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Trial registered on ANZCTR


Registration number
ACTRN12615001199505
Ethics application status
Approved
Date submitted
21/08/2015
Date registered
4/11/2015
Date last updated
27/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A field trial of co-administration of azithromycin and ivermectin mass drug administration for scabies and trachoma.
Scientific title
A field trial investigating the feasibility and safety of co-administration of azithromycin and ivermectin mass drug administration (MDA) for scabies and trachoma.
Secondary ID [1] 287328 0
None
Universal Trial Number (UTN)
Trial acronym
AIM-SI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Trachoma 295966 0
Scabies 295967 0
Condition category
Condition code
Infection 296247 296247 0 0
Other infectious diseases
Skin 296248 296248 0 0
Other skin conditions
Eye 296794 296794 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single arm prospective community intervention trial.

Participants will be invited to take part in a joint MDA program for trachoma and scabies, with the first trachoma MDA dose at the same time as the first of two scabies MDA doses.
All participants are offered the same treatment regardless of the presence or absence of clinical signs of trachoma or scabies at the time of the intervention.

Trachoma MDA: Participants will be offered 1 oral dose of azithromycin (directly observed) at 20 mg/kg, up to a maximum of 1 gm. Pregnant women will be offered a choice of azithromycin or 1% topical tetracycline (twice daily application to the eye for 3 weeks). Individuals aged less than 6 months will be offered topical tetracycline at the same dose as pregnant women.

Scabies MDA: Participants will be offered 2 doses of oral ivermectin (directly observed) at 200 micrograms/kg 7 days apart. Participants for whom ivermectin is contra-indicated will be offered 2 doses of topical 5% permethrin cream 7 days apart. Topical permethrin will be applied to the whole body in line with standard treatment of scabies.

In a subset of randomly selected villages individuals will undergo a skin check to collect baseline data on the prevalence of scabies and impetigo. Diagnosis is made clinically and no samples are collected. Procedures in these villages are otherwise identical with regards to the MDA intervention.
Intervention code [1] 292647 0
Treatment: Drugs
Comparator / control treatment
Single Arm Study - No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295904 0
Coverage of the MDA in the study population, separate for trachoma and scabies MDA.
This is calculated by
Primary Method: Comparing study records to community population data
Secondary Method: Capture-recapture comparing population present when the D1 and D8 doses of Ivermectin are administered
Timepoint [1] 295904 0
1 Month post first dose administration.
Secondary outcome [1] 316899 0
Occurrence of self-reported short-term adverse events. Data will be collected by report to study staff at D1 and D8.
The most commonly reported adverse events are:
1. Headache
2. Dizziness
3. Itch
4. Tummy pain
5. Nausea
6. Vomiting
7. Diarrhoea
8. Fever
Timepoint [1] 316899 0
As the adverse event profile of single dose Ivermectin is well known the focus is on adverse events that accompany co-administration with Azithromycin.
Adverse event data will therefore be collected 1 week post the first study drug dose (time of co-administration)
Secondary outcome [2] 316900 0
The incidence of serious illness occurring in the study population in the 12 month period after MDA compared to the 12 months prior, assessed by review of community hospital and health facility data. Serious illness will be defined as any illness requiring admission to hospital. Serious illnesses will be categorised and rates per 100,000 population calculated.

Timepoint [2] 316900 0
12 Months post first dose administration.
Secondary outcome [3] 316901 0
The incidence of patients attending health clinics in Choiseul province for skin disease related consultations.
Clinic codes for consultations related to skin disease will be used to determine annual rates per 100,000 population.
Timepoint [3] 316901 0
12 months post first dose administration.
Secondary outcome [4] 316902 0
Incidence of patients admitted to hospitals in Choiseul province with severe SSTI in the 12 month period after MDA compared to the 12 months prior.
Hospital codes for admissions for SSTI will be used to identify patients with SSTI and annual rates per 100,000 population will be calculated.
Timepoint [4] 316902 0
12 months post first dose administration.
Secondary outcome [5] 316903 0
Deaths following MDA, assessed by review of community hospital and health facility data will be counted and death rates per 100,000 population calculated.
Timepoint [5] 316903 0
12 months post first dose administration.
Secondary outcome [6] 318335 0
Prevalence of impetigo at months 12 months in 10 randomly selected villages compared to the 10 independent randomly selected villages where a skin check was conducted at baseline.
Impetigo will be diagnosed clinically using standard methodology.
Timepoint [6] 318335 0
12 months post first dose administration.
Secondary outcome [7] 318411 0
Prevalence of scabies at months 12 months in 10 randomly selected villages as compared to the 10 independent randomly selected villages where a skin check was conducted at baseline.
Scabies will be diagnosed clinically using standard methodology.
Timepoint [7] 318411 0
12 months post first dose administration.

Eligibility
Key inclusion criteria
All community members resident in Choiseul province, Solomon Islands able to be included in the study. Treatment is offered to all individuals regardless of the presence/absence of scabies/impetigo/trachoma at the time of MDA.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Allergy to any of the components of the allocated drug regimen
- Currently on, or has taken ivermectin in the previous 7 days
- Clinical diagnosis of crusted scabies: participants with severe or crusted scabies 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 force of infection associated with these crusted cases from diminishing the effect of the MDA.

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)
The entire province of Choiseul was selected to be included in the study.

This study entails two components.
Mass drug administration which will take place in the entire province and an efficacy subgroup which will take place in ten randomly selected villages at baseline and an additional ten randomly selected villages at 12 months.

MDA Inclusion:
In each community, residents will be identified from the most recently available population lists. Local nurses will inform communities of the forthcoming visit by the study team. In each village community members will be given an opportunity to meet the study team, and to understand what is involved and ask questions.

Prior to performing any study specific procedure, verbal consent will be obtained for each subject. Information sheets explaining the study will be distributed to community nurses who will be trained in explaining the study. These information sheets will also be available to study participants. For subjects below the legal age, a parent or legal guardian must also provide verbal consent.

Skin Survey Subgroup.
In addition to the procedures outlined above for MDA, additional steps will be taken in the 20 randomly selected villages (10 at baseline and 10 at 12 months) where prevalence surveys for scabies and impetigo will be conducted by performing skin examinations. The project coordinator and a study nurse will provide additional information on the skin examination and obtain informed consent.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The aim of the MDA programme is to prove that large scale co-administration for the purposes of NTD control programmes is feasible. As such a formal sample size calculation for the MDA component of the study is not appropriate. In the field MDA programmes cover populations of between 10,000-100,000 people at a time. With an anticipated population of between 25-30,000 people taking part in this MDA project it is anticipated we obtain data sufficient to inform wider co-administration efforts.

Coverage (primary outcome)

We will calculate coverage by age group and sex, separately for azithromycin, for single dose of ivermectin/permethrin and for both doses of ivermecting/permethrin, in two ways. First, we will calculate use as a denominator the populations from the most recently available official admininistrative data. Second, we will use the “capture-recapture” method, making use of the two visits for ivermectin/permethrin administration, to calculate an estimate of population size by age groups and sex. This method makes the assumption that the presence or absence of a person at each of the two visits is a random, independent event, and makes use of the proportion present at both, compared to proportions at one visit only, to calculate a population size estimate.
The coverage estimates from the official administrative data will be used to make comparisons with the coverage rates for azithromycin MDA alone in other provinces of the Solomon islands. These comparisons will be made descriptively, understanding that there are multiple factors that may influence coverage. Other factors that may influence coverage, particularly geographic differences, will be considered. The co-administration will be deemed to have been a success for azithromycin MDA if the coverage falls within the range of coverages achieved in other provinces for azithromycin MDA. For ivermectin/permethrin MDA, single dose coverage should be virtually identical to azithromycin coverage.
In further analyses, will analyse coverage by age group and sex.

Safety (secondary outcome)
We will record the number of self-reported AEs, which will be will be categorized as above and expressed as a rate. The rate from this study will be compared to the rate of AEs described in
25 communities in the previous co-administration study (11-30%) and to studies that have documented AEs for single administration of ivermectin and azithromycin respectively. We will document and report any serious AEs.

We will record and report deaths and emergency hospital admissions in Choiseul province in the 3 months following MDA, and compare to the 3 months prior.

Efficacy against scabies (and impetigo) based on skin examinations:
Prevalence of scabies (and impetigo) at 12 months in 10 villages will be compared to prevalence in 10 independently selected villages at baseline. 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 12 months sampling points. With an anticipated baseline prevalence of 20% for scabies and an anticipated efficacy of the intervention of 80% a subset of 10 randomly selected villages provides adequate power to assess this outcome.

Efficacy against severe SSTI requiring hospitalisations
Annual incidence rates of admissions with severe SSTI will be calculated for the pre- and post- intervention periods. We will use Poisson models to assess the impact of MDA by calculating overall and age-specific incidence rate ratios and 95% confidence intervals.

Efficacy against skin disease as measured by presentations to clinics
We will use Poisson models to compare the number of presentations to primary care for skin-related consultations in the pre- and post-intervention periods. Incidence rate ratios (post vs. pre) and 95% confidence intervals will be calculated.

Recruitment
Recruitment status
Completed
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] 7112 0
Solomon Islands
State/province [1] 7112 0
Choiseul Province

Funding & Sponsors
Funding source category [1] 291889 0
Charities/Societies/Foundations
Name [1] 291889 0
International Trachoma Initiative
Address [1] 291889 0
International Trachoma Initiative, 325 Swanton Way; Decatur, Atlanta, GA USA 30030
Country [1] 291889 0
United States of America
Primary sponsor type
University
Name
Murdoch Childrens Research Institute
Address
9th floor, Royal Children’s Hospital, 50 Flemington Road, Parkville VIC 3052, Australia
Country
Australia
Secondary sponsor category [1] 290554 0
None
Name [1] 290554 0
Address [1] 290554 0
Country [1] 290554 0
Other collaborator category [1] 278581 0
University
Name [1] 278581 0
London School of Hygiene & Tropical Medicine
Address [1] 278581 0
LSHTM
Keppel Street
London
WC1E 7HT
Country [1] 278581 0
United Kingdom
Other collaborator category [2] 278582 0
University
Name [2] 278582 0
Kirby Institute
Address [2] 278582 0
University New South Wales,
Sydney
NSW
2052
Country [2] 278582 0
Australia
Other collaborator category [3] 278583 0
Government body
Name [3] 278583 0
Solomon Islands Ministry of Health and Medical Services
Address [3] 278583 0
MHMS Compound, Chinatown, Honiara
Country [3] 278583 0
Solomon Islands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293397 0
National Health Research Ethics Committee
Ethics committee address [1] 293397 0
Ministry of Health and Medical Services,
Honiara
Ethics committee country [1] 293397 0
Solomon Islands
Date submitted for ethics approval [1] 293397 0
Approval date [1] 293397 0
18/08/2015
Ethics approval number [1] 293397 0
15/33
Ethics committee name [2] 293398 0
Royal Children's Hospital - Human Research Ethics Committee
Ethics committee address [2] 293398 0
Research Ethics and Governance
The Royal Children's Hospital Melbourne
Flemington Road
Parkville
3052
Victoria
Ethics committee country [2] 293398 0
Australia
Date submitted for ethics approval [2] 293398 0
Approval date [2] 293398 0
28/08/2015
Ethics approval number [2] 293398 0
35148A

Summary
Brief summary
This study is designed to evaluate the feasibility and safety of co-administration of azithromycin and ivermectin in large populations in these settings and to provide data to support co-administration in other settings.
Alongside this the study aims to evaluate the effectiveness of large scale ivermectin-based MDA for scabies and to addresses the problem of how to scale up MDA for scabies control in high prevalence countries, and specifically in settings where there is already an infrastructure and established need for trachoma MDA.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59730 0
A/Prof Andrew Steer
Address 59730 0
Murdoch Childrens Research Institute
9th floor, Royal Children’s Hospital, 50 Flemington Road, Parkville VIC 3052
Country 59730 0
Australia
Phone 59730 0
+61 (3) 8341 6200
Fax 59730 0
Email 59730 0
Andrew.Steer@rch.org.au
Contact person for public queries
Name 59731 0
A/Prof Andrew Steer
Address 59731 0
Murdoch Childrens Research Institute
9th floor, Royal Children’s Hospital, 50 Flemington Road, Parkville VIC 3052
Country 59731 0
Australia
Phone 59731 0
+61 (3) 8341 6200
Fax 59731 0
Email 59731 0
Andrew.Steer@rch.org.au
Contact person for scientific queries
Name 59732 0
A/Prof Andrew Steer
Address 59732 0
Murdoch Childrens Research Institute
9th floor, Royal Children’s Hospital, 50 Flemington Road, Parkville VIC 3052
Country 59732 0
Australia
Phone 59732 0
+61 (3) 8341 6200
Fax 59732 0
Email 59732 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