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Trial registered on ANZCTR


Registration number
ACTRN12618000461291
Ethics application status
Approved
Date submitted
13/03/2018
Date registered
29/03/2018
Date last updated
9/07/2021
Date data sharing statement initially provided
11/02/2019
Date results provided
9/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Fiji Northern Division Ivermectin Mass Drug Administration for Scabies Trial
Scientific title
Does mass Drug Administration for Scabies Result in Control of Serious Bacterial Complications? A Proof of Concept Towards Global Elimination
Secondary ID [1] 294215 0
Nil known
Universal Trial Number (UTN)
U1111-1210-1713
Trial acronym
Big SHIFT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Scabies 306865 0
Impetigo 306866 0
Skin and soft tissue infections 306867 0
Invasive group A streptococcal infections 306868 0
Invasive Staphylococcus aureus infection 306869 0
Post streptococcal glomerulonephritis 306870 0
Acute rheumatic fever 306871 0
Rheumatic heart disease 306872 0
Bacteraemia 306873 0
Condition category
Condition code
Infection 305971 305971 0 0
Other infectious diseases
Public Health 305972 305972 0 0
Epidemiology
Public Health 305973 305973 0 0
Other public health
Skin 305974 305974 0 0
Dermatological conditions
Cardiovascular 306314 306314 0 0
Other cardiovascular diseases
Blood 306316 306316 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a before-after intervention trial of two doses of ivermectin-based mass drug administration (MDA) delivered to the whole population of the Northern Division of Fiji.

Ivermectin will be offered to all consenting individuals of the Northern Division of Fiji unless an indiviudual is:
- Pregnant or may be pregnant
- Breastfeeding an infant less than 1 week of age
- A child less than 90cm in height
- Taking warfarin
in which case, they will be offered topical permethrin cream instead
or
If they are requiring inpatient hospitalisation or are bedridden in the community, no intervention will be offered.
Initially, the planned dose of ivermectin by height measure was:
90-119cm : 3mg (1 tab)
120-140cm: 6mg (2 tab)
141-158cm: 9mg (3 tab)
>158cm: 12mg (4 tab)

However, an updated dosing regimen was used referring to the schedule developed by Death to Onchocerciasis and Lymphatic Filariasis, using height-weight correlations in Pacific Island populations. The dosing schedule used is as follows:

90-112cm : 3mg (1 tablet)
113-133cm : 6mg (2 tablets)
134-146cm : 9mg (3 tablets)
147-156cm : 12mg (4 tablets)
157-164cm : 15mg (5 tablets)
165-200cm : 18mg (6 tablets)


Permethrin 5% cream:
Adults and children apply the cream from neck to toes and leave it on for a minimum of 8 hours and maximum of 24 hours if possible. Infants under 2 months of age to apply head to toe and leave on for maximum of 4 hours.

2 doses of ivermectin or permethrin (if ivermectin contraindicated) will be given 7-14 days apart. There will be no ongoing doses unless an individual is diagnosed with crusted scabies in which case they will be will be treated with 2 doses of ivermectin (except if ivermectin is contraindicated as outlined above) in conjunction with twice weekly permethrin cream for 1 month, with review at 1,2,3,12 and 24 months. Efforts will be made to control these cases intensively to prevent the high mite load of infection associated with crusted scabies from diminishing the effect of the MDA. These cases will be followed up by the Principal Research Coordinator.

The intervention will be administered by trained distributors already present in the Northern Division from the previous lymphatic filariasis MDA programme. Ivermectin administration and permethrin application (in children under 90cm in height) will be under directly observed therapy. The planned time frame for this to be accomplished will be within 1 month.
Intervention code [1] 300507 0
Treatment: Drugs
Intervention code [2] 300508 0
Prevention
Comparator / control treatment
This is a before-after intervention trial. Outcome measures will be measures in the studied population comparing surveillance data from the Northern Division of Fiji from 12 months prior to ivermectin mass drug administration (where standard therapy should be active) and data over the 12 months following ivermectin mass drug administration.
Control group
Historical

Outcomes
Primary outcome [1] 305006 0
The number of patients (all-ages) with Skin and soft tissue infection(SSTI) requiring hospital admission will be assessed with data acquired through active, prospective surveillance performed by study nurses of clinical cases at Labasa Hospital and through review of routinely collected data through the "Patient Information Sytsem (PATIS)" for the other 3 subdivisional hospitals of the Northern Division namely Savusavu, Nabouwalu and Waiyevo hospital.
Timepoint [1] 305006 0
The number of patients admitted in the 12 month period post delivery of mass drug administration will be compared to the number of patients admitted in the 12 month period prior to MDA delivery.
Primary outcome [2] 305007 0
The number of cases of other severe bacterial complications (invasive disease caused by Streptococcus pyogenes and Staphylococcus aureus, glomerulonephritis and rheumatic fever in children <15 years) presenting to hospital will be assessed with data acquired through active, prospective surveillance performed by study nurses of clinical cases at Labasa Hospital and through review of routinely collected data through the "Patient Information Sytsem (PATIS)" for the other 3 subdivisional hospitals of the Northern Division namely Savusavu, Nabouwalu and Waiyevo hospital.
Timepoint [2] 305007 0
The number of patients admitted in the 12 month period post delivery of mass drug administration will be compared to the number of patients admitted in the 12 month period prior to MDA delivery.
Secondary outcome [1] 343852 0
Prevalence of scabies and impetigo in survey sites will be assessed through village skin site examinations performed within 2 months prior to MDA and at 12 months post MDA. Consenting residents of randomly selected villages will be assessed by trained examiners. The sample size will approximately make up 6% of the population
Timepoint [1] 343852 0
The village site examinations will take place within 2 months prior to the MDA delivery and at 12 months post MDA delivery.
Secondary outcome [2] 343853 0
The number of presentations with scabies and impetigo to primary health care facilities by age group will be assessed through review of routinely collected data from presentations to nursing stations and health centres which are collated into monthly health reports and accessible through the 'Public Health Information System (PHIS)'
Timepoint [2] 343853 0
The number of patients presenting to primary care clinics and outpatients in the 12-month period post delivery of mass drug administration will be compared to the number of patients who presented in the 12-month period prior to MDA delivery.
Secondary outcome [3] 343854 0
The number of cases of other severe bacterial complications (invasive disease caused by Streptococcus pyogenes and Staphylococcus aureus, glomerulonephritis and rheumatic fever in all age groups presenting to hospitals will be assessed with data acquired through active, prospective surveillance performed by study nurses of clinical cases at Labasa Hospital and through review of routinely collected data through the "Patient Information Sytsem (PATIS)" for the other 3 subdivisional hospitals of the Northern Division namely Savusavu, Nabouwalu and Waiyevo hospital.

Timepoint [3] 343854 0
The number of patients admitted in the 12 month period post delivery of mass drug administration will be compared to the number of patients admitted in the 12 month period prior to MDA delivery.
Secondary outcome [4] 343855 0
Counts of all deaths, unexplained deaths and stillbirths in the year following MDA will be assessed through routinely collected census and health data and compared with the 5-year period preceding MDA .
Timepoint [4] 343855 0
The 12-month period following MDA will be compared to the 5 year period prior.
Secondary outcome [5] 343857 0
Population coverage of the programme (single dose and both doses) will be measured by number of ivermectin/permethrin doses distributed to individuals divided by total population which will be ascertained through routinely collected nursing census data.
Timepoint [5] 343857 0
This will be evaluated within 1 month of the commencement of the MDA program
Secondary outcome [6] 343858 0
The composite acceptability and feasibility of the programme will be evaluated through two methods.
1. Community surveys at randomly selected village sites pre- and post-intervention to be conducted on 5% of randomly selected adult participants.
2. Semi-structured interviews undertaken by an independent interviewer with key informants including clinical staff, community members including MDA distributors, health service managers at all levels of the Fiji Ministry of Health and Health Services and relevant non-governmental organisations such as the World Health organisation regional office,
Timepoint [6] 343858 0
The pre-intervention community survey will take place during the same visit as the pre-intervention skin site examination which will be over the 1-2 month period preceding the MDA

The semi-structured interviews will take place over the 12 month period following MDA
Secondary outcome [7] 343859 0
Incremental cost-effectiveness ratios (cost per quality-adjusted life years gained) and affordability (measured in financial streams of cost over a budget cycle) comparing MDA to standard care will be assessed through active collection of data at the Labasa Hospital of length of hospital stay, lab tests conducted, drugs that are administered, procedures, inter-hospital transfers and materials used multiplied by the unit costs of each item.
Quality of life surveys will be conducted using questionnaires including the EQ-5D questionnaire which will be administered to selected individuals at the village skin site examination pre-intervention, comparing individuals with clinical scabies and impetigo and individuals without clinical scabies or impetigo,
Timepoint [7] 343859 0
Active collection of data from Labasa Hospital for the parameters described above will be performed throughout the 12 month period preceding the MDA and compared with the corresponding data collected throughout the 12 month period following MDA

The quality of life surveys will be collected during the pre-intervention skin site examination surveys which will be taking palce within the 2 month period prior to the MDA.

Eligibility
Key inclusion criteria
All consenting residents of the Northern Division are eligible to be included 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 treatment will be given to patients who are seriously ill: inpatients in hospital and bedridden in the community.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size calculation:
Primary endpoints: Based on information collected from the routine hospital reporting system at Labasa Hospital over the last 2 years, we anticipate that there will be 410 cases of hospitalisation for severe SSTI and 172 cases of the combined endpoint of invasive bacterial disease, rheumatic fever and glomerulonephritis in children < 15 years during the pre-intervention period, or annual rates of 293 and 123 per 100 000 respectively. We will have 90% power to detect a 50% reduction in the annual incidence of admissions of patients with severe SSTI from 293 to 147 per 100,000. We will have 80% power to detect a 40% reduction (from 123 to 74 cases per 100,000) in the combined endpoint of admissions in children aged less than 15 years with any of invasive bacterial disease, rheumatic fever or glomerulonephritis. Secondary endpoints: To achieve 90% power to detect a 50% reduction in scabies or impetigo prevalence, from 20% to 10%, or 30% to 15% after ivermectin-based MDA, we will need to examine approximately 9000 people from 10 nursing zone clusters (6 rural, 4 urban). Within each cluster we will sample 3 settlements/villages, with an average population of 300, giving a total of 900 per nursing zone. This sample size will be sufficient to detect 50% reduction with at least 80% power in scabies/impetigo prevalence within rural & urban clusters separately (i.e. from 30% to 15% and 12% to 6% for rural and urban areas respectively). The power calculation assumes 20% refusal and incorporates the design effect, 46 which is a function of cluster size and interclass correlation coefficient.

Data on prevalence of scabies and impetigo pre and post intervention will be collected from community-based skin examinations at randomly selected villages at baseline and 12 months post intervention. At each time point, a sample will be selected using stratified 2 stage cluster sampling methods routinely utilised in demographic health surveys. The first stage of cluster sampling will be at the nursing zone level. All 36 nursing zones will be eligible, but we will stratify the cluster sampling into 2 strata (urban and rural) to account for possible differences in the epidemiology of scabies. First stage selection will be of 4 nursing zones out of 9 urban ones and 6 out of 27 rural ones, undertaken by random sampling using the method of probability proportional to size. At the second stage, 3 villages/settlements with a population size in the range 50-400 within each nursing zone will be selected using simple random sampling. There are a total of 1478 villages and settlements in the Northern Division, of which 531, covering 51% of the total population, have populations within this range.(17) (18) The target sample size to achieve for the skin examinations is 9000 individuals which will account for approximately 6% of the population.

Data analysis plan
Co-primary outcome measures:
We will calculate annual incidence rates of both primary endpoints (all ages) admissions with severe SSTI, and the combined endpoint of admissions with any of rheumatic fever, glomerulonephritis or invasive infection (in children aged less than 15 years). Incidence rates will be calculated separately for the 12 month pre- and post-intervention periods using census data for the Northern Division as the denominator. We will use Poisson models to assess the impact of MDA by calculating overall, age-specific and ethnicity-specific incidence rate ratios and 95% confidence intervals to compare the pre and post periods.

Secondary outcome measures:
1. The prevalence of scabies and impetigo at survey sites will be calculated at 12 months after MDA and compared to the corresponding calculation at baseline. To obtain confidence intervals and test for significance (a=0.05), we will use generalised estimating equations accounting for 2-level clustering within nursing zones and villages/settlements. The Information Criterion for generalised estimating equations will be computed as a model fit statistic.
2. We will record and report deaths and emergency hospital admissions in the week following MDA, and compare to average counts at corresponding time periods in other years.
3. We will use Poisson models to compare the number of presentations to primary care with scabies and impetigo in the pre- and post-intervention periods. Incidence rate ratios (post vs. pre) and 95% confidence intervals will be calculated. In addition we will compare the quarterly point prevalence of scabies and impetigo in children aged < 1 year before and after MDA.
4. Population coverage (single dose and both doses) of the programme will be measured by doses distributed to individuals divided by total population.
5. Survey questionnaires on acceptability and feasibility will be analysed descriptively using means and proportions, and regression analysis will be used to identify associations with demographic characteristics. Responses from the qualitative interviews will be transcribed and analysed thematically, and triangulated with quantitative results to contextualize them.
6. The cost effectiveness of ivermectin-based MDA compared to standard care will be assessed from the Fijian health care provider perspective by modelling direct medical costs and health outcomes associated with the intervention and standard care. A one-year time horizon will be used in the base case analysis, with 5- and 10-year time horizons explored in scenario analyses to assess the longer-term impact of the intervention. Additional scenario analyses will be carried out to evaluate the impact of different prices of ivermectin, and number of MDA cycles needed over the long term. Sensitivity analyses will be conducted to assess the impact of key parameters and assumptions on the results.


Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/07/2018
Actual
16/07/2018
Date of last participant enrolment
Anticipated
30/06/2019
Actual
11/10/2019
Date of last data collection
Anticipated
20/07/2020
Actual
31/07/2020
Sample size
Target
135000
Accrual to date
Final
139977
Recruitment outside Australia
Country [1] 9640 0
Fiji
State/province [1] 9640 0
Northern Division

Funding & Sponsors
Funding source category [1] 298851 0
Government body
Name [1] 298851 0
National Health and Medical research Council
Country [1] 298851 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Murdoch Children's Research Insititute
Address
Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 298192 0
None
Name [1] 298192 0
N/A
Address [1] 298192 0
N/A
Country [1] 298192 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299795 0
Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 299795 0
Ethics committee country [1] 299795 0
Australia
Date submitted for ethics approval [1] 299795 0
09/03/2018
Approval date [1] 299795 0
13/06/2018
Ethics approval number [1] 299795 0
38020A
Ethics committee name [2] 299803 0
Fiji National Research Ethics Review Committee
Ethics committee address [2] 299803 0
Ethics committee country [2] 299803 0
Fiji
Date submitted for ethics approval [2] 299803 0
09/03/2018
Approval date [2] 299803 0
11/05/2018
Ethics approval number [2] 299803 0
2018.38.NOR.

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81594 0
Prof Andrew Steer
Address 81594 0
Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052
Country 81594 0
Australia
Phone 81594 0
+61393454977
Fax 81594 0
Email 81594 0
andrew.steer@rch.org.au
Contact person for public queries
Name 81595 0
Li Jun Thean
Address 81595 0
Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052
Country 81595 0
Australia
Phone 81595 0
+61393455074
Fax 81595 0
Email 81595 0
lijun.thean@mcri.edu.au
Contact person for scientific queries
Name 81596 0
Li Jun Thean
Address 81596 0
Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052
Country 81596 0
Australia
Phone 81596 0
+61430814254
Fax 81596 0
Email 81596 0
lijun.thean@mcri.edu.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
EmbaseProspective surveillance for invasive Staphylococcus aureus and group A Streptococcus infections in a setting with high community burden of scabies and impetigo.2021https://dx.doi.org/10.1016/j.ijid.2021.05.041
EmbaseProspective surveillance of primary healthcare presentations for scabies and bacterial skin infections in Fiji, 2018-2019.2021https://dx.doi.org/10.4269/ajtmh.20-1459
N.B. These documents automatically identified may not have been verified by the study sponsor.