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

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A community based study to compare the safety, efficacy and acceptability of 
a triple drug regimen (Ivermectin, Diethylcarbamazine and Albendazole) with 
a two-drug regimen (Diethylcarbamazine and Albendazole) for lymphatic 
filariasis elimination programme 
 
 
 
 
Vector Control Research Centre  
(Indian Council of Medical Research) 
Indira Nagar 
Puducherry – 605006, India 
 
 
 
In collaboration with 
 
National Vector Borne Disease Control Programme (NVBDCP) 
Delhi and Karnataka 
 
 
Duration of the study 
July 2016 – March 2018 
 
 
Funding agency 
Neglected Tropical Diseases Support Center (NTD-SC) 
Task Force for Global Health 
325 Swanton Way, Decatur GA 30030 
Tel:  404.687.5621, Fax: 404.371.1138 
 
(Revised on 20 September 2017 for Phase II study – effectiveness and efficacy) 
 
 
 

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INVESTIGATORS 
 
Principal Investigator 
 
1. 
Dr. P. Jambulingam 
Scientist “G” and Director 
Vector Control Research Centre 
Pondicherry 
Co-Principal Investigator 
 
2. 
Dr. Vijesh Sreedhar Kuttiatt 
Scientist “E”  
Vector Control Research Centre 
Pondicherry 
 
 
Co-Investigators 
3. Dr. R. J. L. De Britto 
Scientist “F”  
Vector Control Research Centre 
Pondicherry 
 
 
4. Dr. S. Subramanian 
Scientist “F”  
Vector Control Research Centre 
Pondicherry 
 
5. Ms. A. Srividya  
Scientist “D”  
Vector Control Research Centre 
Pondicherry 
 
6. Ms. B. Nandha  
Scientist “B”  
Vector Control Research Centre 
Pondicherry 
 
7. Dr. K. Krishnamoorthy 
Consultant (Rtd. Scientist “G”) 
Vector Control Research Centre 
Pondicherry 
 
Project Co-ordination:  Indian Council of Medical Research, New Delhi 
 
Collaboration:  National Vector Borne Disease Control Programme (NVBDCP) 
Delhi and Karnataka 
 
 

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Table of contents 
Page No. 
LIST OF ABBREVIATIONS ........................................................................................................................ 4 
1. PROTOCOL SUMMARY ................................................................................................................ 5 
2. BACKGROUND AND RATIONALE ................................................................................................. 7 
3. OBJECTIVES .................................................................................................................................. 8 
4. STUDY DESIGN ............................................................................................................................. 8 
4.1 
Selection of study sites ....................................................................................................... 9 
4.2 
Preparatory activities ....................................................................................................... 10 
4.3 
Pre-treatment assessments ............................................................................................. 11 
4.4 
Drug administration ......................................................................................................... 12 
4.5 
Rapid Response for management of adverse events ...................................................... 12 
4.6 
Early post-treatment assessment .................................................................................... 12 
4.7 
Data safety review board (DSRB) ..................................................................................... 14 
4.8 
Acceptability of triple drug regimen ................................................................................ 14 
4.9 
One year post-MDA assessment ...................................................................................... 15 
4.10 
Treatment ......................................................................................................................... 16 
4.11 
Data Collection ................................................................................................................. 16 
5. STATISTICAL CONSIDERATIONS ................................................................................................ 16 
5.1 
Safety data ........................................................................................................................ 16 
5.2 
Effectiveness ..................................................................................................................... 17 
5.3 
Efficacy .............................................................................................................................. 17 
5.4 
Assessing prevalence of antibody .................................................................................... 17 
5.5 
Follow-up of pre-MDA positives ...................................................................................... 18 
6. BIOHAZARD CONTAINMENT ..................................................................................................... 18 
7. DISSEMINATION ACTIVITIES ...................................................................................................... 18 
8. TEAM COMPOSITION AND WORK PLAN ................................................................................... 18 
10. BUDGET ...................................................................................................................................... 22 
11. REFERENCES ............................................................................................................................... 23 
Appendix 1a 
Thomsen et al (2015) Clinical Infectious Disease  
 
 
 
Appendix 1b 
Gyapong et al (2005) Expert Opinion Pharmacotherapy  
 
 
Appendix 2 
Background on study drugs 
 
 
 
 
 
 
Appendix 3 
Study flow 
 
 
 
 
 
 
 
 
Appendix 4 
Information sheet and consent form 
 
 
 
 
Appendix 5 
Participant enrolment form 
 
 
 
 
 
 
Appendix 6 
Participant monitoring form 
 
 
 
 
 
 
Appendix 6a 
Guide for assigning adverse event severity grades 1-4 
 
 
 
Appendix 7 
Adverse event evaluation and report form 
 
 
 
 
Appendix 7a 
Instructions for reporting severe adverse events  
 
 
 
Appendix 8 
Medical monitoring activities 
Appendix 9        Treatment acceptability study guidelines 

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LIST OF ABBREVIATIONS 
Ab 
Antibody 
AE 
Adverse Event/Adverse Experience 
AEERF 
Adverse Event Evaluation and Report Form 
Ag 
Antigenemia 
ALB 
Albendazole 
CRF/eCRF 
Case Report Form also referred to as eCRF (electronic Case Report Form) 
CRO 
Contract Research Organization 
DA 
Diethylcarbamazine and Albendazole (Two Drug Therapy)  
DEC 
Diethylcarbamazine 
DOT 
Directly Observed Treatment 
DSRB 
Data Safety Review Board  
IHEC 
Institutional Human Ethics Committee  
EDC 
Electronic Data Capture 
FTS 
Filariasis Test Strip 
GPELF 
Global Programme to Eliminate Lymphatic Filariasis 
GPS 
Global Positioning System 
ICF 
Informed Consent Form 
ICMR 
Indian Council of Medical Research 
IDA 
Ivermectin, Diethylcarbamazine and Albendazole (Triple Drug Therapy) 
IVM 
Ivermectin 
KAP 
Knowledge, Attitude and Practices 
LF 
Lymphatic Filariasis 
MDA 
Mass Drug Administration 
Mf 
Microfilaria(e) 
NTD 
Neglected Tropical Diseases 
SAE 
Serious Adverse Event/Experience 
SOP 
Standard Operating Procedure 
TAS 
Transmission Assessment Survey 
VCRC 
Vector Control Research Centre 
WHO 
World Health Organization 
 
 
 

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1. PROTOCOL SUMMARY 
 
Study Title 
A community based study to compare the safety, efficacy and 
acceptability of a triple drug regimen (Ivermectin, Diethylcarbamazine 
and Albendazole) with a two-drug regimen (Diethylcarbamazine and 
Albendazole) for lymphatic filariasis elimination programme 
Type of Study 
Community based open intervention study  
Population 
IDA/ Triple Drug Arm: participants more than or equal to 5 years of age 
and above 15 Kg body weight 
DA/ Dual Drug Arm (DA): participants more than or equal to 2 years of 
age 
Number of Treated 
Areas 
Selected communities in Yadgir district, Karnataka based on the results 
of Mf survey in sentinel and spot-check sites 
Duration of participation 
of community members 
Single treatment and daily monitoring of adverse events through Day 7 
Follow up for infection at 1 year post treatment.   
Study Drugs 
Arm 1   (Co-administration of three drugs) 
Ivermectin (3 mg tablets) - 200 µg /kg 
Diethylcarbamazine (100 mg tablets) - 6mg/kg 
Albendazole (400 mg tablets) - flat dose of 400 mg 
Arm2    (Co-administration of two drugs)  
              Diethylcarbamazine (100 mg tablets) - 6mg/kg 
              Albendazole (400 mg tablets) - flat dose of 400 mg 
 
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. 
 To compare the efficacy of IDA vs. DA administered in communities 
for clearance of Mf and filarial antigenemia (Ag) in cohort and 
effectiveness (prevalence) in community settings. 
 To assess and compare the prevalence of antibody (Ab) with that of 
Ag and Mf  
 To assess the presence and intensity of filarial infection on the 
frequency and severity of adverse events. 
 To compare community acceptance of MDA with IDA vs. DA. 
 
 
 

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General flow diagram 
 
 
 
Mf-survey for site selection 
 
Enrolment, Antigenemia & Mf 
Survey and Drug Administration 
Community acceptability survey 
Site selection (matching or 
randomization) for DA (n≥4000) and 
IDA (n≥4000) 
Post 12 months antigenemia, 
antibody and Mf survey 
Clinical monitoring and AE/SAE 
Assessment 

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2. BACKGROUND AND RATIONALE 
 
In 2000, WHO launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to eliminate 
lymphatic filariasis as a public health problem by 2020[1]. The National Health Policy of India2002 set 
the goal of achieving elimination of lymphatic filariasis (LF) in the country by 2015. The National 
Vector-Borne Disease Control Programme (NVBDCP) launched the programme for elimination of LF 
(PELF) in 2004 and adopted the WHO recommended two-drug policy of co-administration of 
diethylcarbamazine (DEC) and albendazole in 2007 [2]. The programme’s current strategy to interrupt 
transmission relies on annual single dose mass drug administration (MDA) of DEC and albendazole 
(DA) given to the eligible population in endemic districts [3]. Disability alleviation and morbidity 
prevention activities include home based management of lymphoedema and surgery for hydrocele.  
 
The programme has made significant progress with Mf levels below 1% in 222 of 255 implementation 
units (IUs) in 2015. Fifty-three IUs have already cleared TAS-1 while 65 IUs will conduct TAS1 and 
another 4 IUs are planning TAS2. Next year’s round of MDA will target133 IUs. Despite this success in 
the majority of districts, microfilaria (Mf) levels have remained >1% in 31 “hard-core” foci (districts). 
The programme has been looking for additional tools to accelerate interruption of transmission in 
these districts and ensure that it meets the goal of elimination by 2020. 
 
Results of a pilot study [4] (Appendix 1a) now confirmed with results from a clinical trial in Papua New 
Guinea (PNG) showed that triple drug therapy [ivermectin, DEC, albendazole (IDA)] is superior to the 
currently recommended two-drug regimen [5] (Appendix 1b) used in the global programme to 
eliminate LF (GPELF) outside of sub-Saharan Africa (DEC, albendazole [DA]). A single dose of IDA 
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 
amicrofilaraemic at that time. These results suggest that IDA permanently sterilizes adult filarial 
worms. Many people treated in these studies experienced transient systemic adverse events (AE) 
commonly associated with DEC or ivermectin treatment of filariasis, and AEs were more frequent after 
IDA than after DA.  However, no serious adverse events (SAE) were observed in these trials or in a trial 
that is currently in progress in the West African country of Côte d’Ivoire. No information is available 
on the frequency or type of AEs following IDA treatment of uninfected persons, but this is expected 
to be low. The dramatic reduction and sustained decrease of mf (zero at 1 year) along with the safety 
profile seen in the PNG studies suggest that the triple drug therapy may be a useful tool for eliminating 
LF in districts in India where Mf rates have remained > 1% following MDA with the standard DA 
regimen. Ivermectin also provides additional benefits for recipients, because it complements the 

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deworming effect of albendazole and because of its effect against lice and scabies and mites. 
Pharmacokinetic studies done in PNG indicated no significant effect of ivermectin on DEC or 
albendazole drug levels [4] (Appendix 1a). 
 
IDA’s potential to accelerate LF elimination in India and around the world has stimulated WHO’s 
interest as well as academic experts and the donor community. Although the studies cited above have 
clearly demonstrated the superiority of the IDA regimen for clearing W. bancrofti mf from the blood, 
more safety and efficacy data are needed before IDA can be rolled out on a large scale as an MDA 
regimen for India. WHO recommends a best practice called “cohort event monitoring” for 
demonstrating safety of new drug regimens for public health program use. Establishing safety for MDA 
through such methodology requires pre and post treatment assessment from at least 10,000 people 
treated across multiple settings (minimum 4000 from India). The current two-drug MDA regimens 
were studied in closely monitored community trials in a similar manner before they were endorsed 
for widespread use in the GPELF. An expanded discussion of mechanisms of action and side effects of 
ivermectin, DEC and albendazole is provided in Appendix 2. It is therefore proposed to conduct a study 
to acquire similar safety data in India before the new IDA regimen can be used in those districts where 
Mf levels have remained > 1% with the following objectives: 
 
3. OBJECTIVES 
 
 
i. 
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. 
ii. 
To compare the efficacy of IDA vs. DA administered in communities for clearance of Mf and 
filarial antigenemia (Ag) in cohort and effectiveness (prevalence) in community settings. 
iii. 
To assess and compare the prevalence of antibody (Ab) with that of Ag and Mf   
iv. 
To assess the presence and intensity of filarial infection on the frequency and severity of 
adverse events. 
v. 
To compare community acceptance of MDA with IDA vs. DA. 
 
4. STUDY DESIGN 
 
This 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 design is provided in Appendix 3. 
 

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4.1 
Selection of study sites 
 
The study will be conducted in Yadgir district (carved out of Gulbarga district) in Karnataka state (Map), 
where 12 rounds of MDA have been conducted since 2004. Mf prevalence has been shown to be 
persistently above 1% during annual surveys conducted by the programme. Impact assessment 
conducted in 2014 and 2015 (prior to 11 and 12th round of MDA) in the sentinel and spot check sites 
(villages) have shown many sites with >1% Mf prevalence (Table 1). As the last MDA took place in Dec 
2015 after the impact assessment, it is necessary to assess current prevalence of microfilaraemia to 
select study sites for the present study. The Mf survey will be carried out jointly by the research team 
and State NVBDCP as a part of impact assessment of the programme in sentinel sites as well as spot-
check sites.  
The minimum sample size required is 550 for a community with a population of 2000. The sample size 
is calculated based on an Mf prevalence of 2% with an error margin of 1% (expected prevalence is in 
the range of 1-3%) and 95% confidence level. Accordingly, a sample of 600 persons will be selected 
from each community (sentinel/ spot check sites) with a known prevalence of >2% and examined for 
Map. Sites showing >1% Mf prevalence in Yadgir district, Karnataka in 2014 

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Mf.  For this purpose, 60 µl blood will be sampled from each selected and consenting person. This 
way, the sites selected for the study are expected to have prevalence of at least 1% during the 
participant enrolment survey (pre-treatment assessment). In case, if the Mf-prevalence is less than 
1% after pre-treatment assessment, additional sites will be selected based on risk ranking (line listing 
of LF cases) to augment the required minimum sample of 4000 in each arm. 
 
Based on the results of the survey, the study sites will be selected and grouped into two arms of 6000 
population each with comparable Mf prevalence. Sites will be assigned for MDA either by 
randomization or by purposive matching considering the population and prevalence of Mf. If the 
prevalence is homogenous across the sites, each site will be randomly assigned to one of the two 
treatment arms. If the prevalence is heterogeneous, sites will be selected into each arm so that the 
population and prevalence between the two treatment arms are similar. 
 
4.2 
Preparatory activities 
4.2.1 
Social mobilization 
 
Prior to the administration of the drugs intense social mobilization activities (Home Visit #1, Appendix 
3) will be conducted to ensure maximum community participation. Briefly, 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. Print and electronic mass media, people-based and 
folk media will be used in this campaign.  
 
4.2.2 
Participant enrolment 
 
Teams will enumerate and record the GPS coordinates of each house within the selected sites (Home 
Visit #2, Appendix 3). Prior to enumeration, all eligible individuals will sign a written, informed consent 
(Appendix 4). In the event that a subject 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. At this time individuals will be evaluated as to whether they fulfil 
the inclusion/exclusion criteria, before they give informed consent. Each individual in the household 
will be assigned a unique barcode ID and their personal details (name, age and sex) will be entered in 
an enrolment e-form (Appendix 5). Household level information on presence of screened windows, 
and use of bed net will also be collected. Eligible individuals for MDA will be identified and included in 
the study.  
 

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4.2.3 
Eligibility 
 
All participants will provide written informed consent before any study procedures are done. 
Participation of minors (less than 18 years of age) will require their assent and the written consent of 
at least one parent.  
Inclusion criteria 
(i) Age ≥ 5 years and body weight above or equal to 15 Kg, male or female for IDA area and age >2 
years for DA arm. 
(ii) Able to provide informed consent or give parental consent to minors to participate in the study  
(iii) No evidence of severe or systemic co-morbidities except for features of filarial disease  
 
Exclusion criteria 
Participants are ineligible to participate in the study, if they have any of the following: 
(i) 
Age < 5 years (ivermectin is not approved for use in children less than 5 years of age) and age 
5 years and above with body weight below 15 Kg for IDA arm and age < 2 years for DA arm 
(ii) 
Pregnant women (DEC, ivermectin and albendazole are not known to be safe for use during 
pregnancy) and women of child bearing age who cannot recall the timing of their last menstrual 
period or who report that their last menstrual period started 4 weeks or longer before the 
enrolment. 
(iii) Severe chronic illness (for example, chronic renal insufficiency, severe chronic liver disease  or 
any illness that is severe enough to interfere with activities of daily living) 
(iv) History of previous allergy to MDA drugs 
 
4.3 
Pre-treatment assessments 
4.3.1 
Health assessment 
 
Each individual will be questioned whether they have a history or signs of LF (hydrocele, lymphedema, 
lymphangitis, lymphadenitis) and whether they had previous MDA for LF and the responses will be 
recorded in the enrolment form (Appendix 5). They will also be asked whether they recently had taken 
albendazole or ivermectin for other conditions. If participants have any potential physical findings 
associated with LF they will be examined for those conditions. The study population will also have the 
same AE evaluation that will be used following treatment. This will include a questionnaire of 
subjective finding such as headache, joint pain, etc. and presence of scabies. This will establish a 
baseline for later assessment of AEs. Individuals will also be questioned for general health (especially 

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acute illness or serious chronic illness) and on last menstrual period to women participants (to 
establish pregnancy for women of childbearing age). 
 
4.3.2 
Screening for filarial antigenemia and microfilaraemia 
 
All the eligible individuals in the selected community ≥5 years of age will be screened using WHO 
approved point-of care filarial antigen test (with approximately 75 μl blood by finger prick), and those 
with positive antigen test will be visited at night (8- 11 pm) for microfilaria testing (60μl measured 
volume thick blood smear) by finger prick method. Blood collection via finger prick is considered to be 
minimal risk and little or no discomfort is anticipated. The results of the tests will be recorded in the 
enrolment e-form (Appendix 5). 
 
4.4 
Drug administration 
 
The two drug combination is a standard MDA with DEC (6mg/kg) and albendazole (flat dose of 400 
mg). The triple drug administration will consist of a single dose of ivermectin (200 µg /kg) added to 
the standard MDA. The dosage schedule for the two drug standard MDA is given in Table 2 and 
ivermectin will be based on body weight (Table 3). Study personnel will directly administer the drugs. 
The study population will be encouraged to have food before swallowing the medicine (without 
chewing the tablets) with a glass of water. Vomited doses will be replaced. The study population will 
be informed about the active follow-ups for adverse events at 12h and 48h, and for passive evaluation 
up to day 7 following treatment. The drugs (quality assured) will be supplied by the companies 
donating for LF elimination programme and the requirement is shown in Table 4. 
 
4.5 
Rapid Response for management of adverse events 
 
Medical teams will be located at strategic places. People and the drug administrators will be informed 
about the availability of such teams including the mobile phone numbers 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 mopping up operations. Each team will have an ambulance 
with a medical officer, a staff nurse and a pharmacist and essential life-saving drugs. 
 
4.6 
Early post-treatment assessment 
4.6.1 
Tiered Adverse Events Monitoring and Management 
 
DEC, ivermectin and albendazole are known to produce adverse events in some treated persons and 
are self-limiting. These events can be non-specific drug related reactions which include headache, 

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anorexia, nausea, abdominal pain, vomiting, dizziness, weakness or lethargy. These symptoms begin 
within 1-2 hours of taking the drug and persist for a few hours and may disappear spontaneously with 
or without symptomatic treatment. Specific parasite related allergic reactions due to destruction of 
microfilariae and adult worms include fever, local inflammations around dead worms and pruritus. 
 
The team that administered the drugs will visit the “treated households” for active monitoring of 
adverse events approximately 12 and 48 hours following drug administration. Every treated person in 
the community will be actively sought to have two post-treatment active event-monitoring sessions. 
Most adverse events, especially the more severe, occur in the first 12 - 48h following treatment 
associated with killing of microfilaria. However, occasional adverse events related to adult worm death 
may be delayed by several days. 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.  To capture these late adverse events 
and to assure that any systemic adverse events that occurred earlier have resolved, the team will also 
visit study villages daily on days 3 through 7 after treatment to record any report of persistent or late-
developing AEs. These evaluations will be documented by filling in pre-printed monitoring forms 
(Appendix 6) using the scoring instructions for AEs (Appendix 6a) and directly entered data into tablet 
computers using a program such as Redcap or EpiInfo. 
 
Mild symptoms and management: In the case of mild symptomatic reactions (objective and localized: 
fever, lymphadenitis, scrotal pain, scrotal swelling, proteinuria, haematuria; subjective or systemic: 
headache, light headedness, nausea, vomiting, abdominal pain, joint pain, malaise, dizziness) local 
health workers/ study team will give antipyretics/analgesics and anti-allergic agents at the time of 
follow-up.  
 
Moderate symptoms and management: Individuals with AEs that interfere with work or school will 
have more detailed assessments with a brief physical examination with measurement of temperature, 
blood pressure and pulse by the physician. If the initial AE monitoring reveals AEs that (a) interfere 
with daily activities and/or a temperature >390C (b) a significant drop in blood pressure and (c) other 
significant objective findings they will be evaluated for potential severe adverse event. The physician 
will provide any required immediate treatment and facilitate admission into the hospital or health 
centre, if deemed necessary. All events with grades ≥ 3 or overnight hospitalization will be referred as 
Severe Adverse Events that require completion of the Adverse Event Evaluation and Report Form 
(AEERF, Appendix 7).  
 

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4.6.2 
Severe adverse event assessment and management protocol 
 
The study population with definite or suspected severe AEs will be referred to medical personnel for 
further evaluation. These evaluations will be documented with AEERF forms (Appendix 7), following 
the instructions (Appendix 7a). An independent Medical Monitor who will decide whether the AEs 
reported are related, possibly related, or unrelated to the treatment will review all severe adverse 
event assessment evaluations. Severe adverse event assessment reports will be sent electronically to 
the Independent Medical Monitor (who has received GCP training and is experienced in clinical trials 
and management of AEs following treatment of lymphatic filariasis). Classification of events as Serious 
Adverse Events and causation (definitely related to MDA, probably, possible, or unrelated) will be 
based on the attending physician’s report and the medical monitor’s opinion. Medical monitor will 
forward severe adverse event assessment reports to the data safety review board. Individuals with 
severe adverse events (whether related or unrelated to drug treatment) will be hospitalized if 
necessary and followed until their symptoms have resolved. All severe adverse events will be reported 
within 48 hours. The report will be submitted to the Chairperson of DSRB nominated by Govt. of India 
within 7 days and the Institutional Humans Ethics Committee (IHEC). Server Adverse event is 
considered as serious adverse event/experience (SAE) when the severity grade is 4 and above. 
 
4.6.3 
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 severe adverse 
event attributable to study treatment, expenses towards medical treatment and/or hospitalization 
will be covered through medical insurance. Participants reporting with severe adverse events in the 
grade 5 will be covered under liability insurance policy. 
   
4.7 
Data safety review board (DSRB) 
 
The DSRB will monitor the type and frequency of AEs and SAEs recorded by the teams and provide 
guidance to the teams in the field. The DSRB and the Institutional Humans Ethics Committee (IHEC) 
may conduct a review after MDA was distributed to 500 people in each treatment area and to consider 
stopping the study if 5 or more of 500 people experienced SAEs attributable to MDA. 
 
4.8 
Acceptability of triple drug regimen 
 
Community acceptance will be measured by surveying community members receiving either the 2-
drug or 3-drug regimens. A survey questionnaire will be designed, pre-tested and used to assess what 

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respondents know about LF, what they think of people with LF, how do they perceive LF affects their 
health, how the health system manages people with LF, especially their perceptions on study drug 
administration and of reactions to treatment and fears of being treated. The sample will include two 
categories of individuals: (i) Mf and Ag positive and (ii) Mf and Ag negative. In estimating the sample 
size for the acceptability survey, estimated acceptability rates are available only for 2-drug regimen. 
In the absence of such information for 3-drug acceptability rate, the difference in the estimate that 
may be expected between the regimen groups cannot be derived for estimating the sample size. As a 
result, this survey will create preliminary data, providing an insight into possible trends in 
acceptability. Therefore, a minimum of 100 individuals above 14 years will be randomly selected in 
each category for the survey in each arm. All the Mf and Ag positive individuals (above 14 years) will 
be included if the number is below 100.  
 
To complement this survey, a series of focus group discussions (FGD) in the community as well as key 
informant interviews (community leaders, health personnel and drug distributors in the same 
communities) to assess perceptions about the 3-drug versus the 2-drug regimen will be conducted at 
the same time along with community survey. Persons from specific groups of people such as women 
of reproductive age, young people, men and community health workers will be included in the FGD to 
understand their perspectives on DOT, AE and messaging for the 3-drug regimen. 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. A range 
of 8-10 individuals will be included from each arm.  
Guidelines for developing questionnaire for community acceptability survey, Key informant interview 
and focus group discussion are given in Appendix 8. 
 
4.9 
One year post-MDA assessment 
 
4.9.1 Effectiveness of IDA versus DA 
 
Effectiveness will be assessed by comparing the pre and 12 months post-MDA prevalence of Mf and 
Ag, and intensity of Mf between the two arms, by testing a cross section of the population in each 
arm. Finger prick blood sample measuring 75 µl, and six blood spots (120 µl), each with 20 µl blood on 
a filter paper for detecting Ag and antibody (Ab) respectively will be collected from the consenting 
individuals in the selected households between 1700 and 2100 hrs by door to door visit. FTS will be 
used for detecting Ag and Wb123 or Bm14 will be used for Ab. All Ag-positives will be further blood 

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smeared for Mf between 2100 and 2300 hrs on the same day. All samples will be processed following 
respective SOPs for FTS, antibody and Mf.    
 
4.9.2 
Efficacy of IDA versus DA 
 
For assessing efficacy, individuals who were positive for either Mf or Ag, prior to MDA will be re-
examined for both Mf and Ag, and also for Ab. A fraction of positive cohorts (Ag and Mf) are expected 
to be covered under the effectiveness survey. If required, special efforts will be made to cover more 
positive cohorts by visiting their households.  
 
4.10 Treatment 
 
Person positive for Ag or Mf will be treated with the 3-drug regimen (Ivermectin, DEC and 
albendazole). 
 
4.11 Data Collection 
4.11.1 Pre-treatment  
 
Data will be collected using tablet-based systems, which will be pre-loaded with appropriate software. 
Field teams will be trained in the use of the instruments and data will be uploaded as soon as entries 
are completed. The secondary data available on other characteristics of the population such as 
migratory pattern, prevalence of co-morbid conditions and malnutrition status will be collected. 
Information on the vectors and transmission parameters will be collected. 
 
4.11.2 Post-treatment  
 
The 12-month post-MDA survey for both efficacy and effectiveness assessment will carried out 
simultaneously. For the effectiveness study, a database developed in EPIINFO software (CDC, Atlanta) 
will be used to capture data using Android based mobile phones, excluding all positive persons in the 
cohort. The data for the cohort will also be captured using tablet-based electronic data capturing (EDC) 
system that was developed and used during pre-MDA survey. The details of all individuals in the cohort 
will be pre-loaded and used to capture data during the 12-month post-MDA survey.  
 
5. STATISTICAL CONSIDERATIONS 
5.1 Safety data 
 
The sample size of ≥4000 in each arm is sufficient to test the hypothesis that the rates of severe AEs 
following IDA or DA are less than 0.1%. 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 villages in the study area are 

VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 17 of 96 
 
relatively low, the study will not be powered to compare rates of SAEs by MDA regimen. The primary 
endpoint for safety studies will be the rates of SAEs that occur in infected and in uninfected subjects 
within the first 7 days post MDA. 
 
5.2 Effectiveness 
 
With a pre-MDA Mf prevalence of ~6% in each arm, the Mf prevalence is expected to be ~2% 12-
months post-MDA considering a coverage of 70% under MDA.  Assuming both IDA and DA are 
equivalent (‘equivalence trial’) in clearing infection and that a difference of 1.2% in infection 
prevalence is considered as equivalent, a sample of 3600 individuals per arm is sufficient to compare 
the effectiveness between the arms. This sample size has 80% power of detecting the true difference 
of more than 1.2% and no more than 5% chance of falsely concluding that the difference is less than 
1.2% when in fact it is more than 1.2%. The sample size was adjusted for a design effect of 1.5 and a 
non-response rate of 10%. With an average family size of 5, a total of 720 households per arm need 
to be selected following systematic sampling method. All the consenting individuals aged five and 
above will be tested for filarial infection in both the arms. 
 
5.3 Efficacy 
 
Assuming an Mf-prevalence of 1% in the study population at baseline, the survey is expected to detect 
at least 60 Mf positives in each arm. A minimum of 35 of these Mf-positives in each arm will be 
retested at 12 months post-treatment for antigenemia and microfilaraemia. 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. Another 
secondary endpoint will be clearance of filarial antigenemia at 12 months post MDA. 
 
5.4 Assessing prevalence of antibody 
 
For assessing the prevalence of antibody, a minimum sample size of 800 per arm was estimated. This 
was arrived at by assuming an antibody prevalence of 25%, with 3% error margin and 95% confidence 
level. As the sampling unit is a household, the sample size is adjusted for a design effect of 1.5 and 
therefore a total of 1250 individuals need to be surveyed. Assuming an average family size of 5, a total 
of 250 households need to be surveyed and all the persons volunteering to participate in the selected 
household will be included in the sample. This sample can be achieved by selecting every 3rd house 
of the 720 households covered for filarial infection in each of the arms. 

VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 18 of 96 
 
 
5.5 Follow-up of pre-MDA positives 
 
From human ethics point of view, all the Ag positive (1263 in IDA and 1031 in DA arms) and Mf positive 
(326 in IDA and 265 in DA arms) individuals detected during enrolment are required to be retested for 
their current infection status. Therefore those Ag/Mf positives not covered under the 
effectiveness/efficacy surveys will be approached and if available will be tested for Ag and Ab. Ag 
positives individuals will be further tested for Mf. 
6. BIOHAZARD CONTAINMENT 
 
Universal precautions for people collecting blood and working with blood samples and proper 
disposal of contaminated materials (test strips, lancets, capillary tubes, blood film slides) will be 
adhered in accordance with the guidelines prescribed by the local health authorities.  
 
7. DISSEMINATION ACTIVITIES 
 
A dissemination workshop will be held after the results are available to inform other stakeholders. 
The results will be published in an open access peer reviewed journal. 
 
8. TEAM COMPOSITION AND WORK PLAN 
 
(i) 
A Social Scientist assisted by a Junior Social Worker, PHC level health educator and community 
liaison persons will be involved in each arm to carry out social mobilization activities in the 
preparatory phase of the study. This activity will precede participant enrolment. The sociologist 
team will approach the households, carry out campaigns and prepare the community for the 
MDA. Each team is expected to complete 140 houses every week.  The sociology teams will also 
be involved in assessing the acceptability using community survey, FGD and KI interviews after 
the completion of drug administration within the recall period of one month. 
 
 
(ii) Another team of six members (one physician, two laboratory technicians one each for sample 
collection and reading antigen test results, one junior nurse, one data entry operator and one 
field assistant) will be responsible for the following activities: consenting, enumeration, pre-
treatment assessments, drug administration and post-treatment AE assessments. The drug 
distributor in the routine MDA programme in the villages and/or community liaison persons will 
be a part of the team. There will be 7 such teams in each arm of the study. Each team will visit 

VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 19 of 96 
 
the house, get the consent from the members, assess pre-treatment health status, screen all the 
available individuals for filarial antigenemia and administer drugs except those who are positive 
for antigenemia. Antigen positive individuals will be tested for microfilaraemia by collecting night 
blood sample after 9.00 PM and then treated.  
 
(iii) A team is expected to complete 8-10 households (~40 individuals) in a day. During the first door 
to door visit, the team will enrol the participants, assess health parameters, screen the individuals 
for filarial infection and provide directly observed treatment. The team will revisit the “treated 
households” for active monitoring of adverse events if any, to manage the AEs on day 1 and 2 
post treatment. Once these activities are completed in these houses, the team will move on to 
the next batch of 10 houses. A team is expected to cover 16-20 households in a week. All the data 
pertaining to these activities will be entered in the e-formats by the DEO in the field itself. In this 
process, a minimum 8-10 weeks is necessary to cover the target population in both the arms 
(refer section 9). A team with similar composition will be formed for assessing Ag and Mf 
prevalence after 12 months post treatment and to treat the positive cases. 
 
(iv) A separate team of a physician and a junior nurse will passively monitor the treated individuals 
(20 - 30 households in a day) for an extended period of 7 days following the treatment in each 
arm. This team will be supported by the existing Rapid Response Team (RRT) in the District 
monitoring and managing the AEs in both the arms.  
 
(v) The Medical Officer(s) and Health Inspectors in the PHCs of respective arms will assist the 
investigators in co-ordinating the activities of the team in the villages and referrals. At the District 
level, the District Health officer (DHO) and the District Vector Borne Disease Control Officer 
(DVBDCO) will provide assistance in selection and organisation of teams for various activities 
including the PHC staff and conducting training programmes and overall supervision. The District 
Health officer will provide support in terms of deploying the Rapid Response Team, referral 
arrangements and Hospital support. 
 
(vi) There will be an independent Medical Monitor who will receive severe adverse event assessment 
reports electronically from the attending physician and forward the report with opinion to the 
DSRB through the PI/Co-PI.  
 
(vii) All the members of the teams who have basic medical skills will be trained on AE evaluations. 
Laboratory Technicians will be trained on blood sampling, smearing, processing and examination 

VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 20 of 96 
 
of slides for Mf, and reading of antigen test results. Hands on training will be given to the data 
entry operators on geo-referencing the households and filling up of e-forms using e-tablets pre-
loaded with appropriate software.  
 

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 21 of 96 
 
9. TIMELINE OF ACTIVITIES 
Oct-17
Nov-17
Dec-17
Jan-18
Feb-18
Mar-18
W1
W2
W3
W4
W1
W2
W3
W4
W1
W2
W3
W4
W1
W2
W3
W4
W1
W2
W3
W4
W1-W4
W1-W4
W1-W4 W1-W4 W1-W4
W1-W4
$1
Staff Recruitment and training
20
Recruitment
$2
Pre screening for Mf for site selection 
4000
8
3
12
DHO DHO 
$3
Selection of study sites and advocay
$4
Preparation of IEC and training the field 
teams
$5
Social mobilization for screening and 
drug distribution
2400 HHS
2
2
66
B
B
B
B
B
B
B
B
B
B
B
B
$6
Sensitization and training for Rapid 
Response team
7
DHO
$7
1.  Patient enrolment
    (i) Obtaining consent
    (ii) Pre-MDA health assessment
     (iii) Screening - Ag  
     (iv) MF screening
2. Drug Distribution
3. Adverse Events Survey  (active)
3. Adverse Events Survey (passive)
2400 HHS
15
6
60
A
A
A
A
A
A
A
A
A
A
A
A
A
$8
Rapid Response team visits
DHO DHO DHO DHO DHO DHO DHO DHO DHO DHO DHO DHO DHO
$9
Post-Treatment Survey - Acceptability
400 
persons
2
2
30
B
B
$10
Post (12 M) -Treatment assessment - Mf 
and Ag survey
2400 HHS
15
2
19
C
C
C
C
C
$11
 Slide processing and examination
990 Agpos
1
3
20
C
C
C
C
C
$12
Data analysis and report writing
Team composition
Team A : Physician(1no.); Technician C (3nos.: 1 for blood sampling, 1 for FTS reading and 1 for Data entry); Nurse/Field Worker (1no.) Field Assistants (1no.) 
Team C: Technician C (2no.); Field Worker (1no.); Field Assistant 1no.); DEO (1no.) 
Team B : Sociologist (1); Junior Social Worker (1)
DHO : Distirct Health Officials 
Recruitment
Activities and time line
Jul-16
Aug-16
Sep-16
Max 
Days
S.No.
Activity
Target
No. of 
Teams
No. of 
person / 
team
Dec 2016 - Nov 2017
Nov-16
Oct-16

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 22 of 96 
 
10. BUDGET 
 
 
 
 
Budget Heads 
Amount in INR 
Amount in 
USD 
Personnel 
₹ 238,38,293.00 
$3,50,929.54 
Field allowances 
₹ 10,80,000.00 
$15,898.95 
Equipment 
₹ 15,22,500.00 
$22,413.11 
Supplies 
₹ 4,02,000.00 
$5,917.94 
Contingency 
₹ 2,80,400.00 
$4,127.84 
Mobility 
₹ 36,00,000.00 
$52,996.51 
Communication 
₹ 1,26,000.00 
$1,854.88 
Field lab 
₹ 15,84,000.00 
$23,318.46 
Miscellaneous (Insurance policy) 
₹ 2,14,700.00 
$3,160.65 
Review and steering committee meetings (ICMR) 
₹ 12,58,200.00 
$18,522.28 
 
₹ 339,06,093.00 
$4,99,140.18 

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 23 of 96 
 
11. REFERENCES 
 
1. World Health Organization (1997). Elimination of lymphatic filariasis as a public health 
problem - resolution of the executive board of the WHO. 
 
2. National Vector Borne Disease Control Programme (2015). http://nvbdcp.gov.in/filariasis-
new.html. 
 
3. World Health Organization (2002). Global Programme to Eliminate Lymphatic Filariasis. 
Annual Report on Lymphatic Filariasis. Geneva: WHO. 
 
4. Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, Schmidt MS, Siba PM, Weil 
GJ, Kazura JW, Fleckenstein LL and King CL (2015). Efficacy, Safety, and Pharmacokinetics of 
Co-Administered Diethylcarbamazine, Albendazole, and Ivermectin for the Treatment of 
Bancroftian Filariasis.Clin Infect Dis. DOI:10.1093/cid/civ882. 
 
5. Gyapong J, Kumaraswami V, Biswas G, Ottesen EA (2005). Treatment strategies 
underpinning the global programme to eliminate lymphatic filariasis. Expert Opin 
Pharmacother.: 6 (2), 179-200. 
 
6. Horton J (2000).  Albendazole: a review of antihelminthic efficacy and safety in humans. 
Parasitology: 121 (Suppl.), S113-S132. 
 
7. Goa KL, Mctavish D, Clissold SP (1991). Ivermectin: a review of its antifilarial activity, 
pharmacokinetic properties and clinical efficacy in onchocerciasis. Drugs: 42 (4), 640-658. 
 
8. Edwards G (2003). Ivermectin. Does P-glycoprotein play a role in neurotoxicity? Filaria J: 2 
(Suppl. 1), S8. 
 
9. Ottesen EA, Campbell WC (1994). Ivermectin in human medicine. J. Antimicrob. Chemother.: 
34 (2), 195-203. 
 
10. Awadzi K, Edwards G, Duke BO et al. (2003). The co-administration of ivermectin and 
albendazole-safety, pharmacokinetics and efficacy against Onchocerca volvulus. Ann. Med. 
Parasitol.: 97(2), 165-178. 
 
11. Ottesen EA (1985). Efficacy of diethylcarbamazine in eradicating infection with lymphatic 
dwelling filariae in humans. Rev. Infect. Dis.: 7 (3), 341-356. 
 
12. Nores J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D (1997). Assessment of the 
efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Trans. R. Soc. Trop. 
Med. Hyg.: 91 (1), 78-81. 
 
 

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 24 of 96 
 
Table 1 Mf prevalence in sentinel and spot check sites in Yadgir district in 2014 and 2015 
 
PHC 
Sub-centre 
Village 
Type 
Population 
Mf % 
(2014) 
Mf % 
(2015) 
Dornalli 
Dornalli 
Doranahalli 
Sentinel 
1369 
5.38 
3.09 
Konkal 
Nazarpur 
Nazarpur 
Sentinel 
2131 
2.20 
1.18 
Petammapur 
Petammapur 
Petammapur 
Sentinel 
3820 
1.90 
3.30 
GGH Shorapur Shorapur 
Ranganpet 
Sentinel 
707 
1.97 
0.40 
Yelheri 
Yelheri 
Yelheri 
Spot-check 
3575 
2.53 
ND 
Sagar 
Sagar 
Sagar 
Spot-check 
6391 
2.95 
ND 
Devargonal 
Devargonal 
Devargonal 
Spot-check 
3300 
3.00 
ND 
Yadgir urban 
NA 
Kalachaputra 
Spot-check 
NA 
0.58 
ND 
Shahapur 
Shahapur 
Shahapur town Spot-check 
NA 
ND 
1.38 
Kandakur 
NA 
Gunjanur 
Spot-check 
NA 
ND 
0.79 
Yeleri 
NA 
Kaladelagundi 
Spot-check 
NA 
ND 
0.92 
Chattanahalli 
NA 
Khanapur 
Spot-check 
NA 
ND 
1.65 
 
NA: Not available 
ND: Not done 
 
Table 2 Drug dosage for DA arm (as per national Guidelines) 
 
Age (Years) 
DEC 
Albendazole 
Dose (mg) 
No. of 100 mg 
tablets 
Dose (mg) 
No. of 400 mg 
tablets 
Less than 2 
0 
0 
0 
0 
2 - 5  
100 
1 
400 
1 
6  - 14 
200 
2 
400 
1 
15 + 
300 
3 
400 
1 
 

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 25 of 96 
 
Table 3 Weight based dosage for ivermectin (all persons of age > 5 years with weight ≥ 15 Kg) 
 
Weight 
(kg) 
Ivermectin 
(mg) 
No.  tablets 
(3 mg) 
Rounded 
No. tablets 
(3 mg) 
 
Weight 
(kg) 
Ivermectin 
(mg) 
No. tablets 
(3 mg) 
Rounded 
No. tablets 
(3 mg) 
< 15 
1.8 
0.6 
0 
 
39 
7.8 
2.6 
3 
15 
3.0 
1.0 
1 
 
40 
8.0 
2.7 
16 
3.2 
1.1 
 
41 
8.2 
2.7 
17 
3.4 
1.1 
 
42 
8.4 
2.8 
18 
3.6 
1.2 
 
43 
8.6 
2.9 
19 
3.8 
1.3 
 
44 
8.8 
2.9 
20 
4.0 
1.3 
 
45 
9.0 
3.0 
21 
4.2 
1.4 
 
46 
9.2 
3.1 
22 
4.4 
1.5 
 
47 
9.4 
3.1 
23 
4.6 
1.5 
 
48 
9.6 
3.2 
24 
4.8 
1.6 
2 
 
49 
9.8 
3.3 
25 
5.0 
1.7 
 
50 
10.0 
3.3 
26 
5.2 
1.7 
 
51 
10.2 
3.4 
27 
5.4 
1.8 
 
52 
10.4 
3.5 
28 
5.6 
1.9 
 
53 
10.6 
3.5 
29 
5.8 
1.9 
 
54 
10.8 
3.6 
4 
30 
6.0 
2.0 
 
55 
11.0 
3.7 
31 
6.2 
2.1 
 
56 
11.2 
3.7 
32 
6.4 
2.1 
 
57 
11.4 
3.8 
33 
6.6 
2.2 
 
58 
11.6 
3.9 
34 
6.8 
2.3 
 
59 
11.8 
3.9 
35 
7.0 
2.3 
 
60 
12.0 
4.0 
36 
7.2 
2.4 
 
61 
12.2 
4.1 
37 
7.4 
2.5 
 
62 
12.4 
4.1 
38 
7.6 
2.5 
 
63 
12.6 
4.2 
 
 
 
 
 
64 
12.8 
4.3 
 
 
 
 
 
65 
13.0 
4.3 
 
 
 
 
 
66 
13.2 
4.4 
 
 
 
 
 
>67 
13.4 
4.5 
 
  
 
 
 
 
 
 
 
 
 
 

 
VCRC Triple Drug Therapy Protocol – revised with phase II  
         Page 26 of 96 
 
Table 4 Drug requirements for the two arms, IDA and DA 
 
#  Based on 200 µg per Kg body weight 
* Required for retreatment of positives and marginal increase in population size during the selection 
of villages 
 
Drug 
Age 
group 
(Years) 
Population 
No. of 
tablets 
per 
person 
Total no. 
Tablets 
Additional 
tablets * 
Grand total 
(Tablets) 
DEC 100 mg 
All  > 2 
years 
12000 
2.5 
30000 
7500 
37500 
Albendazole 400 mg 
All  > 2 
years 
12000 
1 
12000 
3000 
15000 
Ivermectin  3mg# 
All  >5 
years 
6000 
1-4* 
21600 
5400 
27000