Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000738325
Ethics application status
Approved
Date submitted
11/05/2017
Date registered
22/05/2017
Date last updated
20/01/2020
Date data sharing statement initially provided
15/02/2019
Date results information initially provided
15/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Fiji Integrated Therapy (FIT) - Triple therapy for lymphatic filariasis, scabies and soil transmitted helminths in Fiji
Scientific title
Community Based Safety Study of 2-drug (Diethylcarbamazine and Albendazole) versus 3-drug (Ivermectin, Diethylcarbamazine and Albendazole) Therapy for Lymphatic Filariasis, Scabies and Soil Transmitted Helminths in Fiji
Secondary ID [1] 291900 0
None
Universal Trial Number (UTN)
Trial acronym
FIT
Linked study record
NCT02899936
CTRI/2016/10/007399

Health condition
Health condition(s) or problem(s) studied:
lymphatic filariasis (LF) 303212 0
scabies 303213 0
impetigo 303214 0
soil transmitted helminths (STH) 303215 0
Condition category
Condition code
Infection 302647 302647 0 0
Other infectious diseases
Public Health 302648 302648 0 0
Other public health
Skin 302649 302649 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
IDA1 Arm:
- ivermectin, diethylcarbamazine and albendazole Day 0,
- permethrin Day 0 if excluded from ivermectin
IDA2 Arm:
- ivermectin, diethylcarbamazine and albendazole Day 0, ivermectin Day 8
- permethrin Day 0 and Day 8 if excluded from ivermectin

Details of dosing:
- ivermectin: 200 mcg/kg oral
- diethylcarbazine: 6mg/kg oral
- albendazole 400mg oral
- permethrin 5% cream topical: apply to whole body and wash off after 4hrs when less than 2 months; apply to whole body and wash off after 8hrs when 2 months and older.

Directly observed therapy (DOT) will be used for ivermectin, diethylcarbamazine and albendazole.
Instructions will be provided for application of permethrin cream when distributed but application will not be observed, since this is normally done at night to avoid inadvertent washing/rubbing off during daytime activities. Assistance by another person (household member/support person) will be required for application to ensure coverage of whole body.

Exclusion criteria for ivermectin, diethylcarbamazine and albendazole:
- severe illness (chronic renal insufficiency, severe chronic liver disease, or any illness that is severe enough to interfere with activities of daily living);
- allergy to ivermectin, diethylcarbamazine or albendazole;
- pregnant;
- breastfeeding within 7 days of delivery;
- less than 2 years old; OR
- less than 15 kg

In addition if less than 5 years old excluded from ivermectin.

Exclusion criteria for permethrin:
- allergy to permethrin
- crusted scabies
Intervention code [1] 298027 0
Treatment: Drugs
Comparator / control treatment
The control group will be the DA Arm. Villages randomised to this Arm will receive standard therapy for LF and scabies in Fiji.
DA Arm:
- diethylcarbamazine and albendazole Day 0
- permethrin Day 8 if scabies present in participant or household member
Details of dosing:
- diethylcarbazine: 6mg/kg oral
- albendazole 400mg oral
- permethrin 5% cream topical: apply to whole body and wash off after 4hrs when less than 2 months; apply to whole body and wash off after 8hrs when 2 months and older.

Directly observed therapy (DOT) will be used for diethylcarbamazine and albendazole.
Instructions will be provided for application of permethrin cream when distributed but application will not be observed, since this is normally done at night to avoid inadvertent washing/rubbing off during daytime activities. Assistance by another person (household member/support person) will be required for application to ensure coverage of whole body.

Exclusion criteria for diethylcarbamazine and albendazole:
- severe illness (chronic renal insufficiency, severe chronic liver disease, or any illness that is severe enough to interfere with activities of daily living);
- allergy to diethylcarbamazine or albendazole;
- pregnant;
- breastfeeding within 7 days of delivery;
- less than 2 years old; OR
- less than 15 kg

Exclusion criteria for permethrin:
- allergy to permethrin
- crusted scabies
Control group
Active

Outcomes
Primary outcome [1] 302056 0
Determine the frequency, type, and severity of adverse events following triple drug therapy (IDA) compared to standard two drug therapy (DA) in LF infected and uninfected individuals in a community.

Participants will be interviewed and asked to report their general health status at baseline before receiving treatment and daily for the 2 days following treatment (Active Adverse Event Monitoring phase). For 3 to 7 days following treatment, anyone unwell the preceding day will be actively followed, other participants will be interviewed only if they feel unwell and present to the study team (Passive Adverse Event Monitoring phase).
At any stage if they describe being unwell, further questions to determine type and severity of symptom(s) experienced will be asked and recorded according to pre-defined adverse event table. If moderate to severe symptoms they will have further medical assessments as required.
The majority of adverse events expected are related to effective action of the medications on the parasites. Possible side effects include abdominal pain, nausea, vomiting, diarrhoea, fever, painful glands groin/neck/armpits, itch, swelling, headache, joint pain, fatigue, weakness, dizziness, fainting, racing heart or an allergic reaction (itchy rash, difficulty breathing, chest tightness and/or swelling face/tongue).

Methods of assessment:
LF infection status will be determined by Filiarial Test Strip (FTS) and microfilariae (mf) smears.
Adverse events - interviews +- medical assessment
Timepoint [1] 302056 0
Community members will be actively followed daily for 2 days after treatment, and passively followed for period 3-7 days after treatment.
Secondary outcome [1] 334643 0
To compare the efficacy of IDA to DA administered in communities for clearance of microfilariae (mf) and filarial antigenemia (composite outcome). Methods of assessment: FTS and Dried Blood Spot (DBS) for filarial antigenemia. mf smears and membrane filtration (24 month follow-up only) for microfilariae
Timepoint [1] 334643 0
Baseline, 12 months and 24 months
Secondary outcome [2] 334644 0
To assess the effect of intensity of filarial infection on the frequency and severity of adverse events.

Methods of assessment:
FTS and mf results
Documented adverse events
Timepoint [2] 334644 0
FTS and mf results at baseline will be compared to documented adverse events monitored for 7 days following treatment.
Secondary outcome [3] 334645 0
To evaluate the impact of IDA on scabies prevalence

Methods of assessment:
Skin examination
Timepoint [3] 334645 0
Baseline and 12 months
Secondary outcome [4] 334646 0
To evaluate the impact of IDA on STH (hookworm, ascaris, trichuris and strongyloides) prevalence

Methods of assessment:
Stool samples will be analysed using Kato-katz method, as well as PCR.
Timepoint [4] 334646 0
Stool collected at baseline (pre-treatment), 4 weeks (individual response), and 12 months (community prevalence).
Secondary outcome [5] 334647 0
To compare acceptability and feasibility of IDA to DA in communities at risk of LF, scabies and STH (composite outcome).

Methods of assessment:
Acceptability Survey, designed specifically for the Triple therapy studies
Focus group discussions
Interviews with key informants
Timepoint [5] 334647 0
Approximately 4 weeks following treatment
Secondary outcome [6] 334983 0
To evaluate the impact of IDA on impetigo prevalence.

Methods of assessment:
Skin examination
Timepoint [6] 334983 0
Baseline and 12 months
Secondary outcome [7] 334984 0
To evaluate the effect of 1 versus 2 doses of ivermectin on scabies prevalence.

Methods of assessment:
Skin examination
Timepoint [7] 334984 0
Baseline and 12 months
Secondary outcome [8] 334985 0
To evaluate the effect of 1 versus 2 doses of ivermectin on impetigo prevalence.

Methods of assessment:
Skin examination
Timepoint [8] 334985 0
Baseline and 12 months

Eligibility
Key inclusion criteria
All community members will be invited to participate in the study
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
No informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Villages will be randomised by central computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Village randomisation - all participants in one village will be randomised to the same therapy. Randomisation will occur using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The total enrolment target of 4000 is based on total population of the two islands chosen for the study - Rotuma and Gau.
The de-identified data will be joined with data from other sites (Papua New Guinea, Haiti, India, Indonesia) to provide the numbers to evaluate the primary outcome.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/07/2017
Actual
13/07/2017
Date of last participant enrolment
Anticipated
27/10/2018
Actual
19/11/2018
Date of last data collection
Anticipated
24/10/2019
Actual
24/10/2019
Sample size
Target
4000
Accrual to date
Final
4773
Recruitment outside Australia
Country [1] 8894 0
Fiji
State/province [1] 8894 0
Rotuma and Gau islands in Eastern Division

Funding & Sponsors
Funding source category [1] 296405 0
Other Collaborative groups
Name [1] 296405 0
The Task Force for Global Health
Country [1] 296405 0
United States of America
Funding source category [2] 303992 0
University
Name [2] 303992 0
Death to Onchocerciasis and Lymphatic Filariasis (DOLF) Project, Washington University in St Louis
Country [2] 303992 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Murdoch Children's Research Institute
Address
Royal Children's Hospital
50 Flemington Rd
Parkville, Victoria
Australia 3052
Country
Australia
Secondary sponsor category [1] 295469 0
None
Name [1] 295469 0
Address [1] 295469 0
Country [1] 295469 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297631 0
Royal Children's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 297631 0
50 Flemington Rd, Parkville, Victoria, 3052
Ethics committee country [1] 297631 0
Australia
Date submitted for ethics approval [1] 297631 0
05/07/2016
Approval date [1] 297631 0
12/09/2016
Ethics approval number [1] 297631 0
36205
Ethics committee name [2] 297646 0
Fiji National Health Research and Ethics Review Committee
Ethics committee address [2] 297646 0
Dinem House, 88 Amy St, Toorak, Suva, Fiji
Ethics committee country [2] 297646 0
Fiji
Date submitted for ethics approval [2] 297646 0
11/07/2016
Approval date [2] 297646 0
21/04/2017
Ethics approval number [2] 297646 0
2016.81.MC

Summary
Brief summary
Lymphatic Filariasis (LF), scabies and soil transmitted helminths (STH) are common neglected tropical diseases affecting the people of Fiji. There is a dedicated LF eradication program supported by the World Health Organization (WHO), however scabies and STH are currently managed on an individual level with symptomatic treatment as required.
In an attempt to reduce the prevalence of LF globally, research is being undertaken into alternative, more effective treatment options. A recent study in Papua New Guinea demonstrated a new triple drug therapy (ivermectin, diethylcarbamazine and albendazole) is superior to the currently recommended two drug therapy (diethylcarbamazine and albendazole) used by WHO LF programs in the Pacific. However, adverse events were more frequent. Despite no serious adverse events being observed, it is necessary to conduct further studies to review the safety of this new triple therapy before it can be endorsed as an effective mass drug administration (MDA) regimen for LF in endemic countries. Fiji’s burden of LF, that has been recalcitrant to previous MDA with diethylcarbamazine and albendazole, make it an ideal site to obtain further efficacy and safety data of the triple therapy.
Ivermectin given to communities as MDA has been proven to be effective in reducing the community prevalence of scabies. What is not known is the effects of one dose versus two doses of ivermectin as MDA. This question will be reviewed within the design of the community randomised study. The prevalence of impetigo in a community is linked to scabies and this will also be reviewed.
Ivermectin and albendazole are both effective individually against STH. The effectiveness of this combination of treatment as MDA in Fiji for STH has not been studied. The effectiveness for the individual in the short-term and the community in the longer-term will be reviewed.
In addition, the acceptability and feasibility of the new therapy in communities at risk of these three diseases will be reviewed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74654 0
Prof Andrew Steer
Address 74654 0
Murdoch Children's Research Institute
Royal Children's Hospital
50 Flemington Rd, Parkville, Victoria, 3052
Country 74654 0
Australia
Phone 74654 0
+61393455522
Fax 74654 0
Email 74654 0
andrew.steer@rch.org.au
Contact person for public queries
Name 74655 0
Prof Andrew Steer
Address 74655 0
Murdoch Children's Research Institute
Royal Children's Hospital
50 Flemington Rd, Parkville, Victoria, 3052
Country 74655 0
Australia
Phone 74655 0
+61393455522
Fax 74655 0
Email 74655 0
andrew.steer@rch.org.au
Contact person for scientific queries
Name 74656 0
Prof Andrew Steer
Address 74656 0
Murdoch Children's Research Institute
Royal Children's Hospital
50 Flemington Rd, Parkville, Victoria, 3052
Country 74656 0
Australia
Phone 74656 0
+61393455522
Fax 74656 0
Email 74656 0
andrew.steer@rch.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of fiji: A cluster randomised trial.2020https://dx.doi.org/10.1371/journal.pntd.0008106
EmbaseIndividual Efficacy and Community Impact of Ivermectin, Diethylcarbamazine, and Albendazole Mass Drug Administration for Lymphatic Filariasis Control in Fiji: A Cluster Randomized Trial.2021https://dx.doi.org/10.1093/cid/ciab202
EmbaseCommunity control strategies for scabies: A cluster randomised noninferiority trial.2021https://dx.doi.org/10.1371/journal.pmed.1003849
N.B. These documents automatically identified may not have been verified by the study sponsor.