ANZCTR - Registration

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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 information initially provided

17/02/2020

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]

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

Impetigo

Skin and soft tissue infections

Invasive group A streptococcal infections

Invasive Staphylococcus aureus infection

Post streptococcal glomerulonephritis

Acute rheumatic fever

Rheumatic heart disease

Bacteraemia

Condition category

Condition code

Infection

Other infectious diseases

Public Health

Epidemiology

Public Health

Other public health

Skin

Dermatological conditions

Cardiovascular

Other cardiovascular diseases

Blood

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]

Treatment: Drugs

Intervention code [2]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

The 12-month period following MDA will be compared to the 5 year period prior.

Secondary outcome [5]

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]

This will be evaluated within 1 month of the commencement of the MDA program

Secondary outcome [6]

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]

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]

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]

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]

Fiji

State/province [1]

Northern Division

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical research Council

Address [1]

Research Committee Secretariat
NHMRC GPO Box 1421 Canberra ACT 2601

Country [1]

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]

None

Name [1]

N/A

Address [1]

N/A

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Children's Hospital Human Research Ethics Committee

Ethics committee address [1]

Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/03/2018

Approval date [1]

13/06/2018

Ethics approval number [1]

38020A

Ethics committee name [2]

Fiji National Research Ethics Review Committee

Ethics committee address [2]

Ministry of Health,
Level 2, Dinem House,
88 Amy Street,
Toorak,
Suva,Fiji

Ethics committee country [2]

Fiji

Date submitted for ethics approval [2]

09/03/2018

Approval date [2]

11/05/2018

Ethics approval number [2]

2018.38.NOR.

Summary

Brief summary

This project aims to evaluate the impact of ivermectin mass drug administration (MDA) for scabies in a large population on the incidence of serious bacterial complications that may arise from scabies and associated impetigo. These complications include skin and soft tissue infections, bloodstream infections, invasive bacterial infections, rheumatic fever and kidney disease. The sample studied will be the population of the Northern Division (~135,000 people) of Fiji whereby ivermectin-based MDA will be offered to all consenting individuals. There will be a 12 month period of surveillance pre and post MDA where incidence of these conditions will be monitored via hospital and clinic presentations and selected village site skin examinations. In addition, this study aims to review the safety, coverage, acceptability, feasibility and cost effectiveness of a large MDA programme compared to standard care. The results from this trial will have direct implications on national public health policy in Fiji and more generally populations where scabies is endemic. The findings of reduced bacterial complications from MDA and health cost averted will greatly strengthen the case for targeted global elimination through MDA.

Trial website

Not applicable

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Andrew Steer

Address

Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052

Country

Australia

Phone

+61393454977

Fax

[email protected]

Contact person for public queries

Name

Dr Li Jun Thean

Address

Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052

Country

Australia

Phone

+61393455074

Fax

[email protected]

Contact person for scientific queries

Name

Dr Li Jun Thean

Address

Royal Children's Hospital,
50 Flemington Rd, Parkville VIC 3052

Country

Australia

Phone

+61430814254

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Type	Is Peer Reviewed?	Citations or Other Details
Study results article	Yes	Thean LJ., Jenney a., Engelman D., Romani L., Wand... [More Details]
Study results article	Yes	Thean LJ., Romani L., Engelman D., Jenney A., Wand... [More Details]
Study results article	Yes	Thean, L.J., Jenney, A., Engelman, D., Romani, L.,... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Prospective surveillance of primary healthcare presentations for scabies and bacterial skin infections in Fiji, 2018-2019.	2021	https://dx.doi.org/10.4269/ajtmh.20-1459
Embase	Prospective surveillance for invasive Staphylococcus aureus and group A Streptococcus infections in a setting with high community burden of scabies and impetigo.	2021	https://dx.doi.org/10.1016/j.ijid.2021.05.041

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically