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Trial registered on ANZCTR


Registration number
ACTRN12613000474752
Ethics application status
Approved
Date submitted
17/04/2013
Date registered
29/04/2013
Date last updated
29/04/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
The efficacy of mass drug administration strategies to control scabies in a highly endemic population.
Scientific title
The efficacy of mass drug administration strategies to control scabies in a highly endemic population.
Secondary ID [1] 282141 0
APP1032310 National Health and Medical Research Council (NHMRC)
Universal Trial Number (UTN)
Trial acronym
Skin Health Intervention: Fiji Trial (SHIFT)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Scabies 288640 0
Skin sores 288641 0
Other parasitic diseases (strongyloidiasis, ascariasis and trichuriasis) 288642 0
Lymphatic filariasis 288643 0
Common skin diseases (fungal infections, eczema) 288644 0
Condition category
Condition code
Skin 288981 288981 0 0
Dermatological conditions
Public Health 288982 288982 0 0
Epidemiology
Infection 289277 289277 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This community intervention trial is a prospective comparison of efficacy and safety of 3 different treatment regimens for scabies. Two of the regimens involve Mass Drug Administration (MDA) and the third is standard of care treatment of symptomatic people and their household contacts. Each of the treatment regimens has beenrandomly assigned to the population of 1 of 3 separate island groups, by a person independent form the investigator. After 100% of the sample is reviewed at the initial study visit, study outcomes and adverse events will be assessed at 3 months (analysing 20% of sample), 12 months (entire sample, 100%), and 24 months (20% of sample), with 12 months being the primary endpoint.

Interventions: Each one of the islands will be assigned to one of the following intervention arms. Assignment will be random, but we note that the study is not formally designed as a randomised trial. In all 3 arms, all residents will be invited to participate, and a skin examination will be undertaken at the initial study visit in those who consent to participate.
1. Oral ivermectin based MDA: Participants will be offered 1 dose of oral ivermectin at 200 ug/kg, unless contra-indicated (as follows). Ivermectin will be replaced by topical permethrin 5% cream in the following “ivermectin contra-indication” groups: children under 15 kg, pregnant and breastfeeding women (as according to onchocerciasis guidelines), people with neurologic disease such as Parkinson’s Disease or cerebral palsy, and people taking medication that is metabolised by the cytochrome p450 pathway. We estimate the number excluded from the ivermectin group to be approximately 20% of the population (10% being children under 15kg and 10% due to pregnancy, lactation or other contraindication); we will deal with this in our analysis by using an intention to treat approach. At 1 week, those in whom clinical scabies, itch or rash was observed at the initial visit will be offered a 2nd dose of the same treatment that they received at the initial visit.
2. MDA of topical permethrin 5%: Participants will be offered a dose of topical permethrin cream 5%, followed by a 2nd dose at 1 week for those in whom clinical scabies, itch or rash was observed at the initial visit.
3. Standard of care: Those found to have scabies will be referred to the local health care worker for treatment according to the Fiji IMCI guidelines which advise a single application of permethrin 5% for those with scabies and for their families, and a 2nd dose at 2 weeks if symptoms and signs of scabies persist.

Administration of scabies treatment: Participants assigned to permethrin 5%(either as part of MDA or for clinical reasons) will receive a tube of cream and will be asked to apply the cream from neck to toes, and leave it on for a minimum 8 hours and a maximum of 24 hours. For children aged less than 5 years, parents will be asked to apply cream as a directly observed therapy before they leave the clinic. Older children and adults will be able to apply their treatment at home. For participants assigned to ivermectin, the dose will be determined according to body weight and treatment will be administered under supervision before participants leave the clinic. Participants with very severe or crusted scabies (so-called “Norwegian scabies”) will be treated with 2 doses of ivermectin (except if ivermectin is contraindicated as outlined above) with a second dose being administered at 7 to 14 days, in conjunction with twice weekly permethrin cream for 1 month. In cases where ivermectin is contraindicated, in people with crusted scabies, ivermectin will replaced by two doses of permethrin cream 5%, one at baseline and one at 7 to 14 days, with review at 1, 2, 3,12 and 24 months. The trained study nurse will administered the second dose of treatment to crusted scabies participants and will follow up on adherence weekly and communicate with the study coordinator.
Intervention code [1] 286748 0
Treatment: Drugs
Comparator / control treatment
3. Standard of care arm: Those found to have scabies will be referred to the local health care worker for treatment according to the Fiji IMCI guidelines which advise a single application of permethrin 5% for those with scabies and for their families, and a 2nd dose at 2 weeks if symptoms and signs of scabies persist.
Control group
Active

Outcomes
Primary outcome [1] 289100 0
1. To assess the efficacy of MDA using either a) topical permethrin or b) oral ivermectin for scabies, compared to standard of care treatment using topical permethrin, in an endemic population. Efficacy will be measured by clinical examination for scabies and impetigo using a standardised clinical examination tools.
Timepoint [1] 289100 0
12 months
Primary outcome [2] 289101 0
2. To assess whether oral ivermectin is at least as effective as topical permetrhin as MDA strategy for scabies. Efficacy will be measured by clinical examination for scabies and impetigo using a standardised clinical examination tools.
Timepoint [2] 289101 0
12 months
Secondary outcome [1] 301787 0
3. To assess the safety of MDA using topical permethrin or oral ivermectin. Safety data will be actively collected in the period 7-14 days after administration of medication by direct questions to participants and passively collected for the duration of the study by collection of data from health clinics.
Timepoint [1] 301787 0
12 months
Secondary outcome [2] 301788 0
4. To evaluate the impact of MDA for scabies on other parasitic diseases (strongyloidiasis, ascariasis and trichuriasis), by parasitological examination of stool samples.
Timepoint [2] 301788 0
12 months
Secondary outcome [3] 301789 0
5. To evaluate the cost-effectiveness of the three alternative treatment regimens. Cost effectiveness will be measured by calculation of an incremental cost effectiveness ratio, defined as the incremental cost per case of scabies adverted.
Timepoint [3] 301789 0
12 months

Eligibility
Key inclusion criteria
We have chosen 3 isolated island communities, each with a total population of approximately 800, as the sites for this study. These communities are culturally and geographically similar and are large enough to have a wide distribution of age groups that resembles the national population make up, but are small enough that they are only connected to the main island by a weekly boat service, and so receive relatively few visitors.
All residents of the selected islands, willing to participate and sign a written consent form are eligible to participate in the study.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Person not residents of the selected islands and not willing to sign a written consent form.

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)
Each of the 3 selected islands have been randomly allocated an intervention: oral ivermectin, topical permethrin or standard of care with topical permethrin.
After the an intervention has been randomly allocated to a site, all participants of that site (island) have been invited to participate in the study, they have received oral and written information in the local language and asked to sign a written consent for if willing to participate. Only those who have agreed to sign the consent form have been enrolled in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a "picking number from a hat" procedure. Each intervention was assigned to a number which was put in a box. A person, independent from the study, was assigned to a study site, blinded and asked to pick a number from the hat.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size: The primary end point of the study is the reduction in prevalence of scabies at 12 months from baseline. The main comparison is between the two MDA arms and the standard of care arm at 12 months. Previous research suggests that the overall prevalence of scabies will be approximately 23% at baseline and it might fall to 5% in the MDA arms (using permethrin or ivermectin) compared to 10% in the standard care arm. This difference is the minimum that we would judge to be of clinical relevance. Assuming 80% response rate of the total community of 1000 and 20% loss to follow up at 12 months, a total of 1,920 participants (640 in each of the 3 arms) are needed to detect a difference of 5% (i.e 5% vs 10% at 12 months) between the randomised groups with at least 90% power. The study will also have at least 80% power to show the non-inferiority of oral ivermectin compared to topical permethrin as MDA strategy for a difference of not more than 3% scabies prevalence at 12 months. Also, at 3 months we will collect and analyse scabies prevalence data in 20% of all 3 treatment arms (160 participants in each arm, total 480 participants). These data will be utilised to monitor progress and to provide an update to the participating sites. In the unlikely event that the lower limit of the confidence interval for the reduction in scabies for both MDA arms indicated an absolute drop in prevalence of 3% or less, we will review uptake of the MDA in detail. However, this outcome is unlikely given data from previous studies using ivermectin or permethrin, and if the trial continues the prevalence data at 3 months will be a valuable aid in interpreting findings at 12 months.

Statistical analysis: Analysis will be performed as follows:
1. Efficacy against scabies (and skin sores): The efficacy outcome measures will be combined across the two MDA communities, and compared with the standard treatment community. The statistical test of significance for this comparison, to be applied at the two-sided 0.05 level, will be a modified version of the chi-squared test that takes account of the sample sizes in both the baseline and later sampling points.
2. Efficacy against other conditions: the same analysis method as for 1) will be used for hypertension, anaemia, renal impairment, haematuria, and specific parasitic infections (filariasis, soil transmitted helminiths).
3. Safety: Safety outcomes will be compared as proportions at each time point between the 3 communities, using the chi-squared test.
4. Health economic outcomes (cost-effectiveness analysis CEA): CEA of the alternative treatment strategies will be evaluated using a Markov model (age- and sex-structured) representing the events related to scabies in the participants in the 3 island communities. The CEA will be conducted following recommendations of the Panel on Cost Effectiveness in Health and Medicine. We will compare the incremental costs and health outcomes of standard care with those of each of the 2 MDA arms from the perspective of a single health care payer. The time horizon is over the 2-year study period. A 3% discount rate will be applied to the health outcomes and costs in the second year. Sensitivity analysis will be conducted allowing identification of key factors such as treatment cost, adherence and discount rate (0% and 5%).
The main comparisons will be made initially without accounting for any differences in communities, apart from baseline prevalence of the scabies and age (5 year age groups). Adjustment of comparisons for other factors will be undertaken as secondary analyses only if there is clear evidence of imbalance and these factors appear to be linked to primary outcomes.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 4943 0
Fiji
State/province [1] 4943 0
Eastern Division

Funding & Sponsors
Funding source category [1] 286912 0
Government body
Name [1] 286912 0
National Health and Medical Research Council (NHMRC)
Address [1] 286912 0
Level 1, 16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 286912 0
Australia
Primary sponsor type
Hospital
Name
Murdoch Childrens Research Institute, Royal Children's Hospital
Address
Murdoch Childrens Research Institute
Royal Children's Hospital
Flemington Road, Parkville
Victoria 3052 Australia
Country
Australia
Secondary sponsor category [1] 285699 0
University
Name [1] 285699 0
University of New South Wales
Address [1] 285699 0
High St
Kensington NSW 2052
Country [1] 285699 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288970 0
Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 288970 0
50 Flemington Rd
Parkville, VIC 3052
Ethics committee country [1] 288970 0
Australia
Date submitted for ethics approval [1] 288970 0
21/06/2012
Approval date [1] 288970 0
02/08/2012
Ethics approval number [1] 288970 0
32099A
Ethics committee name [2] 288971 0
Fiji National Health Research Ethics Review Committee
Ethics committee address [2] 288971 0
Dinem House
88 Ami Street
Toorak, Suva
Ethics committee country [2] 288971 0
Fiji
Date submitted for ethics approval [2] 288971 0
17/07/2012
Approval date [2] 288971 0
20/09/2012
Ethics approval number [2] 288971 0
2012 47

Summary
Brief summary
Scabies is a major cause of morbidity in many developing countries, and leads to economic disadvantage and reduced quality of life. This proposal addresses the problem of scabies control in high prevalence countries, through the investigation of the efficacy of two alternative mass drug administration (MDA) regimens in Fiji compared to the current standard of care, which centres on treatment of symptomatic cases and their direct contacts.

AIMS
Primary Aims:
1. To assess the efficacy of MDA using either a) topical permethrin or b) oral ivermectin for scabies, compared to standard of care treatment using topical permethrin, in an endemic population.
2. To assess whether oral ivermectin is at least as effective as topical permetrhin as MDA strategy for scabies.
Secondary Aims:
3. To assess the safety of MDA using topical permethrin or oral ivermectin
4. To evaluate the impact of MDA for scabies on other parasitic diseases (strongyloidiasis, ascariasis and trichuriasis).
5. To evaluate the cost-effectiveness of the three alternative treatment regimens.
Hypotheses:
1. Scabies prevalence following MDA treatment protocols using permethrin or ivermectin will be lower than under the standard care treatment.
2. Oral ivermectin will be at least as effective as topical permethrin as MDA.
3. MDA using permethrin or ivermectin is safe.
4. There will be a reduction in the prevalence of other parasitic diseases following MDA, compared to standard of care for scabies.
5. MDA of scabies using permethrin or ivermectin will be cost-effective compared with standard of care treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38562 0
Dr Andrew Steer
Address 38562 0
Centre for International Child Health
Murdoch Childrens Research Institute (MCRI)
50 Flemington Rd, Parkville
Victoria 3052
Country 38562 0
Australia
Phone 38562 0
+61393454977
Fax 38562 0
Email 38562 0
Andrew.Steer@rch.org.au
Contact person for public queries
Name 38563 0
Dr Andrew Steer
Address 38563 0
Centre for International Child Health
Murdoch Childrens Research Institute (MCRI)
50 Flemington Rd, Parkville
Victoria 3052
Country 38563 0
Australia
Phone 38563 0
+61393454977
Fax 38563 0
Email 38563 0
Andrew.Steer@rch.org.au
Contact person for scientific queries
Name 38564 0
Dr Andrew Steer
Address 38564 0
Centre for International Child Health
Murdoch Childrens Research Institute (MCRI)
50 Flemington Rd, Parkville
Victoria 3052
Country 38564 0
Australia
Phone 38564 0
+61393454977
Fax 38564 0
Email 38564 0
Andrew.Steer@rch.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary