined in the protocol) and 
submit a signed attestation for the informed consent process training. The investigators will 
accept either signed (cursive) or printed signatures or a witnessed mark in the case of illiterate 
study participants on the consent form.  
Only the principal investigators and study staff authorized and trained to obtain consent will 
consent participants for this study. Only individuals who have signed the consent form and meet 
eligibility criteria will be enrolled in the study. 
12.4 Participant Privacy  
Privacy of the study participants will be maintained by assigning study participants a unique 
study identification number (UNID). All data, blood samples and laboratory results will be 
recorded and analyzed by UNID with no personal identifiers.  All information collected, including 
demographic information about enrolled participants will be kept confidential and available only 
to the investigators and authorized study personnel such as the data manager. 
Though most data will be collected on tablets, all written forms (i.e., consent and any paper data 
collection forms) will be stored in a designated locked area with limited access. All forms will be 
labelled and filed in cabinets with the study protocol umber, PI’s names and collection dates. 
These cabinets will be metal and have functioning locks. Keys will be kept with the Project 
Coordinator.  All electronic devices on which data are entered will be password protected. PIs 
and/or Project Coordinatorr will authorize access. The paper forms will be stored for the duration 
of the study plus three years per IRB protocol for primary data storage. 
12.5 Data Ownership 
The data are the property of PNGIMR. The Principal Investigators, Co-investigators and key 
personnel may use the results of this study for publications, presentations at scientific meetings or 
as preliminary data for subsequent grant applications. Confidentiality of study participants will be 
maintained by not using names or personal identifiers. PNGIMR will provide de-identified data 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 41 of 90 
from the study to DOLF for use in publications and presentations that present results across 
different study sites. At least one Papua New Guinea based researcher will be included as an 
author for any publications with data from Papua New Guinea.  
The study site Project Coordinator will permit access to all documents and records that may 
require inspection by the funding agencies, governmental regulatory agencies, institutional 
review boards or its authorized representatives.  

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 42 of 90 
13 PUBLICATION POLICY  
Manuscripts should be submitted for publication no later than one year following the date of the 
“last patient/last visit”. This study includes follow-up data collection past the primary end point, 
including acceptability and efficacy results. It is not necessary to wait for the follow-up studies to 
be completed in order to publish the primary safety data. 
Endemic country investigators have an obligation to publish the results of DOLF studies 
conducted in their country. These results benefit the national NTD programs and the citizens of 
the country where the study was completed. DOLF collaborating institutions are willing to help 
their endemic country partners with the data analysis, manuscript preparation, publication fees, 
etc. However, the lead author should be an investigator from the country where the study was 
performed. 
DOLF scientists will be responsible for publishing the results from the aggregated data that 
combines the results from multiple study sites. The purpose of these manuscripts is to consider 
the similarities and differences in results obtained in different countries. These publications will 
not include as much detailed data or analyses as the country specific publications. Publications 
that report multi-country results will have at least one co-author from each country included in 
the manuscript. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 43 of 90 
14 
LITERATURE REFERENCES 
1.  
Hooper PJ, Bradley MH, Biswas G, Ottesen EA. The Global Programme to Eliminate 
Lymphatic Filariasis: health impact during its first 8 years (2000-2007). Annals of tropical 
medicine and parasitology. 2009;103 Suppl 1:S17-21. 
2.  
Hooper PJ, Chu BK, Mikhailov A, Ottesen EA, Bradley M. Assessing progress in 
reducing the at-risk population after 13 years of the global programme to eliminate 
lymphatic filariasis. PLoS neglected tropical diseases. 2014;8(11):e3333. 
3.  
Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, et al. Efficacy, Safety, 
and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and 
Ivermectin for Treatment of Bancroftian Filariasis. Clin Infect Dis. 2016;62(3):334-41. 
4.  
Romani L, Whitfeld MJ, Koroivueta J, Kama M, Wand H, Tikoduadua L, et al. Mass Drug 
Administration for Scabies Control in a Population with Endemic Disease. The New 
England journal of medicine. 2015;373(24):2305-13. 
5.  
Graves PM, Makita L, Susapu M, Brady MA, Melrose W, Capuano C, et al. Lymphatic 
filariasis in Papua New Guinea: distribution at district level and impact of mass drug 
administration, 1980 to 2011. Parasites & vectors. 2013;6:7. 
6.  
Bockarie MJ, Tavul L, Ibam I, Kastens W, Hazlett F, Tisch DJ, et al. Efficacy of single-
dose diethylcarbamazine compared with diethylcarbamazine combined with albendazole 
against Wuchereria bancrofti infection in Papua New Guinea. Am J Trop Med Hyg. 
2007;76(1):62-6. 
7.  
Bockarie MJ, Tisch DJ, Kastens W, Alexander ND, Dimber Z, Bockarie F, et al. Mass 
treatment to eliminate filariasis in Papua New Guinea. The New England journal of 
medicine. 2002;347(23):1841-8. 
8.  
Weil GJ, Kastens W, Susapu M, Laney SJ, Williams SA, King CL, et al. The impact of 
repeated rounds of mass drug administration with diethylcarbamazine plus albendazole 
on bancroftian filariasis in Papua New Guinea. PLoS neglected tropical diseases. 
2008;2(12):e344. 
9.  
Yahathugoda TC, Supali T, Rao RU, Djuardi Y, Stefani D, Pical F, et al. A comparison of 
two tests for filarial antigenemia in areas in Sri Lanka and Indonesia with low-level 
persistence of lymphatic filariasis following mass drug administration. Parasites & 
vectors. 2015;8:369. 
10.  
Weil GJ, Ramzy RM. Diagnostic tools for filariasis elimination programs. Trends in 
parasitology. 2007;23(2):78-82. 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 44 of 90 
11.  
Thomsen, E.K., et al., Efficacy, Safety, and Pharmacokinetics of Coadministered 
Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. 
Clin Infect Dis, 2015. 
12. 
Horton, J., Albendazole: a review of anthelmintic efficacy and safety in humans. 
Parasitology, 2000. 121 Suppl: p. S113-32.  
13. 
Goa, K.L., D. McTavish, and S.P. Clissold, Ivermectin. A review of its antifilarial activity, 
pharmacokinetic properties and clinical efficacy in onchocerciasis. Drugs, 1991. 42(4): p. 
640-58.  
14. 
Edwards, G., Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J, 
2003. 2 Suppl 1: p. S8.  
15. 
Ottesen, E.A. and W.C. Campbell, Ivermectin in human medicine. J Antimicrob 
Chemother, 1994. 34(2): p. 195-203. 
16. 
Awadzi, K., et al., The co-administration of ivermectin and albendazole--safety, 
pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol, 
2003. 97(2): p. 165-78. 
17. 
Ottesen, E.A., Efficacy of diethylcarbamazine in eradicating infection with lymphatic-
dwelling filariae in humans. Rev Infect Dis, 1985. 7(3): p. 341-56. 
18. 
Bockarie, M.J., et al., Randomised community-based trial of annual single-dose 
diethylcarbamazine with or without ivermectin against Wuchereria bancrofti infection in 
human beings and mosquitoes. Lancet, 1998. 351(9097): p. 162-8. 
19. 
Noroes, J., et al., Assessment of the efficacy of diethylcarbamazine on adult 
Wuchereria bancrofti in vivo. Trans R Soc Trop Med Hyg, 1997. 91(1): p. 78-81. 
 
 
 

 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 45 of 90 
LIST OF APPENDICES 
Appendix 1:  Study Drug Flow Diagram (country specific) 
Appendix 2:  Participant Enrollment Form [Example] 
Appendix 3:  Participant Monitoring Form Example 
Appendix 4:  Guide to Assigning Adverse Event Severity 
Appendix 5:  Adverse Event Evaluation and Report Form (AEERF) [Example] 
Appendix 5a:  Required Reporting & Guidelines for SAE(s) 
Appendix 6:  Informed Consent Form [Example] 
Appendix 7  
Treatment Acceptability Study Protocol 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 46 of 90 
APPENDIX 1: 
STUDY FLOW DIAGRAM (COUNTRY SPECIFIC) 
 
 
 
 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 47 of 90 
APPENDIX 2: 
PARTICIPANT ENROLLMENT FORM [EXAMPLE]  
 
Participant ID (Barcode): 
 
1. SITE INFORMATION 
Team (required): 
 
Data Entry Clerk ID (required): 
Enrollment Date (required) (DD-MM-YYYY): 
Consent Method (required) 
☐Self 
☐Parent 
☐Other guardian (specify): 
☐Teacher 
☐No consent (STOP) 
Enrollment Location 
☐Home 
☐School 
☐Village meeting point 
 
Enrollment Village:  
 
2. PARTICIPANT INFORMATION AND MEDICAL HISTORY 
Gender:   ☐M    ☐F 
Note: if exact date is not known, birth year is sufficient 
Age (Years): 
Birth Day (DD): 
Birth Month 
(MM): 
Birth Year 
(YYYY): 
Village of Residence: 
House Number: 
Participant ID (Barcode): 
(affix barcode at the top of each form AND write in ID number at top of each page) 
Females only:  When was the date of your last menstrual period? (read options) 
☐Definitely less than 4 weeks ago 
☐Post-menopause 
☐4 weeks of longer (STOP) 
☐Uncertain (STOP) 
Males only:  Do you have swelling or enlargement of your scrotum? 
☐Yes   ☐No 
Males only:  Do you feel pain in your testicles or scrotum?    
☐Yes   ☐No 
Do you have any of the following chronic medical conditions? (read options) 
☐Hypertension (high blood pressure) 
☐Asthma or chronic lung disease 
☐Chronic kidney disease (renal insufficiency) 
☐Diabetes 
☐Other (specify): 
Do you have swelling in your arms or legs (lymphedema)?    
☐Yes   ☐No 
If participant reports lymphedema exam them and confirm presence of edema.   
Left arm 
☐No edema 
☐Yes edema  
Left leg  
☐No edema 
☐Yes edema 
Right arm  
☐No edema 
☐Yes edema 
Right leg  
☐No edema 
☐Yes edema 

 
Appendix 2: PARTICIPANT ENROLLMENT FORM [Example]  
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 48 of 90 
Did you use a bed net last night?  
☐Yes   ☐No 
Does your house have screens on the windows? 
☐Yes   ☐No 
Do you spray indoors to prevent mosquitos? 
☐Yes   ☐No 
Did you swallow medicines during MDA treatment for filariasis in the last twelve months?  
(If YES enter the date) 
☐Yes 
Date of last MDA (MM-YYYY):___________    ☐Do not remember date 
☐No 
☐Uncertain 
☐N/A—no MDA distributed 
Have you ever taken the following medication called…? 
 
Albendazole? 
 
☐Yes  ☐No  ☐Don’t know 
 
Ivermectin?  
 
☐Yes  ☐No  ☐Don’t know 
 
DEC?  
 
☐Yes  ☐No  ☐Don’t know 
 
 
3. AE ASSESSMENT 
Today, were you too sick to work or go to school? 
☐Yes (exclude, but finish the pre-treatment assessment) 
☐No 
EXPLAIN: Now I will ask you some questions about your health during the past two days. 
In the past 2 days have you experienced…? 
..Fever 
☐Yes   ☐No 
..Dizziness, giddiness, or fainting 
☐Yes   ☐No 
..Confusion  
☐Yes   ☐No 
..Drowsiness 
☐Yes   ☐No 
..Headache 
☐Yes   ☐No 
..Cough 
☐Yes   ☐No 
..Difficulty breathing (wheezing or dyspnea)  
☐Yes   ☐No 
..Nausea 
☐Yes   ☐No 
..Vomiting 
☐Yes   ☐No 
..Diarrhea 
☐Yes   ☐No 
..Stomach pain 
☐Yes   ☐No 
..Unusual swelling, beyond baseline lymphedema 
☐Yes   ☐No 
 
Specify Location:   ☐Arm   ☐Leg   ☐Breast   ☐Scrotum 
..Joint or muscle pain 
☐Yes   ☐No 
..Weakness 
☐Yes   ☐No 
..Swelling or pain in your armpit or groin  
☐Yes   ☐No 
..Men only:  pain in you testicles or scrotum 
☐Yes   ☐No 
..Itchy skin 
☐Yes   ☐No 
..Rash (specify location): 
☐Yes   ☐No 

 
Appendix 2: PARTICIPANT ENROLLMENT FORM [Example]  
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 49 of 90 
Is the rash in the spaces between your fingers? 
☐Yes ☐No 
..Other illness or symptoms (specify): 
☐Yes   ☐No 
Have you ever suffered from scabies? (note: use local name for scabies) 
☐Yes 
☐No 
☐Don’t know 
Additional notes or comments: 
 
4. EXAMINATION 
Team (required): 
Clinician (required): 
Data Entry Clerk ID (required): 
Measurements 
Values / status 
Height (cm) 
 
Weight (kg) 
 
BMI (calculated) 
 
Scabies 
☐Yes   ☐No 
 
If Yes, please take photograph 
 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 50 of 90 
APPENDIX 3: 
PARTICIPANT MONITORING FORM [EXAMPLE] 
 
FOR: Day 1 & 2, if needed days 3-7 
 
Participant ID (Barcode): 
 
Use this form for active monitoring of adverse events on day 1 (24 hours) and 2 (48 hours) 
following therapy, as well as for recording symptoms reported by those presenting with 
complaints on days 3-7 post-treatment. 
Team (required): 
Clinician (required): 
Data Entry Clerk ID (required): 
 
1. PARTICIPANT INFORMATION 
Gender:   ☐M    ☐F 
Age (Years):  
Village of Residence: 
Treatment Village: 
Treatment Date (DD-MM-YYYY):                     
 
2. ASSESSMENT INFORMATION 
Day 1 and 2: All participants should be asked all the questions in Table 1. 
Days 3-7: Any participant who presents with a complaint should be asked all the questions in 
Table 1 
Table 1:  Reported Symptoms 
 
Record a symptom grade from 0-5 for each day on which the participant experienced 
symptoms.  
 
For participants reporting ANY symptom, complete every questions in Table 1.  
 
Refer to the Appendix 4 for symptom-specific scoring criteria. 
 
Anyone with a symptom typed in bold needs to have Table 2 completed. 
 
Symptom Grading 
0 = No adverse event or within normal limits 
1 = Mild adverse event, does not interfere with work or school 
2 = Moderate adverse event, interferes with work or school at least 1 day 
3 = Severe and undesirable adverse event; interferes with ADL, requires medical assessment 
4 = Potentially life-threatening or disabling adverse event; requires transfer to medical facility 
5 = Death  
 
Symptoms/Signs 
Since you took the tablets have you 
experienced…? 
Post-treatment day(s) on which symptoms 
or signs were present 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
..Fever 
 
 
 
 
 
 
 
..Dizziness, giddiness, or fainting 
 
 
 
 
 
 
 
..Confusion 
 
 
 
 
 
 
 
..Drowsiness 
 
 
 
 
 
 
 
..Headache 
 
 
 
 
 
 
 

Appendix 3: PARTICIPANT MONITORING FORM [Example] 
 
FOR: Day 1 & 2, if needed days 3-7 
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 51 of 90 
..Cough 
 
 
 
 
 
 
 
..Difficulty breathing (wheezing or dyspnea) 
 
 
 
 
 
 
 
..Nausea 
 
 
 
 
 
 
 
..Vomiting 
 
 
 
 
 
 
 
..Diarrhea 
 
 
 
 
 
 
 
..Stomach pain 
 
 
 
 
 
 
 
..Unusual swelling, beyond baseline lymphedema (specify location below)  
Arm 
 
 
 
 
 
 
 
Leg 
 
 
 
 
 
 
 
Breast 
 
 
 
 
 
 
 
Scrotum 
 
 
 
 
 
 
 
..Joint or muscle pain 
 
 
 
 
 
 
 
..Weakness 
 
 
 
 
 
 
 
..Swelling or pain in your armpit or groin 
 
 
 
 
 
 
 
..Men only: pain in your testicles or scrotum 
 
 
 
 
 
 
 
..Itching skin 
 
 
 
 
 
 
 
..Rash (specify location and brief 
description): 
 
 
 
 
 
 
 
 
 
..Other illness or symptoms (specify): 
 
 
 
 
 
 
 
 
 
 
If there is any symptom grade ≥ 3, you must notify the supervising medical officer and 
the participant must be evaluated by the medical team.    
 
 
 

Appendix 3: PARTICIPANT MONITORING FORM [Example] 
 
FOR: Day 1 & 2, if needed days 3-7 
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 52 of 90 
Table 2:  Physical Examination 
 
You must complete this table for any participant reporting any bolded symptom in Table 1 
OR for any symptom grade ≥2  
 
Record the result under the column that corresponds to the day the assessment was 
taken.   
Measurements 
Post-treatment day(s) 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Height (cm) 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
BMI (calculated) 
 
 
 
 
 
 
 
Temperature 
 
 
 
 
 
 
 
Blood pressure, sitting 
 
 
 
 
 
 
 
Blood pressure, lying down (measure only 
if sitting systolic BP <100) 
 
 
 
 
 
 
 
Post-Exam Adverse Event Grade (Assign grade of 0-5 for the adverse reactions below based 
on physical exam. See Appendix 4 under “post-exam assessment” for specific grading criteria) 
Allergic reaction 
 
 
 
 
 
 
 
Hypotension (low blood pressure) 
 
 
 
 
 
 
 
Lymphangitis (streaks of redness, 
warmth, and swelling in arms or legs) 
 
 
 
 
 
 
 
 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 53 of 90 
APPENDIX 4: 
GUIDE TO ASSIGNING ADVERSE EVENT SEVERITY 
 
 (Grade 0 = no symptoms; grade 5 = death from adverse event) 
Symptoms/Signs 
Grades 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening 
Fever (non-axillary 
temperatures only) 
38.0 – 39.0ºC 
39.1 – 40.0ºC 
> 40.0ºC 
> 40.0ºC for > 48 hrs 
Dizziness, 
giddiness, or 
fainting 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
for 1 day, but 
no fainting 
Any loss of 
consciousness 
(fainting) 
- 
Confusion or 
excess drowsiness* 
Mild, not 
interfering with 
work or school 
Moderate; 
confusion or 
drowsiness 
interfering with 
ability to work 
Confusion, loss 
of memory, or 
sleepiness 
interfering with 
activities of daily 
living 
Delerium, inability rouse, 
or coma  
Fatigue 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school  
at least 1 day 
Unable to 
perform 
activities of daily 
living, > 1day 
Required hospitalization 
Headache 
Mild pain not 
interfering with 
work or school 
Moderate pain; 
pain or 
analgesics 
interfering with 
ability to work 
or attend school 
Severe pain; 
pain or 
analgesics 
interfering with 
activities of daily 
living 
Disabling, duration > 48 
hr 
Cough 
Mild, relieved 
by non-
prescription 
medication 
Requiring 
narcotic 
antitussive 
Severe cough or 
coughing 
spasms, poorly 
controlled by 
treatment 
Hospitalization or 
respiratory failure 
requiring mechanical 
ventilation 
Difficulty breathing 
(wheezing or 
dyspnea) 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
for 1 day 
Severe, more 
than 1 day and 
required transfer 
to clinic or 
hospital 
Hospitalization or 
respiratory failure 
requiring mechanical 
ventilation 
Nausea 
Able to eat 
Oral intake 
significantly 
decreased 
No significant 
intake, requiring 
IV fluids 
- 
Vomiting 
1 episode in 24 
hours over 
pretreatment 
2-5 episodes in 
24 hours over 
pretreatment 
≥ 6 episodes in 
24hours,  or 
need for IV 
fluids 
(0upatient) 
Hemodynamic collapse 
or overnight 
hospitalization 

 
Appendix 4: GUIDE TO ASSIGNING ADVERSE EVENT SEVERITY 
 
 (Grade 0 = no symptoms; grade 5 = death from adverse event) 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 54 of 90 
Symptoms/Signs 
Grades 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening 
Diarrhea 
Increase of < 4 
stools/day over 
pre-treatment 
Increase of 4-6 
stools/ day, or 
nocturnal stools 
Increase of ≥ 7 
stools/ day or 
need for 
outpatient 
parenteral 
support for 
dehydration 
Physiologic 
consequences wth 
hemodynamic collapse 
or requiring 
hospitalization 
Abdominal pain 
Mild pain not 
interfering with 
work or school 
Moderate pain; 
pain or 
analgesics 
interfering with 
ability to work 
or attend school 
Severe pain; 
pain or 
analgesics 
interfering with 
activities of daily 
living 
Disabling, duration > 48 
hr 
Unusual swelling 
(beyond baseline 
lymphedema) 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
1 day  
Severe, unable 
to work/school 
>1 day 
Severe, limiting activities 
of daily living (unable to 
walk) > 2 days 
Joint or muscle pain 
Mild pain not 
interfering with 
work or school 
Moderate pain; 
pain or 
analgesics 
interfering with 
ability to work 
or attend school 
Severe pain; 
pain or 
analgesics 
interfering with 
activities of daily 
living 
Disabling, duration > 48 
hr 
Swelling or pain in 
your armpit or 
groin* 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
1 day  
Severe, unable 
to work/school 
>1 day 
Severe, limiting activities 
of daily living (unable to 
walk) > 2 days 
Men only:  testicular 
or scrotal pain 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
1 day  
Severe, unable 
to work/school 
>1 day 
Severe, limiting activities 
of daily living (unable to 
walk) > 2 days 
Itching skin 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
1 day  
Severe, unable 
to work/school 
>1 day 
 
Rash 
 
 
Localized rash 
(covers only 
one part of the 
body) 
Diffuse rash 
(covers multiple 
parts of the 
body)  
Diffuse rash 
(covers multiple 
parts of the 
body) AND has 
any blisters or 
ulcers or mouth 
sores 
Extensive areas with 
blisters or ulcers OR 
peeling or blackening of 
skin 
Other illness or 
symptoms  
 
 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school  
at least 1 day 
Unable to 
perform 
activities of daily 
living, > 1day 
Required hospitalization 
 

 
Appendix 4: GUIDE TO ASSIGNING ADVERSE EVENT SEVERITY 
 
 (Grade 0 = no symptoms; grade 5 = death from adverse event) 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 55 of 90 
Post-Exam 
Assessment 
Grades 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening 
Acute allergic 
reaction 
Transient rash, 
drug 
Fever <38ºC 
(<100.4ºF) 
Urticaria, drug 
fever ≥38ºC 
(≥100.4ºF) 
and/or 
asymptomatic 
bronchospasm 
Symptomatic 
bronchospasm, 
requiring 
parenteral 
medication(s) 
with or without 
urticaria 
Anaphylaxis with 
hypotension required 
hospitalization 
Hypotension (low 
blood pressure) 
Changes, but 
not requiring 
therapy 
(including 
transient 
orthostatic 
hypotension) 
Requiring brief 
fluid 
replacement 
(such as oral 
rehydration) but 
not 
hospitalization 
Requiring i.v. 
fluids without 
overnight 
hospitalization.  
No sequelae. 
Required overnight 
hospitalization for i.v. 
fluids, or Shock 
(acidemia and impaired 
vital organ function due 
to tissue 
hypoperfusion) 
Lymphangitis 
Mild, not 
interfering with 
work or school 
Moderate, 
unable to work 
or attend school 
1 day  
Severe, unable 
to work/school 
>1 day 
Severe, limiting 
activities of daily living 
(unable to walk) > 2 
days 
 
Note on general aspects of grading 
0 = No adverse event or within normal limits 
1 = Mild adverse event, does not interfere with work or school 
2 = Moderate adverse event, interferes with work or school at least 1 day 
3 = Severe and undesirable adverse event; interferes with ADL, requires medical assessment 
4 = Potentially life-threatening or disabling adverse event; requires transfer to medical facility 
5 = Death  
 
Note: Any event ≥ grade 3 requires a medical evaluation and notification of the medical officer. 
Any grade 3, 4 or 5 event or overnight hospitalization requires an Adverse Event Evaluation and 
Report Form. 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 56 of 90 
APPENDIX 5: 
ADVERSE EVENT EVALUATION AND REPORT FORM (AEERF) 
[EXAMPLE] 
 
Participant ID (Barcode): 
 
Instructions: Complete this form AFTER completing the Participant Monitoring Form for 
anyone with symptoms or signs of grade 3 or higher (unable to perform activities of daily 
living without assistance for at least one day). The purpose of this form is to provide additional 
information on more severe adverse events and to assist the medical officer in determining 
whether a Serious Adverse Event (SAE) has occurred. Please refer to Appendix 5a for 
definitions.  
 
Clinician (required): 
 
1. PARTICIPANT INFORMATION 
Participant ID (Barcode): 
 
Gender:   ☐M    ☐F 
Age:_____Years 
Weight:_____Kg 
Height:_____cm 
Village of Residence: 
 
2. MDA TREATMENT 
Treatment Date (DD-MM-YYY)___________ 
Treatment Village:______________________ 
Anything irregular about treatment? 
☐No   ☐Yes (specify): 
Medications received 
 Albendazole  (dose:____mg) 
 DEC 
 
(dose:____mg) 
 Ivermectin 
(dose:____mg) 
Was this the first time you have ever been treated with one of the MDA medications? If 
No, explain when and circumstances of prior treatment.  
 
Albendazole ☐Yes ☐No (explain): 
DEC 
 
☐Yes ☐No (explain): 
Ivermectin 
☐Yes ☐No (explain): 
 
3. OTHER MEDICATIONS AT TIME OF MDA  
Please include prescription and non-prescription medications/supplements/herbal remedies 
taken within 5 days of the MDA.  DO NOT include medications used to treat the SAE. 
Medication 
Indication 
Dose and 
Frequency 
Days on which each medication was taken, relative to 
MDA (if taken the day of MDA, mark “0”; the day 
before, mark “-1”; the day after, “+1”, and so forth.) 
 
 
 
-5   -4   -3   -2   -1   0   +1   +2   +3   +4   +5  uncertain 
 
 
 
-5   -4   -3   -2   -1   0   +1   +2   +3   +4   +5  uncertain 
 
 
 
-5   -4   -3   -2   -1   0   +1   +2   +3   +4   +5  uncertain 
 
 
 
-5   -4   -3   -2   -1   0   +1   +2   +3   +4   +5  uncertain 
4. DESCRIPTION OF THE ADVERSE EVENT 

Appendix 5: ADVERSE EVENT EVALUATION AND REPORT FORM 
(AEERF) [Example] 
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 57 of 90 
Date of onset (DD-MM-YYYY): 
How long after drugs were taken did the 
event begin? 
_____hours  OR _____days 
Clinical signs and symptoms (please describe) 
 
 
 
 
 
Do you (the clinician) think this adverse event is/was life-threatening? 
☐Yes  
☐No  
Was the participant hospitalized? 
 
☐Yes  
☐No  
If yes, indicate 
1. Date of admission (DD-MM-YYYY): 
 
2. Reason for admission: 
 
3. Date of discharge (DD-MM-YYYY): 
 
4. Clinical course, including drug treatments given to treat adverse event: 
 
 
 
 
 
Attach a copy of any medical records relating to the diagnosis and treatment of the adverse 
event 
Laboratory results and diagnostic tests (indicate date, test name, and results): 
 
 
 
 
 
 
 

Appendix 5: ADVERSE EVENT EVALUATION AND REPORT FORM 
(AEERF) [Example] 
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 58 of 90 
5. ADVERSE EVENT OUTCOME (Check only ONE) 
☐Recovering/resolving 
 
 
☐Not recovered/not 
resolved 
 
 
☐Recovered/resolved 
Date: (DD-MM-YYY) 
 
☐Recovered/resolved 
with sequelae 
Date:(DD-MM-YYY) 
Sequelae: 
☐Unknown 
☐Fatal 
(death) 
 
Date:(DD-MM-YYY) 
 
Autopsy: ☐Not done   ☐Done (provide report)   ☐Planned     ☐ Status Unknown 
 
Death certificate: ☐Provided   ☐Requested   ☐Not available   ☐ Status Unknown 

Appendix 5: ADVERSE EVENT EVALUATION AND REPORT FORM 
(AEERF) [Example] 
 
Participant ID (Barcode): 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 59 of 90 
6. CONCLUSIONS (to be completed by the health-care provider) 
Presumptive diagnosis: 
 
Do you think this adverse event was caused by the MDA medications? Refer to Appendix 5a for 
detailed explanation of choices. 
 Definitely  
 Probably (explain): 
 Possibly (explain): 
 Unrelated 
If “unrelated”, what do you believe was the cause of the adverse event? 
 
 
Does this event meet the criteria for a Serious Adverse Event (SAE)?  Refer to Appendix 5a for 
detailed definitions of criteria. 
 
 Yes, based on the following criteria 
 Death 
 Life-threatening  
 Hospitalization  
 Disability or permanent damage 
 Other serious important medical event: specify 
 
 No 
 
 
REPORTER INFORMATION AND SIGNATURES 
Investigator Name: 
Investigator Signature:                                 Date:  
Reporter Name: 
Reporter Signature:                                      Date:  
Reporter’s phone number: 
Reporter’s email address: 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 60 of 90 
APPENDIX 5a:  
REQUIRED REPORTING GUIDELINE FOR SERIOUS ADVERSE 
EVENTS 
 
 
An Adverse Event Evaluation and Report Form (AEERF) should be completed for every severe 
adverse event (those scoring grade 3 or higher, see Appendix 4). However, a grade 3 or severe 
adverse event is NOT the same as a Serious Adverse Events (SAE) and the majority of grade 3 
adverse events will not be classified as SAE. The term "severe" is often used to describe the 
intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the 
event itself, however, may be of relatively minor medical significance (such as severe 
headache). This is not the same as "serious," which is based on patient/event outcome or action 
criteria usually associated with events that pose a threat to a patient's life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.  
The AEERF should guide the medical monitor or health care provider evaluating the patient 
experiencing a severe AE to determine whether a SAE has occurred.  All SAE must be reported 
promptly. (See Safety Reporting Plan for SAE Reporting Timeline) 
Required Reporting  
A written report or case report form (CRF—in this study, the AEERF) must be sent from the 
local physician and local medical monitor by email (scanned records) in the stated timeframes to 
the Country PI, Global Medical Monitor including the Project PI for the events listed below.  
Guidelines for Reporting - Standard Reporting Information   
The following information should be included in the initial report/CRF (additional 
information may be requested): 
Minimum Criteria for Reporting  
Information for final description and evaluation of a case report may not be 
available within the required time frames for reporting outlined below. Initial 
reports should be submitted within the prescribed time as long as the following 
minimum criteria are met: an identifiable patient; an identifiable reporting 
source; and an event or outcome that can be identified as serious. Follow-up 
information should be actively sought and submitted as it becomes available.  
 
 

Appendix 5a: REQUIRED REPORTING GUIDELINE FOR SERIOUS 
ADVERSE EVENTS 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 61 of 90 
Complete the following information if available on the initial report and complete a follow-up 
report as new or additional information becomes available as noted below: 
 
Description of the event 
Date, time of onset 
Clinical history 
Associated signs and symptoms 
Temporal association with study agent 
Medical management, including rationale 
Pertinent laboratory tests 
Severity – see definitions or toxicity score 
Causal relationship to the study drug/vaccine 
 
Other information 
Relevant past medical history 
Concomitant medications 
Autopsy report or expectation of an autopsy in the case of death 
 
Outcome of event 
Date, time of resolution, if resolved 
 
Plans for study participants 
Follow-up 
Treatment of event 
Return to treatment/Contraindicate 
 
Location/Study Centre 
 
Reporting Physician 
 
Verification of notification to IRB and Safety Monitor or DSMB 
Definitions 
 
Adverse Event [Experience] (AE): 
Any untoward medical occurrence, including dosing errors, that may arise during 
administration of study agent, and which may or may not have a causal relationship with 
the study agent. 
 
Unexpected Adverse Event [Experience]: 
Any adverse experience that has not been previously observed (i.e., included in the 
labelling), whether or not the event is anticipated because of the pharmacologic 
properties of the study agent. 

Appendix 5a: REQUIRED REPORTING GUIDELINE FOR SERIOUS 
ADVERSE EVENTS 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 62 of 90 
 
Serious Adverse Event (SAE): 
Any adverse event occurring at any dose that results in any of the following outcomes: 
a. Death 
b. Life threatening – defined as an experience that places the patient or participant, in 
the view of the Investigator, at immediate risk of death from the reaction as it 
occurred.  (Note; this does not include a reaction that, had it occurred in a more 
severe form, might have caused death.) 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
d. Results in a congenital anomaly or birth defect 
e. Results in a persistent or significant disability or incapacity 
f. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or participant and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  (The event might be defined as serious based on progression of 
grade if Toxicity Tables are being used.) 
Severity  
Adverse experience/events should be assessed by the on-site investigator as to their 
severity and/or intensity. 
a. Life threatening 
b. Severe: incapacitating with inability to work or do usual activity 
c. Moderate: enough discomfort to cause interference with usual activity 
d. Mild: awareness of sign or symptom, but easily tolerated 
Relationship or Association with Use of Study Agent or Participation in the Study 

Appendix 5a: REQUIRED REPORTING GUIDELINE FOR SERIOUS 
ADVERSE EVENTS 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 63 of 90 
Causal relationship with the investigational study treatment must be assessed by the on-site 
investigator using the following or similar terms: 
 
Definite – clear-cut temporal association, with a positive re-challenge test or laboratory 
confirmation. 
 
Probable – clear-cut temporal association, with improvement upon drug withdrawal, and 
not reasonably explained by the particpant’s known clinical state. 
 
Possible – less clear temporal association; other aetiologies are possible. 
 
None – no temporal association with the study drug; related to other aetiologies such as 
concomitant medications or conditions, or participant’s known clinical state. 
Other Reporting 
Investigators are reminded that they may have other reporting obligations: 
 
For all studies, there must be compliance with the clinical site Ethics/IRB’s policy for 
reporting adverse events. (As soon as possible for SAEs and as required for AEs.) 
 
 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 64 of 90 
APPENDIX 6A: 
 INFORMED CONSENT FORM [EXAMPLE] 
 
Participant ID (Barcode): 
 
This is a research study conducted by the Papua New Guinea Institute of Medical Research 
(PNGIMR) and Case Western Reserve University in Cleveland, Ohio (USA).  It includes only 
individuals who choose to take part.  Please take your time to make your decision.  Discuss it 
with your friends and family.  
 
In this consent form the term “you” may refer to you or your child. You are being asked to take 
part in this study because you live in an area where you may become sick with lymphatic 
filariasis. You are being asked to consent for yourself and/or your child or children 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is being done to learn about the side effects people have when they take different 
kinds of medications to a parasite.  The parasite causes hydroceles (bol solap) and 
lymphedemia (leg solap). This parasite is a small round worm that lives in your body. We call 
this illness lymphatic filariasis (LF). 
 
We want to collect information about how your body reacts to these medications.  We want to 
know if there is a difference between taking two drugs or three.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
Approximately 6,000 adult men, women and children will take part in this study. 
 
WHAT IS INVOLVED IN THE STUDY? 
 
You will be in this study for one year.  You will be put in one of 2 groups at random, similar to 
flipping a coin.   As part of this study one group take the standard two-drug treatment of 
Diethylcarbamize (DEC) and Albendazole (ALB) and another group will take a three-drug 
therapy of Diethylcarbamize (DEC), Albendazole (ALB) and Ivermectin (IVM). Before you 
receive any medication, we will take a small amount of blood from your finger by fingerprick to 
see if you are infected with LF.   If you are infected we will ask you to return at night to get 
another fingerprick to see if there are worms in your blood.   Even if test does not show infection 
you will be treated with drugs anyway because you may still be infected with LF because the 
tests can only identify heavy infections.  
 
After you take the medication, a member of the study team will follow up with you 1 to 2 days 
later too see how you’re are feeling.  During these visits the study team will take your temperate, 
blood pressures and ask how you are feeling.  The study team will also return to your village 3 
to 7 days to ask if you are not feeling well.  If you are not, then we will exam you.  If your illness 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 65 of 90 
is severe then the study team will have you see a doctor who can provide treatment. The study 
team will record information about how you are feeling at each visit.    
 
If you tested positive for LF at the beginning of the study, the study team will collect a small 
amount of blood from a finger prick 12 months after you’re took the medication.  If you still have 
LF, you will be treated again with the standard Papua New Guinea MDA treatment.  
 
After we have finished the study, we will ask some of you about how you felt about the study.  
 
HOW LONG WILL I BE IN THE STUDY? 
 
You will be in this study for one year. We may test your blood for the presence of parasites or 
what makes your blood strong after six months and 12 months. Some of these tests may be 
performed in other countries such as the Australia or the United States where these tests are 
available.   
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.   
 
CAN I BE TERMINATED FROM THIS STUDY? 
 
Your participation in this study may be discontinued by the investigators if you move away from 
the study area during the study.  
 
(For Women)  CAN I BE IN THIS STUDY IF I AM PREGNANT? 
 
No, you cannot be in this study if you are pregnant at study enrollment.  Being a part of this 
study while pregnant may expose your unborn child to unknown risks.  If you are a woman of 
childbearing age, the study team will ask you are if you are pregnant.  
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The risk of drawing blood from a finger prick is minimal, although some people become 
lightheaded after giving blood. You may experience momentary discomfort and/or bruising. 
Children may be uncomfortable and cry when blood is drawn. You will be watched by members 
of the research team and given an opportunity to rest if you feel lightheaded. Infection, excess 
bleeding, clotting, or lightheadedness may occur after a finger prick, but these events are 
unlikely. If you develop a local infection within 7 days at the site on your arm or finger from 
where we took the blood, we will provide transportation to your local provincial health facility and 
a voucher to cover the costs of medications to treat this infection. 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 66 of 90 
 
When you take these medications, your body may react to the dying worms by developing a 
fever or you may feel tired or have body aches.  This usually means that the drugs are killing 
worms.  When you take three drugs, the medication may kill the worms faster which may lead to 
more severe side effects.  
 
The following are some possible side effects of the three drugs you will be given, although these 
side effects are small with a single dose of the drug: 
 
(DEC): – You might experience itching and swelling of face, headache, joint pain, unusual 
tiredness or weakness.  These side effects will pass.  Less common side effects you may 
experience are dizziness, nausea or vomiting.  Fever, painful and tender glands in groin, neck 
armpits or skin rash can occur and usually happens because you are infected with LF.    
 
(ALB):  You might experience headache, nausea, stomach pain and vomiting that are usually 
associated with heavy intestinal helminth (worms in the belly) infections.   There is a very small 
chance that you might develop rash, hives, itching, difficulty breathing, tightness in the chest, 
swelling of the mouth, face, lips, or tongue, dark urine.   
   
(IVM):  You might experience are diarrhea, dizziness and nausea.   There is a very small 
chance that you might develop rash; hives; itching; difficulty breathing; tightness in the chest; 
swelling of the mouth, face, lips, or tongue; eye pain, swelling, or redness; fainting; and fast 
heartbeat. 
 
If you experience any of these side effects of the drugs you will be treated for them by the health 
center physicians/staff. 
  
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
This study will help treat your infection for LF and intestinal worms. The investigators hope that 
the information learned from this study will benefit people in Papua New Guinea as well as in 
other areas of the world affected by LF.  From this work it may be possible to reduce the 
number of MDA (mass drug administration) treatments needed to treat the disease. 
 
WHAT OTHER OPTIONS ARE THERE? 
 
You do not have to participate in this study.  Taking part in this study is voluntary.  You may 
leave the study at any time.  Leaving the study will not result in any penalty or loss of benefits to 
which you are entitled.  If you have LF you will be referred to the local health center and be 
treated according to current treatment guidelines.  The current treatment for LF is a single dose 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 67 of 90 
of DEC and ALB given once a year for seven years.  This is part of mass drug treatment (MDA) 
for LF administered by the PNG Board of Health.   
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will keep the information we collect about you confidential. Your blood sample will not have 
any identifying information about you on it. Any test results we obtained as part of the study will 
be shared with the health care providers at the health center, only with your approval.  This will 
occur even if you ineligible for the study or decide to withdraw at any time. 
 
U.S. NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL TRIAL DATABASE: A description 
of this clinical trial will be available on http:///www.clinicaltrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a 
summary of the results.  You can search this website at any time to find out information about 
the trial and basic results. 
 
WHAT ARE THE COSTS? 
 
There is no cost to you to participate in this study.  You will receive no payment for taking part in 
this study. All study drugs and laboratory tests will be paid for by the study. If you develop a 
local infection within 2-7 days at the site on your hand or arm from where we drew the blood, we 
will provide transportation to your local provincial health center and a voucher to cover the costs 
of medications to treat this infection. 
 
STORAGE AND USE OF SAMPLES FOR FUTURE STUDIES 
 
Samples of your blood will be stored in a freezer at the laboratories of the Papua New Guinea 
Institutes of Medical Research’s laboratories and also at the laboratories of the Center for 
Global Health & Diseases at Case Western Reserve University in Cleveland, Ohio (USA), and 
may be used for future testing related to scientific studies not described here, including tests for 
genetic polymorphisms and immunity related to malaria, filariasis and other infectious diseases. 
However these samples will only be used with approval from the Papua New Guinea Institute of 
Medical Research’s Institutional Review Board and the Principal Investigators’ primary 
Institutional Review Board.  You will not be contacted for additional consent. You may still 
participate in this study if you do not consent to us using your samples for future scientific 
studies about diseases affecting your community.  If you check “no,” then your samples will be 
stripped of your identification number in the database after the completion of this study and will 
not be used by the investigators after the study is completed.  
 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 68 of 90 
If you change your mind in the future, you may contact Dr. Leanne Robinson or Dr. Moses 
Laman, Senior Research Fellows at Papua New Guinea Institute of Medical Research in writing 
or by phone at the Papua New Guinea Institute of Medical Research (Madang) (675/422-2909). 
 
Consent for use of your blood  
samples for future studies    
 
 
yes 
 
 
 
no 
(Please check one box only) 
 
Summary of your rights as a participant in a research study 
 
Your participation in this research study is voluntary.  Refusing to participate will not alter your 
usual health care or involve any penalty or loss of benefits to which you are otherwise entitled.  
If you decide to join the study, you may withdraw at any time and for any reason without penalty 
or loss of benefits.  If information generated from this study is published or presented, your 
identity will not be revealed.  In the event new information becomes available that may affect the 
risks or benefits associated with this study or your willingness to participate in it, you will be 
notified so that you can decide whether or not to continue participating in the study.   
 
If you experience physical injury or illness as a result of participating in this research study, 
medical care is available at the local Health Center or, if more severe, you will be transported to 
the local district hospital.  If you illness is determined to be related to taking the anti-filarial 
drugs, we will cover all appropriate medical costs. 
 
Disclosure of your study records 
 
Efforts will be made to keep the personal information in your research record private and 
confidential, but absolute confidentiality cannot be guaranteed.  The University Hospitals Case 
Medical Center Institutional Review Board and/or the Papua New Guinea Institute of Medical 
Research Institutional Review Board may review your study records.  In addition, for treatment 
studies, the study sponsor and possibly foreign regulatory agencies may also review your 
records.  If your records are reviewed your identity could become known. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
________________________________________ has described to you what is going to be 
done, the risks, hazards, and benefits involved. The study coordinators, Livingstone Tavul or 
James Suamani can be contacted at 72930700 (Livingstone), 71066112 (James) (cell phones) 
if you have any questions.   If you have any questions, concerns or complaints about the study 
in the future, you may also contact him later. Dr. Peter Siba, Director of the PNGIMR or his 
representative, can be contacted about individual rights as a research participant.  If you are 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 69 of 90 
unable to contact Mr. Suamani or Mr. Tavul, you may call the Institute of Medical Research 
(Madang) (675) 422-2909.   
 
After we have finished distributing the drugs for lf, we will ask some of you how you felt 
about the study. 
SIGNATURE 
 
Signing below indicates that you have been informed about the research study in which you 
voluntarily agree to participate; that you have asked any questions about the study that you may 
have; and that the information given to you has permitted you to make a fully informed and free 
decision about your participation in the study.  By signing this consent form, you do not waive 
any legal rights, and the investigator(s) or sponsor(s) are not relieved of any liability they may 
have.  A copy of this consent form will be given to you. 
 
 
 
Signature of Participant                                                                                           Date 
x 
 
Printed Name of Participant 
 
 
x  
Signature of Participant                                                                                           Date 
x  
Printed name of minor if used to obtain assent 
 
x  
Signature of Parent/Legal Guardian                                        Date 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 70 of 90 
x 
 
Printed name of Parent/Legal Guardian  
x 
 
If Legal Guardian, indicate relationship to child 
 
 
Study personnel (only individuals designated on the checklist may obtain consent) 
x 
 
 
Signature of person obtaining informed consent                                                    Date 
x 
 
Printed name of person obtaining informed consent  
x 
 
 
  
Signature of Witness                                                                                         Date 
x 
Printed Name of Witness 
 
 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 71 of 90 
Assessment of Informed Consent 
 
Yes 
No 
Do you understand the consent form? 
 
 
Do you have any questions? 
 
 
Question: 
 
 
 
 
 
Do you have to participate in this study? 
 
 
Will you stay overnight at the Health Center during the study? 
 
 
Will we take blood from you during this study? 
 
 
Can you refuse to participate in the study at any time? 
 
 
Is there any charge for being in the study? 
 
 
Will you receive any money for being in the study? 
 
 
Do you know who to call if you have questions? 
 
 
 
Waiver of Consent and Assent Justification 
 
Request for Waiver of Consent Documentation (45 CFR 46 117(c)(2) and 21 CFR 
56.109(c)(1)) for Census, Georeferencing and Randomization portion of the study 
  
The research presents no more than minimal risk or harm to the participants and involves no 
procedures for which written consent is normally required outside of the research context (45 
CFR 46 117(c)(2) and 21 CFR 56.109(c)(1)). 
  
The waiver of consent documentation is being requested for the census and geo-referencing 
portion of the study. The study procedures for this preliminary portion of the protocol will involve 
regional health workers and study team member collecting the name age and sex of each 
person who resides in the home.  The information collected does not involve any physical risk to 
participants.  If a head of household does not want to provide this information they can refuse. 
Consent is implied by the head of household and residents providing the study team members 
with this information. The information collected is standard information the regional health works 
have access.   
  
 
Request for Waiver of Assent for minors ages 5-17 (45 CFR 46.408 and 21 CFR 50.55) for 
the Census, Georeferencing and Randomization portion of the study 
  
Explain how the research involves no more than minimal risk. 

APPENDIX 6A: INFORMED CONSENT FORM [EXAMPLE] 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 72 of 90 
This portion of the study involves collecting of a minors name, age and sex. No physical 
procedures will be conducted that would involve risk to the child. 
  
Explain why the waiver or alteration of assent will not adversely affect the rights and welfare of 
the participants. 
It will be at the discretion of the head of household or the child’s parents to determine if this 
information is provided. This is in line with the culture of Papua New Guinea and does not 
violate this child’s rights. 
  
Explain why the research could not practicably be carried out without the waiver or alteration of 
assent. 
Without the census and geo-referencing portion of the study will assist the study team members 
in determine which communities in the region will be selected for this study.  It is not feasible to 
collected written consent form all residents of a village since in the short amount of time needed 
to conduct the census and geo-referencing portion of this study. Potential participates will sign a 
consent form prior taking any study medication. 
 
Request for Waiver of Assent for minors ages 7-13 (45 CFR 46.408 and 21 CFR 50.55) for 
the Evaluation for filariasis antigenemia and microfilaria & Two-drug therapy (DA) and 
triple drug therapy (IDA) portion of the study 
 
This study is requesting a waiver of assent for minors ages 7-13 who are enrolled into the 
evaluation for filariasis antigenemia and microfilaria & Two-drug therapy (DA) and triple drug 
therapy (IDA) portion of the studyMinors ages 14-17 who participate in the valuation for filariasis 
antigenemia and microfilaria & Two-drug therapy (DA) and triple drug therapy (IDA) portion of 
the study will sign on the parental consent form 
 
Explain how the research holds out a prospect of direct benefit that is important to the health or 
well-being of the children and is available only in the context of the research. 
 
This process reflects the cultural norms and practices usually employed in studies in PNG, and 
respect the roles parents and the community have in the informed consent process. Minors from 
ages 5 to 7 years do not need to give assent to the study. Respecting the cultural norms and 
practices in PNG, minors between the ages of 7 and 13 will not sign an assent form.  There will 
be direct benefit to minor’s participating in this study, in that those infected will be treated for the 
LF infection and transmission to the whole community will be reduced under either regimen. 

 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
Page 73 of 90 
APPENDIX 7: 
TREATMENT ACCEPTABILITY STUDY PROTOCOL 
Protocol for a treatment acceptability study following the Triple Drug Community Safety 
Trial 
 
Finalized 4 May 2016 
 
Research team 
Alison Krentel PhD, Investigator, Bruyère Research Institute, Ottawa Canada 
Joshua Bogus MPH, Global Health Project Manager for Operations, DOLF project, Washington 
University, USA 
Research assistant, Bruyère Research Institute 
Research coordinator to be determined in each country 
 
A. Summary 
As part of the larger “Community Based Safety Study of 2-drug versus 3-drug Therapy for 
Lymphatic Filariasis” a study to assess treatment acceptability in the community is planned in 
each research site: Papua New Guinea, Indonesia, Haiti, Sri Lanka and India. The overall aim of 
this research is to understand the community’s acceptance of the 3-drug regimen as well as 
gain insight into the feasibility of administering this new therapy in the future. Part of the 
investigation will include assessing community member’s perception of the possible adverse 
events experienced as a result of the 3-drug therapy, and how that might affect future rounds of 
mass drug administration (MDA) at the community level. Community acceptance will be 
measured using a survey to community members receiving treatment during the trial. In 
addition, focus group discussions (FGD) will be carried out with community members and 
community health workers to further investigate acceptability of the new therapy. To 
complement the community survey and focus group discussions, a series of key informant 
interviews are proposed with community leaders and health personnel in the same communities 
to assess perceptions about the 3-drug versus the 2-drug regimen as well as gain insight into 
the feasibility of distributing the new regimen as well as perceptions about managing adverse 
events. 
 
B. Rationale for the study 
With the introduction of a new treatment regimen for the elimination of lymphatic filariasis (LF), 
understanding community perceptions about the treatment, its adverse events (AE) as well as 
its efficacy will be an important component of assessing the acceptability of the 3-drug therapy. 
In particular, perceptions about the severity of experienced or observed AE, the efficacy of the 
treatment in killing the worms and understanding the positive presence of AE will be important 
to investigate. 
 
Research has demonstrated the important impact that AE can have on individuals’ acceptance 
of LF treatment using the 2-drug regimen [1, 2]. In some areas where MDA has been ongoing 
for many years, we might expect these AE to be objectively of minimal clinical significance, yet 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 74 of 90 
subjectively community members continue to report “fear of AE” as a deterrent to comply with 
MDA. In recent research in a low prevalence area in Indonesia, 33% of individuals interviewed 
reported experiencing some form of side effect or AE as a result of taking the LF treatment (A. 
Krentel personal experience). Thomsen et al (2016) reported a higher rate of AE in those who 
were administered the 3-drug regimen versus those who received the 2-drug therapy [3]. As the 
wider application of this new therapy is considered, it will be important to understand if the 
perception of these AE is different in between the two treatment arms.  
 
Another important deterrent to compliance with MDA is a lack of understanding of the benefit of 
treatment [4, 5]. The 3-drug regimen has been shown to be highly effective in the reduction of 
microfilariae [3]; therefore communicating this message to participants will be of crucial 
importance. Measuring participants’ understanding of this message will be essential in 
determining their acceptance of AE associated with the treatment. In PNG and in neighboring 
Indonesia when communities understand the reasons AE occur, they welcome them as a sign 
that the drugs are working [6, 7]. Knowing if this message also works with the 3-drug therapy 
where more AE are expected to occur is important in the future promotion of this treatment.  
 
For the purposes of this research, a mixed method approach is recommended, combining the 
use of a community survey, focus group discussions and in depth interviews with key 
informants. The community survey will allow a robust comparison of treatment acceptability 
between those receiving the 2-drug regimen and those receiving the 3-drug regimen. A 
composite score will measure acceptability, combining outcomes like the respondents’ intention 
to take the treatment again and willingness to recommend it to other family members. 
Acceptability will be analyzed by the impact of some of the known factors that impact 
compliance: perception of AE, knowledge about AE, perceptions about the drug characteristics 
(safe, number of pills, taste), knowledge of vector, belief that the treatment is associated with 
health, and others. In order to assess the difference between the two treatment arms, the 
sampling frame for the community survey will take into account which regimen the individual 
received.  
 
To complement the community surveys and provide further in depth analysis, focus group 
discussions (FGD) are planned with specific groups in the community, namely men, women, 
young people and community health workers. The FGDs will provide further insight and depth 
for some of the questions asked in the community survey. Specifically FGDs will investigate 
issues expected to relate to the 3-drug regimen: number of pills, perception of AE, how to 
ensure directly observed treatment and proposed messages to encourage compliance.  
 
These results will be further substantiated by interviews with key community leaders, as well as 
community and professional health workers working in LF elimination at the village level. These 
interviews will provide an understanding of the macro level issues that key informants perceive 
as critical to consider with the use of the 3-drug therapy. With this, interview respondents will be 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 75 of 90 
asked what advantages and concerns they have with regards to the 3-drug regimen based on 
their participation in and understanding of the safety trial. 
 
The outcome of this research will provide operational recommendations to accompany the 
safety study. These will inform additional acceptability research if the 3-drug regimen is adopted 
as global policy. An important outcome will be to determine if there are any real differences in 
community acceptance of the 3-drug regimen when compared to the standard treatment. If 
there are any differences, then further investigation may be recommended. In addition, the 
global programme will need to consider how to adjust the delivery protocols and recommended 
messages used by community drug distributors giving out the 3-drug regimen. The acceptability 
study will provide a preliminary understanding of these issues and will provide important insights 
into the use of this regimen on a wider scale.    
 
C. Study Objectives 
A. Measure the perception of AE reported by safety trial participants, comparing those in 
the 2-drug versus 3-drug arms 
B. Assess the overall acceptability in the community of the 3-drug regimen, as compared to 
the 2-drug regimen 
C. Assess the overall acceptability in the community of those individuals who are MF 
positive, as compared to those who are MF negative 
D. Investigate the acceptability and feasibility of delivering the 3-drug regimen   
 
D. Community Survey 
Community surveys are often called Knowledge, Attitudes and Practice (KAP) surveys because 
they use a cross sectional survey design to understand what community members know about 
disease, treatment and prevention; how they perceive factors related to the disease and finally 
what they do about it (e.g. take a drug, hang a bednet, use a condom). For the purposes of this 
survey, it is recommended to use a cross sectional survey design.  However the terminology 
and format of the KAP may not be the most appropriate questionnaire design for the study 
proposed. Specific knowledge about LF disease is not a strong predictor for compliance in MDA 
for LF, with the exception of knowing that mosquitoes transmit LF [8, 9]. For the purposes of this 
research, focusing on knowledge of LF disease may not inform community acceptability of the 
3-drug regimen as compared to the 2-drug regimen. Furthermore research has shown that there 
are important intrinsic reasons that affect people’s decisions to take or not to take the LF 
treatment during MDA. Social norms of compliance, emotional cues, altruism and an individual’s 
personal situation have all been shown to be associated with taking the LF drug [5, 10-12]. 
Understanding some of these intrinsic factors associated with taking the 3-drug regimen as 
opposed to the 2-drug regimen will be important in building a picture of community acceptability. 
As a result, although there may be similarities in some of the questions asked, it is 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 76 of 90 
recommended to call the community survey a “treatment acceptability survey” as opposed to a 
“KAP survey.”  
 
1. Timing 
Coverage surveys are recommended to occur as soon as possible after MDA occurs in order to 
reduce recall bias in respondents [13]. In order to allow some space between the clinical 
assessment and monitoring of AE in the community trial as well as some time for the effects of 
ivermectin to become apparent, the community survey should occur at least two weeks after the 
completion of the drug administration, and preferably no later than one month afterwards.  
 
Once the safety trial is completed, the community survey can begin. 
 
2. Questionnaire Development 
Questionnaire development is based on previous LF surveys carried out in Indonesia and in 
Papua New Guinea. In addition, known influences based on the most recent literature on 
compliance will be included in the acceptability survey, where appropriate.  
 
Questionnaires will be written in English and translated into the local language. In order to test 
the understandability of the questionnaire with the local population, the enumerators will give 
advice on the vocabulary used during the training and a small sample of individuals will be 
administered the questionnaire prior to survey implementation. At the end of this testing, these 
respondents will be asked to comment on the questions themselves, whether they were clear 
and the language was appropriate. Changes will be made if needed. The questionnaire will then 
be translated back into English.  
 
3. Sampling Frame 
In estimating the sample size for the acceptability survey, one of the challenges we have is that 
we do not know the estimated acceptability rates in people who have received the 3-drug 
regimen. From recent research in Indonesia (A. Krentel, personal experience) in low (MF 
rate=1%) and high prevalence (MF=8%) areas, we know that acceptability with DEC+ALB, as 
measured in the intent to take the LF drugs again, was measured as 79% and 82% respectively.  
 
Because we do not have a 3-drug acceptability rate, we cannot estimate the difference we might 
expect in between the regimen groups. As a result, this survey will create preliminary data, 
estimating the difference in acceptability rates between those individuals receiving the 2 and 3 
drug regimens as well as the difference in rates between those with positive MF rates at the 
start of the safety trial and those who are MF negative. This survey will provide insight into 
possible trends in acceptability and will inform if further investigation is needed.  
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 77 of 90 
In each country, one research site will be identified for the acceptability survey. 100 individuals 
will be interviewed in each of the four strata (2-drug, 3-drug, MF(-), MF(+)), totaling 400 
individuals in each of the 5 countries: 
 
 
Strata 1: n=100 receiving the 2-drug regimen, MF (+) and antigen (+) 
 
Strata 2: n=100 receiving the 2-drug regiment, MF (-) 
 
Strata 3: n=100, receiving the 3-drug regimen, MF (+) and antigen (+) 
 
Strata 4: n=100, receiving the 3-drug regimen, MF (-) 
 
In the low prevalence areas we recognize that it will not be possible to identify 200 MF (+) 
individuals, so in these locations we will oversample those who are MF positive until we have 
identified all of the individuals and the remaining sample will be filled with antigen positive 
individuals. For the purposes of analysis, we expect to combine the results from all five-research 
countries to increase the overall power in the sample. 
 
In order to identify the participants in the sample, once the safety trials have been completed, 
the enrollment lists will be sent to the statistician at Washington University in St. Louis who will 
select individuals randomly according to the 4 stratums. Only one member of each household 
will be accepted for the survey. In addition, convenience factors will be taken into consideration, 
particularly where certain areas are remote and may be difficult for enumerators to reach in a 
timely manner.   
 
Enumerators will travel to the house to interview the identified individual. Data will be collected 
using the REDCap system. Where individuals are not present at the time of the enumerator’s 
visit, the enumerator can make a second attempt to reach them. After that, if they continue to 
remain unavailable, another randomly selected individual in the same treatment arm can 
replace them. 
 
Because of the nature of the research questions, those individuals about the age of 14 years will 
be included in the survey sample. In addition, chronic manifestations of the disease begin to 
show at adolescence, so personal experience with LF may begin at this age [14]. 
 
4. Outcome of Interest: 
Acceptability of the 3-drug therapy will be measured in a composite score from the following 
questions:  
- 
Intention to take LF drugs in the future measured on a 5-point scale ranging from “I will 
never take this drug again” to “I will definitely take this drug again.” (Adapted from Liau 
and Zimet 2001 ) 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 78 of 90 
- 
Willingness to encourage other family members to take the LF drug, if offered in the 
future measured as a 5-point scale ranging from “I will never encourage my family to 
take the LF drugs” to “I will definitely encourage my family to take the LF drugs.” 
- 
Overall feeling about the LF elimination program as a 5-point scale ranging from “Very 
negative” to “Very positive” 
- 
Perception of health since taking the LF drugs as a 5-point scale ranging from 
“Considerably worse” to “greatly improved” 
- 
In addition to the scoring, each outcome can be converted to a binary variable for 
multivariate modeling. 
 
- 
Inputs / Exposure variables:  
- 
SES data 
- 
Data from safety trial (clinical presence of AE, MF rate, household information) 
- 
Treatment arm (2-drug versus 3-drug) 
- 
Informed about the treatment before receiving the drug (e.g. did they receive any 
information) 
- 
Belief in the efficacy of the treatment to eliminate / prevent LF (e.g. believe that the 
drugs work to prevent / treat LF) 
- 
Belief in the efficacy of the treatment to treat scabies (e.g. believe that the drugs work to 
treat scabies) 
- 
Belief in the efficacy of the treatment to treat other intestinal worms (e.g. believe that the 
drugs work to treat worms) 
- 
Knowledge of the ‘positive’ component of AE (e.g. occur because the medicine is 
working) 
- 
Perception of AE (e.g. none, mild, moderate, severe) 
- 
Understanding that taking LF medicine is good for promoting health 
- 
Knowledge that mosquitoes transmit LF 
- 
Perception that the rest of the family/ household would take the LF drugs, if offered in 
the future (yes/no) 
- 
Belief that the drug distributors are doing a good job (using a 10-point scale) 
- 
Perceptions of the drugs (e.g. safe, neutral, dangerous) 
- 
Components of the drugs (e.g. number, size, taste of pills) 
- 
Emotions surrounding LF treatment (e.g. how does taking LF treatment make you feel?) 
 
6. Analysis 
For the data cleaning and data reduction, the following steps will be performed: 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 79 of 90 
- 
Check response bias 
- 
Clean the raw data set (range check, consistency checks)  
- 
Transfer corrected data set to STATA statistical software (Stata Corporation, College 
Station, Texas). 
- 
Group continuous variables into categorical variables, namely age. Recode certain 
variables where needed. 
 
For the analysis, a descriptive analysis of the whole dataset will be prepared. The data from the 
community survey will be linked to the safety trial within the REDCap system.  
 
Likert scales will be analyzed as both dichotomous and as continuous variables.  
 
For both of the predictors of acceptability (drug regimen and presence of MF) logistic regression 
models will be created. Presence of AE as measured in the clinical surveys will be considered in 
the analysis, as will subjective perceptions of AE.  
 
 
E. Focus Group Discussion 
 
1. Timing 
The focus group discussions will take place at the same time as the community survey, in the 
same communities. 
 
2. Sampling Frame 
For the focus group discussions, we will identify persons from specific groups of people:  
women of reproductive age, young people, men and community health workers. The rationale 
behind the selection of each of these groups is related to the prevailing evidence of their 
participation in MDA in the literature. Women of reproductive age often do not comply with 
treatment because they are either pregnant or breastfeeding, however they are often the 
gatekeepers for health in the household and ensure members of their household takes the 
treatment when offered. Men and young people have been known to be less compliant with 
MDA and so understanding their perceptions about the 3-drug regimen, MDA in general and 
soliciting their advice about how best to promote and reach their communities will be 
informative. Finally, as community health workers are usually the persons responsible for 
distributing the drug at the community level, understanding their perspectives on DOT, AE and 
messaging for the 3-drug regimen is important.  
 
For the FGD, women, young men and men will be selected from the cohort of individuals 
receiving the 3-drug regimen.  
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 80 of 90 
3. Range of issues to explore include:  
- 
How is LF elimination different / similar from the other health programs in their village? 
- 
What are the health benefits from taking the treatment? 
- 
What are the social benefits from taking the treatment? 
- 
Do people like to take the pills in front of the distributor? Why or why not?  
- 
How do you feel about the number of pills that you have to take? 
- 
Why don’t people want to take it? 
- 
Did you have any side effects after you took the drugs (positive or negative)? How did 
you feel about them? 
- 
What suggestions do you have to promote MDA to their community? Household? 
- 
Are there any specific messages you would recommend to us? 
 
4. Analysis 
Recorded focus group discussions will be transcribed word for word in the local language. They 
will be translated into English. A second researcher with knowledge of English and the local 
language will check translation, sampling portions of each transcript and back translating them 
from English to the local language to check the reliability of the translation. The researchers will 
read through each transcript, recording emergent themes in an Excel matrix. NVivo will be used 
to assess trends and patterns in the interview transcripts.   
 
 
F. In depth interviews with key informants 
 
1. Timing 
The key informant interviews will take place at the same time as the community survey, in the 
same communities. 
 
2. Sampling Frame 
A purposive sampling frame will be used, with individuals identified based on their leadership 
and cultural position with the village as well as their involvement with LF elimination and with the 
community trial. With this in mind, a range of 8-10 individuals will be included in the sample. In 
order to understand the acceptability of administering the 3-drug regimen, individuals to be 
interviewed would need to be those persons who are either directly involved with LF activities in 
the village or who would be involved in MDA in the future. Suggestions include community 
and/or religious leaders, community health workers, teachers.  
 
3. Range of issues to explore include: 
- 
What are the advantages of the 3-drug therapy in MDA? Disadvantages? 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 81 of 90 
- 
What opportunities do they see in the administration of the 3-drug therapy, versus the 2-
drug therapy? 
- 
What concerns or challenges do they see in the administration of the 3-drug therapy, 
versus the 2-drug therapy? 
- 
How do they feel about the number of pills that the community is asked to take?  
- 
How do they feel about the side effects people might have / have? 
- 
What suggestions do they have to promote MDA in this village? This province? The 
country? What messages would they recommend using? 
- 
Which groups of people do they think will be difficult to reach with future MDA? Why? 
Any advice to approach them? 
 
4. Analysis 
Recorded interviews will be transcribed word for word in the local language. They will be 
translated into English. A second researcher with knowledge of English and the local language 
will check translation, sampling portions of each transcript and back translating them from 
English to the local language to check the reliability of the translation. The researcher will read 
through each transcript, recording emergent themes in an Excel matrix. NVivo will be used to 
assess trends and patterns in the interview transcripts.   
 
 
G. Ethical Considerations 
 
1. Community Survey 
Ethical approval will be obtained from the local national research institution in each country as 
well as Washington University in St. Louis, Case Western University and Bruyère Research 
Institute.  
 
Prior to giving consent to participate, the enumerator will read out the information sheet in the 
local language containing the aim of the survey, the length of time it is expected to take (15 
minutes) as well as the protection of confidentiality for each respondent. Following this, each 
respondent will be asked to sign the informed consent form and where respondents are 
illiterate, a mark can be made. The enumerator will indicate that informed consent has been 
given.  Age of eligible respondents is 14 years of age and older. For those aged 14 – 18 years, 
parental consent will be sought and provided on the informed consent form before the interview 
can begin. All forms will remain with the research team and will not contain any personal 
information other than the individual’s signature.  
 
At the end of the interview, each respondent will be given an information sheet with the principal 
investigator’s contact details, should there be any questions. With this sheet, the respondent will 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 82 of 90 
also receive a brief information sheet on lymphatic filariasis, the mass drug administration and 
who is eligible for treatment.  
 
The data will be stored on Washington University servers during the duration of the study. After 
the study ends, electronic copies of the de-identified datasets will be kept by the PI indefinitely. 
 
2. Focus Group discussions 
Ethical approval will be obtained from the local national research institution in each country as 
well as Washington University in St. Louis, Case Western University and Bruyère Research 
Institute.  
 
The interviewer will read the informed consent form to each person participating in the focus 
group discussion. The respondents will be asked to each sign an informed consent form for their 
participation. All interviews will be recorded with the permission of the respondent. Where 
permission is not granted, the interviewer will ask to take notes throughout the interview.  
 
Any identifying information (name, address) will not be recorded. Individuals will not be identified 
in the transcripts or in the recordings and their anonymity will be maintained in all reporting and 
in the manuscripts. Transcripts of the interviews will remain with the research team. 
 
The data will be stored with the PI, under password protection. After the study ends, electronic 
copies of the de-identified datasets will be kept by the PI indefinitely. 
 
 
3. In-depth interviews with key informants 
Ethical approval will be obtained from the local national research institution in each country as 
well as Washington University in St. Louis, Case Western University and Bruyère Research 
Institute.  
 
The interviewer will read the informed consent form to each person participating in the interview. 
The respondents will be asked to sign an informed consent form for their participation. All 
interviews will be recorded with the permission of the respondent. Where permission is not 
granted, the interviewer will ask to take notes throughout the interview.  
 
Any identifying information (name, address) will not be recorded and the identity of the 
respondent will be kept confidential in reporting. Transcripts of the interviews will remain with 
the research team. The data will be stored with the PI under password protection. After the 
study ends, electronic copies of the de-identified datasets will be kept by the PI indefinitely.  
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 83 of 90 
References 
 
1. 
Krentel A, Fischer PU, Weil GJ. A Review of Factors That Influence Individual 
Compliance with Mass Drug Administration for Elimination of Lymphatic Filariasis. PLoS 
neglected tropical diseases. 2013;7(11):e2447. Epub November 21, 2013. doi: 
doi:10.1371/journal.pntd.0002447. 
2. 
Babu BV, Babu GR. Coverage of, and compliance with, mass drug administration under 
the programme to eliminate lymphatic filariasis in India: a systematic review. 
Transactions of the Royal Society of Tropical Medicine and Hygiene. 2014;108(9):538-
49. Epub 2014/04/15. doi: 10.1093/trstmh/tru057. PubMed PMID: 24728444. 
3. 
Thomsen E, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, et al. Efficacy, Safety, 
and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and 
Ivermectin for Treatment of Bancroftian Filariasis. Clinical Infectious Diseases. 
2016;62(3):334-41. doi: 10.1093/cid/civ882. 
4. 
Ramaiah KD, Kumar KNV, Hosein E, Krishnamoorthy P, Augustin DJ, Snehalatha KS, et 
al. A campaign of 'communication for behavioural impact' to improve mass drug 
administrations against lymphatic filariasis: structure, implementation and impact on 
people's knowledge and treatment coverage. Annals of Tropical Medicine and 
Parasitology. 2006;100(4):345-61. doi: 10.1179/136485906x105598. PubMed PMID: 
WOS:000238656500007. 
5. 
Babu BV, Suchismita M. Mass drug administration under the programme to eliminate 
lymphatic filariasis in Orissa, India: a mixed-methods study to identify factors associated 
with compliance and non-compliance. Transactions of the Royal Society of Tropical 
Medicine and Hygiene. 2008;102(12):1207-13. doi: 
http://dx.doi.org/10.1016/j.trstmh.2008.05.023. PubMed PMID: 20083317171. 
6. 
Bockarie MJ, Tisch DJ, Kastens W, Alexander NDE, Dimber Z, Bockarie F, et al. Mass 
treatment to eliminate filariasis in Papua New Guinea. New England Journal of Medicine. 
2002;347(23):1841-8. 
7. 
Krentel A, Fischer P, Manoempil P, Supali T, Servais G, Rückert P. Using knowledge, 
attitudes and practice [KAP] surveys on lymphatic filariasis to prepare a health promotion 
campaign for mass drug administration in Alor District, Indonesia. Tropical Medicine & 
International Health. 2006;11(11):1731-40. 
8. 
Cantey PT, Rao G, Rout J, Fox LM. Predictors of compliance with a mass drug 
administration programme for lymphatic filariasis in Orissa State, India 2008. Tropical 
Medicine and International Health. 2010;15(2):224-31. doi: 
http://dx.doi.org/10.1111/j.1365-3156.2009.02443.x. PubMed PMID: 2010046751. 
9. 
Mathieu E, Lammie PJ, Radday J, Beach MJ, Streit T, Wendt J, et al. Factors associated 
with participation in a campaign of mass treatment against lymphatic filariasis, in 
Leogane, Haiti. Annals of Tropical Medicine and Parasitology. 2004;98(7):703-14. doi: 
10.1179/000349804x3135. PubMed PMID: WOS:000224651200006. 
10. 
Krentel A, Aunger R. Causal chain mapping: a novel method to analyse treatment 
compliance decisions relating to lymphatic filariasis elimination in Alor, Indonesia. Health 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 84 of 90 
Policy Plan. 2011. Epub 2011/06/30. doi: 10.1093/heapol/czr048. PubMed PMID: 
21712348. 
11. 
Fraser M, Taleo G, Taleo F, Yaviong J, Amos M, Babu M, et al. Evaluation of the 
program to eliminate lymphatic filariasis in Vanuatu following two years of mass drug 
administration implementation: results and methodologic approach. The American 
journal of tropical medicine and hygiene. 2005;73(4):753-8. 
12. 
Nandha B, Sadanandane C, Jambulingam P, Das P. Delivery strategy of mass annual 
single dose DEC administration to eliminate lymphatic filariasis in the urban areas of 
Pondicherry, South India: 5 years of experience. Filaria J. 2007;6:7. Epub 2007/08/28. 
doi: 10.1186/1475-2883-6-7. PubMed PMID: 17718908; PubMed Central PMCID: 
PMC2020462. 
13. 
Worrell C, Mathieu E. Drug Coverage Surveys for Neglected Tropical Diseases: 10 
Years of Field Experience. American Journal of Tropical Medicine and Hygiene. 
2012;87(2):216-22. 
14. 
Witt C, Ottesen EA. Lymphatic filariasis: an infection of childhood. Tropical Medicine & 
International Health. 2001;6(8):582-606. 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 85 of 90 
Information Sheet And Informed Consent For Community Survey 
 
 
As part of the “Community Based Safety Study of 2-drug versus 3-drug Therapy for Lymphatic 
Filariasis” that just happened in your area last month, we are asking some people who 
participated in that study to take part in a short survey so that we can understand more about 
lymphatic filariasis [or local name], the drugs used in the safety trial and health in general. Your 
name was selected randomly from the list of people who participated in that safety trial. 
 
It is important that you understand why we are doing this survey, so please read this information 
sheet carefully. If you have any more questions, ask the interviewer and they will try to answer 
them for you.  
 
We are interested in the experiences people had participating in the safety trial and what they 
understand about lymphatic filariasis [or local name]. We would like to talk to about 400 people 
in this area so that we can understand better how people felt about taking the LF drugs. Your 
participation is entirely voluntary and you are under no obligation to participate. Whether or not 
you choose to participate, your status and access to health care will not be affected in any way.  
 
If you do choose to help with this study, we will only need about 15 minutes of your time to ask 
you some questions. At any time during this discussion, you are free to stop and withdraw from 
the study. You do not have to give the interviewer a reason. 
 
The information that you provide during our discussion will be completely confidential.  We will 
record your answers on a tablet. All digital files will remain with the main investigator and will be 
password protected. 
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 86 of 90 
Consent for Community Survey 
 
 
I have read the information sheet provided or it has been read to me concerning this study and I 
understand what will be required of me if I participate in this study, which will be a verbal 
interview and discussion. 
 
My questions regarding this study have been answered by: _________________. 
 
I understand that at any time I may withdraw from this study without giving a reason and without 
having any effect on my access to health care. 
 
I agree to take part in this study. 
 
 
Signature of the respondent: ______________________________________ 
 
Signature of a witness: __________________________________________ 
 
 
Signature of the enumerator to indicate that the informed consent has been read and the 
information sheet given to the respondent:  __________________________________ 
  
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 87 of 90 
Information sheet and informed consent for in depth interviews with key 
informant 
 
 
As part of the “Community Based Safety Study of 2-drug versus 3-drug Therapy for Lymphatic 
Filariasis” that just happened in your area last month, we are asking some people who 
participated in that study to take part in a verbal discussion so that we can understand more 
about lymphatic filariasis [or local name], the drugs used in the safety trial and health in general.  
It is important that you understand why we are doing this survey, so please read this information 
sheet carefully. If you have any more questions, ask the interviewer and they will try to answer 
them for you.  
 
We are interested in the experiences people had participating in the safety trial and what they 
understand about lymphatic filariasis [or local name]. We would like to talk to about 8 people in 
this area so that we can understand better how people felt about taking the LF drugs. Your 
participation is entirely voluntary and you are under no obligation to participate. Whether or not 
you choose to participate, your status and access to health care will not be affected in any way.  
 
If you do choose to help with this study, we will only need about one hour of your time to ask 
you some questions and to discuss informally. At any time during this discussion, you are free to 
stop and withdraw from the study. You do not have to give the interviewer a reason. 
 
The information that you provide during our discussion will be completely confidential and we 
will not even write down your name or address.  We will take some written notes during our 
discussion and if you agree, we may also record the interview using a digital recorder so that it 
will be easier to remember what we discussed. All digital files will remain with the main 
investigator and your name and address will not be recorded. We will write down the 
conversation and store it safely, with a password. Other researchers may ask to look at our 
discussion together, and we may share it with them, provided that they respect the same rules 
of confidentiality.  
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 88 of 90 
Consent for in depth interviews with key informant 
 
 
I have read the information sheet provided or it has been read to me concerning this study and I 
understand what will be required of me if I participate in this study, which will be a verbal 
interview and discussion. 
 
My questions regarding this study have been answered by: _________________. 
 
I understand that at any time I may withdraw from this study without giving a reason and without 
having any effect on my access to health care. 
 
I agree to take part in this study. 
 
 
Signature of the respondent: ______________________________________ 
 
Signature of a witness: __________________________________________ 
 
 
Signature of the enumerator to indicate that the informed consent has been read and the 
information sheet given to the respondent:  __________________________________ 
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 89 of 90 
Information Sheet And Informed Consent For Focus Group Discussion 
Participants 
 
 
As part of the “Community Based Safety Study of 2-drug versus 3-drug Therapy for Lymphatic 
Filariasis” that just happened in your area last month, we are asking some people who 
participated in that study to take part in a focus group discussion so that we can understand 
more about lymphatic filariasis [or local name], the drugs used in the safety trial and health in 
general.  It is important that you understand why we are doing this survey, so please read this 
information sheet carefully. If you have any more questions, ask the interviewer and they will try 
to answer them for you.  
 
We are interested in the experiences people had participating in the safety trial and what they 
understand about lymphatic filariasis [or local name]. We would like to talk to about 4 groups of 
people in this area so that we can understand better how people felt about taking the LF drugs. 
Your participation is entirely voluntary and you are under no obligation to participate. Whether or 
not you choose to participate, your status and access to health care will not be affected in any 
way.  
 
If you do choose to help with this study, we will only need about one hour of your time to ask 
you some questions and to discuss informally. At any time during this discussion, you are free to 
stop and withdraw from the study. You do not have to give the interviewer a reason. 
 
The information that you provide during our discussion will be completely confidential and we 
will not even write down your name or address.  We will take some written notes during our 
discussion and if you agree, we may also record the interview using a digital recorder so that it 
will be easier to remember what we discussed. All digital files will remain with the main 
investigator and your name and address will not be recorded. We will write down the 
conversation and store it safely, with a password. Other researchers may ask to look at our 
discussion together, and we may share it with them, provided that they respect the same rules 
of confidentiality.  
 
 
 

APPENDIX 7 TREATMENT ACCEPTABILITY STUDY PROTOCOL 
 
 
 
DOLF_IDA_Papua New Guinea_Protocol v2.1_05Jul17 
 
 
 
 
Page 90 of 90 
Consent for Focus Group Discussion Participants 
 
 
I have read the information sheet provided or it has been read to me concerning this study and I 
understand what will be required of me if I participate in this study, which will be a verbal 
interview and group discussion. 
 
My questions regarding this study have been answered by: _________________. 
 
I understand that at any time I may withdraw from this study without giving a reason and without 
having any effect on my access to health care. 
 
I agree to take part in this study. 
 
 
Signature of the respondent: ______________________________________ 
 
Signature of a witness: __________________________________________ 
 
 
Signature of the enumerator to indicate that the informed consent has been read and the 
information sheet given to the respondent:  __________________________________