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Trial registered on ANZCTR


Registration number
ACTRN12618001086257
Ethics application status
Approved
Date submitted
20/06/2018
Date registered
28/06/2018
Date last updated
23/07/2019
Date data sharing statement initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Regimens of Ivermectin for Scabies Elimination: a cluster randomised non-inferiority trial of one versus two doses of ivermectin for the control of scabies using a mass drug administration strategy.
Scientific title
Regimens of Ivermectin for Scabies Elimination: a cluster randomised non-inferiority trial of one versus two doses of ivermectin for the control of scabies using a mass drug administration strategy.
Secondary ID [1] 295252 0
Nil known
Universal Trial Number (UTN)
Trial acronym
RISE (Regimens of Ivermectin for Scabies Elimination)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Scabies 308419 0
Impetigo 308422 0
Soil transmitted helminths 313766 0
Condition category
Condition code
Infection 307408 307408 0 0
Other infectious diseases
Public Health 307409 307409 0 0
Other public health
Skin 307440 307440 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a community-based study of mass drug administration (MDA). All community members of selected villages are eligible for participation and all community members who have provided consent are able to be included. Treatment will be offered to all consenting community members, regardless of scabies diagnosis, who do not meet the exclusion criteria for treatment:
- Allergy to any of the components of the allocated drug regimen,
- Currently on, or has taken ivermectin in the previous 7 days,
- Has had topical 5% permethrin applied within previous 7 days,
- Refusal to take treatment,
- Considered by study nurses to be too ill for treatment

This study investigates the efficacy of two alternative MDA strategies of oral ivermectin for scabies control, namely one dose (Group 1) and two doses (Group 2).
1. Group 1 - Oral ivermectin-based MDA (single dose): Participants will be offered 1 dose of oral ivermectin at 200ug/kg unless contra-indicated. Ivermectin will be replaced by topical permethrin cream in "ivermectin contraindication" groups (see below) as per guidelines for onchocerciasis programmes and product information (Onchocerciasis and Its Control, 1995, Report of a WHO Expert Committee on Onchocerciasis Control, World Health Organisation; Product Information Iver P Ivermectin 3mg tablet, 2015, Elea Argentina). No treatment will be given to participants who are considered by the study nurse to be extremely ill as they will be unable to provide consent.
2. Group 2 - Oral ivermectin based MDA (two-doses): Participants will be offered the first dose of MDA treatment as in the single dose group, and then a second dose 7 to 14 days later, identical to the first. Contra-indication guidelines will be followed as per group 1.

Ivermectin is a registered, routinely manufactured and marketed drug produced respectively by Elea Laboratories.

The dose of ivermectin will be determined according to body weight and/or height, and treatment will be administered under direct supervision before participants leave the clinic. The recommended dose for scabies is 200 µg/kg. The dose range of 160-250 µg/kg is being used so the tablets can be cut evenly for distribution. The weight range used in this study is narrower than that recommended on the Product Information booklet so that a more accurate dose equivalent to 200 µg/kg can be delivered. The ivermectin dosage per weight for scabies MDA (dose 1 and dose 2) will be as follows:
15-18 kg 3.0 mg
19-27 kg 4.5 mg
28-36 kg 6.0 mg
37-55 kg 9.0 mg
56-74 kg 12.0 mg
75-100 kg 15.0 mg
>100kg 18.0 mg

Ivermectin will be replaced by topical permethrin cream in the following cases:
" pregnant women
" mothers nursing infants during the first week of life
" children under 12.5kg or 90cm
Any medication that participants are taking will be cross checked against the list of medications that interact with ivermectin and are contraindicated.

All participants will be screened for contraindications for ivermectin. Participants will be asked whether they think they are pregnant and/or breastfeeding. If a participant is pregnant or unsure if pregnant, topical permethrin cream will be offered instead of oral ivermectin. Children under 12.5kg / 90cm will be offered permethrin cream. Participants with neurologic diseases such as Parkinson's Disease or cerebral palsy, and people taking medication that is metabolised by the cytochrome p450 pathway will be offered permethrin cream. Any medication that participants are taking will be cross checked against the list of medications that interact with ivermectin or permethrin and are contraindicated.

If a participant is allergic or hypersensitive to any component of ivermectin, permethrin or crotamiton, that medication will not be offered.
Intervention code [1] 301586 0
Treatment: Drugs
Comparator / control treatment
Control group is Group 2 who will receive the standard dosing regime, one dose at day 1 followed by a second dose 7 to 14 days later, identical to the first.

The second dose will be administered by the study team as directly observed therapy.
Control group
Dose comparison

Outcomes
Primary outcome [1] 306383 0
The prevalence of scabies at month 12 compared to month 0 by study treatment arm, assessed by skin examination performed by trained nurse examiners.
Timepoint [1] 306383 0
12 months following MDA.
Secondary outcome [1] 348300 0
The prevalence of scabies at month 24 compared to month 0 by study treatments, assessed by skin examination performed by trained nurse examiners.
Timepoint [1] 348300 0
24 months following MDA.
Secondary outcome [2] 348301 0
The prevalence of impetigo at month 24 and 12 compared to month 0 by study treatments, assessed by skin examination performed by trained nurse examiners.
Timepoint [2] 348301 0
Both 12 and 24 months following MDA.
Secondary outcome [3] 348302 0
The prevalence of presentations to primary health clinics by age group (less or greater than 1 year) with scabies at month 24 compared to month 0 by study treatments.

For this outcome, passive surveillance will entail reviewing routinely collected summary data from hospital records at Gizo Hospital.
Timepoint [3] 348302 0
24 months following MDA.
Secondary outcome [4] 348303 0
The number of adverse events measured by passive surveillance in the 12 months after MDA compared by study treatments. Adverse events will be monitored through passive surveillance for 24 months after the intervention by review of clinic records. Clinic records will be reviewed 24 months after MDA, and the number of AEs reported by study participants in the time period between MDA and the 24-month point will be collected.

Ivermectin is considered to have a very good safety profile and over 1 billion single doses have been distributed for the control of neglected tropical diseases wordwide. There have been little or no adverse events other than minor reversible events. (Mectizan Donation Program. www.mectizan.org (accessed 17/03/2010); Tielsch JM, Beeche A. Impact of ivermectin on illness and disability associated with onchocerciasis. Trop Med Internat Health 2004; 9(4): A45-56; Ottesen EA, Hooper PJ, Bradley M, Biswas G. The global programme to eliminate lymphatic filariasis: health impact after 8 years. PLoS Negl Trop Dis 2008; 2(10): e317)

Adverse reactions listed are listed as per the product information statement from Elea for Iver P, Ivermectin 3mg. Side effects and adverse events are generally mild and last only a short period. Adverse events include the Mazzotti reaction (when used for microfilariasis), pruritus, conjunctivitis, arthralgia, myalgia, fever, edema, lymphadenitis, adenopathies, nausea, vomiting, diarrhoea, orthostatic hypotension, tachycardia, asthenia, rash and headaches. Ophthalmological side effects are also reported. These include eye discomfort, eyelid oedema, anterior uveitis, conjunctivitis, limbitis, keratitis, chorioretinitis or choroiditis. Other reported side effects include; somnolence , non-specific temporary ECG, temporary eosinophilia, high levels of transaminases, increased haemoglobin, conjunctival haemorrhage, orthostatic hypotension, worsening of bronchial asthma, toxic epidermal necrolysis, Stevens-Johnson syndrome, seizures, hepatitis and increase of bilirubin.
Timepoint [4] 348303 0
12 months following MDA.
Secondary outcome [5] 348444 0
The prevalence of presentations to primary health clinics by age group (less or greater than 1 year) with impetigo at month 24 compared to month 0 by study treatments.

For this outcome, passive surveillance will entail reviewing routinely collected summary data from hospital records at Gizo Hospital.
Timepoint [5] 348444 0
24 months following MDA
Secondary outcome [6] 372918 0
The prevalence of each STH (Ascaris spp., Necator americanus, Ancylostoma spp. and Trichuris spp.). For this outcome, stool collection will take place at baseline, 12 and 24 months and will be tested for STH using quantitative PCR.
Timepoint [6] 372918 0
Both 12 and 24 months following MDA
Secondary outcome [7] 372919 0
The intensity of each STH (Ascaris spp., Necator americanus, Ancylostoma spp. and Trichuris spp.). For this outcome, stool collection will take place at baseline, 12 and 24 months and will be tested for STH using quantitative PCR.
Timepoint [7] 372919 0
At both 12 and 24 months after MDA.

Eligibility
Key inclusion criteria
All community members of selected villages who have provided consent are able to be included in this study. Provision of consent at baseline is for skin examination and treatment (as per allocated group), unless exclusion criteria for treatment are met in which case only skin examination will be conducted.
Consent will be obtained at 12 months and at 24 months for skin examination only and all individuals who provide consent at these times will be included in the follow up assessment.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
If a potential participant meets any of the following exclusion criteria, they will be able to be included in the study (i.e. be enrolled and undergo skin examination) but will not receive treatment:
- Allergy to any of the components of the allocated drug regimen,
- Currently on, or has taken ivermectin in the previous 7 days,
- Has had topical 5% permethrin applied within previous 7 days,
- Refusal to take treatment,
- Considered by study nurses to be too ill for treatment

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)
Allocation will be undertaken by a study statistician using computerised central randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Islands will be randomly assigned to one of the treatment arms in a 1:1 ratio. A randomised list will be prepared by the study statistician.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample size calculations were based on the primary outcome, the difference in prevalence of scabies between month 0 and month 12 in each arm. A standard Monte Carlo simulation method with 1000 repetitions was used to estimate the required sample size and number of villages to achieve statistical power of 80% (Boos D, Stefanski LA. Monte Carlo Simulation Studies. Springer Text in Statistics; 2012: 363-83). Based on preliminary data, it was conservatively assumed that scabies prevalence across villages varies between 10% and 30% (mean 20%, standard deviation, SD, 5%) at baseline. Using the effect size measured in SHIFT, it was assumed that in the two-dose regimen, the prevalence of scabies in villages measured at 12 months would be between 1% and 5% (mean 3%, SD 1%), while in the one-dose regimen a prevalence between 3% and 9% was assumed (mean 6%, SD 2%). The average cluster (village) size was assumed to be 250 individuals with a range of 200 to 300.

A non-inferiority margin of + 5% (12-month scabies prevalence one-dose regimen minus 12-month scabies prevalence two-dose regimen) is considered clinically relevant. The one-dose regimen would be described as non-inferior to the two-dose regimen if the upper-bound of the two-sided 95% confidence interval for the difference in prevalence was less than or equal to 5%. Based on these assumptions, 20 villages randomised equally (10 in each arm) would be sufficient to achieve the required power.
Based on previous studies, the expected prevalence of scabies should fall below 2% in the two-dose arm. If the upper limit of the 95% confidence interval falls within the 5% margin then the difference is considered of clinical and public health relevance.

There is sufficient sample size to measure all secondary outcomes.

A standard approach for analysis of cluster randomised clinical trial data will be employed. In each village, the prevalence of scabies will be calculated at baseline, 12 months and 24 months. The prevalence of scabies will be calculated by dividing the number of participants who show signs of scabies on skin examination by the denominator. The denominator for prevalence calculations will be all community members that consented at each timepoint regardless of whether they received treatment or not - that is, the same participants will not necessarily attend at all 3-time points.

For each village, the difference in prevalence between baseline and 12 months will be calculated. The means of these differences will be calculated in the two treatment arms and compared between the two treatment arms by calculating the difference between the means and the ratio of the means. If the upper limit of the two-sided 95% confidence interval of the mean difference between the two study arms is less than or equal to 5% (the clinically relevant non-inferiority margin) the one-dose regimen would be described as non-inferior.

The analysis will be based on the intention to treat population, including all participants in each village regardless of actual treatment status. The secondary study outcomes will be analysed using the same methodology.

Recruitment
Recruitment status
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] 10573 0
Solomon Islands
State/province [1] 10573 0
Western Province

Funding & Sponsors
Funding source category [1] 299842 0
Government body
Name [1] 299842 0
National Health and Medical Research Council
Address [1] 299842 0
16 Marcus Clarke Street, Canberra City, ACT 2600
Country [1] 299842 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
Royal Children's Hospital, 50 Flemington Road, Parkville, VIC 3052
Country
Australia
Secondary sponsor category [1] 299196 0
None
Name [1] 299196 0
None
Address [1] 299196 0
None
Country [1] 299196 0
Other collaborator category [1] 280185 0
Other
Name [1] 280185 0
The Kirby Institute
Address [1] 280185 0
Level 6, Wallace Wurth Building, High Street, Kensington, NSW 2052
Country [1] 280185 0
Australia
Other collaborator category [2] 280186 0
University
Name [2] 280186 0
Australian National University
Address [2] 280186 0
The Australian National University, Canberra, ACT 2600
Country [2] 280186 0
Australia
Other collaborator category [3] 280187 0
University
Name [3] 280187 0
The London School of Hygiene and Tropical Medicine
Address [3] 280187 0
Keppel St, Bloomsbury, London WC1E 7HT, United Kingdom
Country [3] 280187 0
United Kingdom
Other collaborator category [4] 280188 0
Government body
Name [4] 280188 0
Solomon Islands Ministry of Health
Address [4] 280188 0
Ministry of Health Building, Chinatown, Honiara, Solomon Islands
Country [4] 280188 0
Solomon Islands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300719 0
The Royal Children's Hospital Human Research Ethics Committee [EC00238]
Ethics committee address [1] 300719 0
Royal Children's Hospital, 50 Flemington Road, Parkville, VIC 3052
Ethics committee country [1] 300719 0
Australia
Date submitted for ethics approval [1] 300719 0
11/04/2018
Approval date [1] 300719 0
07/05/2019
Ethics approval number [1] 300719 0
38099A
Ethics committee name [2] 300746 0
Solomon Islands Ministry of Health Ethics Committee
Ethics committee address [2] 300746 0
Ministry of Health Building, Chinatown, Honiara, Solomon Islands
Ethics committee country [2] 300746 0
Solomon Islands
Date submitted for ethics approval [2] 300746 0
15/06/2018
Approval date [2] 300746 0
17/05/2019
Ethics approval number [2] 300746 0
HRE005/18

Summary
Brief summary
Mass drug administration using oral Ivermectin has been shown to be highly effective for the control fo endemic scabies. However, a potential barrier to its widespread use a a public health initiative is that, unlike some other neglected tropical diseases, the optimal treatment of scabies requires two doses of ivermectin, one week apart. This dosing schedule doubles the drug costs as well as increasing the infrastructure requirements. This study aims to determine if one dose of ivermectin is as effective as the traditional dosing schedule in reducing population prevalence of scabies in an MDA strategy. The study will be conducted in the Western Province of the Solomon Islands where previously numerous observational and interventional research on scabies has been conducted and where scabies is known to be endemic. This trial will inform health policy in the Pacific and have major public health implications for the many other countries where scabies is endemic.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84594 0
Prof Andrew Steer
Address 84594 0
Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville 3052, VIC
Country 84594 0
Australia
Phone 84594 0
+61 1300766439
Fax 84594 0
Email 84594 0
Andrew.Steer@rch.org.au
Contact person for public queries
Name 84595 0
Prof Andrew Steer
Address 84595 0
Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville 3052, VIC
Country 84595 0
Australia
Phone 84595 0
+61 1300766439
Fax 84595 0
Email 84595 0
Andrew.Steer@rch.org.au
Contact person for scientific queries
Name 84596 0
Prof Andrew Steer
Address 84596 0
Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville 3052, VIC
Country 84596 0
Australia
Phone 84596 0
+61 1300766439
Fax 84596 0
Email 84596 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 other documents available
Summary results
No Results