co-administration of azithromycin and ivermectin mass drug administration (MDA)

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Research paper for medical peer review journal. The paper is half written but need to be completed and be coherent. It will go to top journal in the field so experience writer only.
Protocol Version 1
A field trial of co-administration of azithromycin and ivermectin mass drug administration (MDA)
VERSION 01 June 2nd 2015
CONFIDENTIAL
This document is confidential and the property of Murdoch Childrens Research Institute. No part of it may be transmitted reproduced published or used without prior written authorization from
the institution.
STATEMENT OF COMPLIANCE
This document is a protocol for a clinical research study. The study will be conducted in compliance with all stipulations of this protocol the conditions of ethics committee approval the NHMRC
National Statement on Ethical Conduct in Human Research (2007) and the Note for Guidance on Good Clinical Practice (CPMP/ICH-135/95
PROTOCOL SYNOPSIS
Title A field trial of co-administration of azithromycin and ivermectin mass drug administration (MDA)
Objectives Primary Aims:
To assess the feasibility of conducting a joint MDA for trachoma and scabies control in a large population.
Secondary Aims:
1. To assess the safety of co-administration of azithromycin and ivermectin MDA for trachoma and scabies control.
2. To assess the efficacy of MDA for scabies and impetigo control in large island population
Design A prospective community intervention trial to assess the feasibility safety and efficacy of MDA for trachoma and scabies control in Choiseul province of the Solomon Islands.
Outcomes The primary outcome is the coverage of the MDA in the study population separate for trachoma and scabies MDA.
The secondary outcomes are: 1) the incidence of serious illness and deaths occurring in the study population in the 3 month period after MDA compared to the 3 months prior; 2) the proportion of
people self-reporting adverse events following receipt of the MDA drugs compared to previously reported rates for the agents; 3) the prevalence of scabies and impetigo at 12 months after MDA in 10
randomly selected villages compared to the prevalence at baseline (day 1) in 10 independent randomly selected villages; 4) the incidence of patients attending health clinics in Choiseul province
for skin disease related consultations.
Study Duration 1 year
Interventions 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.
Trachoma MDA: Participants will be offered 1 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 topical
tetracycline. Individuals aged less than 6 months will be offered topical tetracycline.
Scabies MDA: Participants will be offered 2 doses of oral ivermectin (directly observed) at 200 g/kg 7 days apart. Participants for whom ivermectin is contra-indicated will be offered 2 doses of
topical permethrin cream 7 days apart.
Number of subjects Approximately 26000 people
Population All individuals living in Choiseul province who agree to participate.
GLOSSARY OF ABBREVIATIONS
ABBREVIATION TERM
AE Adverse Events
NCCDC National Centre for Communicable Disease Control
MCRI Murdoch Childrens Research Institute
LSHTM London School of Hygiene & Tropical Medicine
MDA Mass Drug Administration
MHMS Ministry of Health and Medical Services
NHMRC National Health and Medical Research Council
NTD Neglected Tropical Diseases
SAE Serious Adverse Events
SOP Standard Operating Procedures
SSTI Skin and Soft Tissue Infections
UNSW University of New South Wales
WHO World Health Organization
1. INVESTIGATORS AND FACILITIES
1.1 Study Locations
Choiseul Province is one of ten provinces of the Solomon Islands and has a total population of approximately 26000 people. The province consists of 14 wards. Health care is provided by 17 nurse
aid posts 10 rural health clinics 1 area health centre and 2 hospitals. In 2014 the Solomon Islands government began implementing MDA for trachoma in 9 out of its ten provinces as part of the WHO
SAFE strategy.1 Following a recent regional trachoma meeting the government recently decided to complete the national coverage by adding the province of Choiseul.
Figure 1. Communities chosen for the study
1.2 Study Management
The trial will be coordinated by a research team led by the principal investigator a study doctor and a study coordinator. Informed consent discussions and clinical assessments will be conducted
by trained nursing study staff the study doctor and the study coordinator. The study coordinator will be delegated responsibility for subjects follow-up visits data collection and maintenance of
study documentation. Handling of investigational products will be the responsibility of the study coordinator under supervision from the Principal investigator.
1.2.1 Principal Investigator
Associate Professor Andrew Steer MBBS PhD
Murdoch Childrens Research Institute
Phone: +613 9345 4638
Fax: +613 9345 6667
Email: [email protected]
1.2.2 Statistician and other investigators
Statistician:
Associate Professor Handan Wand
Kirby Institute University of New South Wales
Sydney Australia
Phone: +61 2 9385 0861
Email: [email protected]
Other investigators and members of the Research Team
Mr Oliver Sokana
NTD Officer
Solomon Islands Ministry of Health
Dr Titus Nasi
Paediatrician
Solomon Islands Ministry of Health
Professor John Kaldor
Epidemiologist
Kirby Institute University of New South Wales
Dr Michael Marks
Clinical Research Fellow
London School of Hygiene and Tropical Medicine
Ms Lucia Romani
Study Coordinator
Kirby Institute University of New South Wales
Dr Daniel Engelman
Paediatrician
Murdoch Childrens Research Institute
Dr Margot Whitfeld
Dermatologist
University of New South Wales
1.2.3 Internal Trial Committees
A trial steering committee will be established to provide general oversight of the trial including decisions on protocol development and protocol deviations response to issues arising throughout
trial and interpretation of findings.
1.2.4 Independent Safety and Data Monitoring Committee
An independent data and safety monitoring committee will be established to oversee the safety and progress of the trial.
1.3 Sponsor
Murdoch Childrens Research Institute
1.4 Funding and resources
Funding for the study is from Murdoch Childrens Research Institute University of New South Wales and the London School of Hygiene and Tropical Medicine.
2. INTRODUCTION AND BACKGROUND
2.1 Background Information
Mass Drug Administration
MDA for neglected tropical diseases has made a major contribution to public health across the world. Over the past two decades the MDA strategy has been adopted to treat whole populations that are
infected or at risk of infection without requiring individual diagnosis. The biological basis of MDA varies across pathogens but generally rests on the premise that the chain of transmission can
only be broken by targeting people regardless of symptoms or other evidence of the presence of infection. MDA has been highly effective in the control of several major neglected tropical diseases
and is supported by WHO and multiple partners through large regional and global programmes such as the Global Elimination of Trachoma (GET 2020) the Global Lymphatic Filariasis Elimination
Programme the Onchocerciasis Elimination Programme in the Americas and the African Programme for Onchocerciasis Control. The five pharmaceutical agents that have been particularly prominent in MDA
are ivermectin azithromycin albendazole diethylcarbamzine and praziquantel. Over 700 million people receive these essential medicines annually with ivermectin by the far the most frequently
delivered drug.
MDA in the Solomon Islands for trachoma
Trachoma is the most common infectious cause of blindness globally. It is caused by ocular infection with Chlamydia trachomatis. Transmission is favoured in poor communities where crowding is
common and access to water and sanitation inadequate. Repeated reinfection over many years causes scarring of the upper eyelid. The resultant inversion of the lashes abrades the eyeball and the
abrasion leads to corneal opacification and visual impairment. The SAFE strategy is used for the control of trachoma: surgery for inturned lashes antibiotics for active disease facial
cleanliness and environmental improvement.2
The World Health Organization (WHO) recommends that a country conduct mass drug administration with azithromycin in areas where the prevalence of trachomatous follicular inflammation (TF) is above
10% in children aged 1-9 years old. Provincial trachoma assessments were completed by the Solomon Islands Ministry of Health and Medical Services (MHMS) between 2011-13. Nine out of ten provinces
met the WHO criteria for conducting mass drug administration and this was undertaken in 2014. Choiseul was the only province in which MDA was not initially conducted.
A regional trachoma meeting was held in Suva Fiji in March 2014 attended by the WHO Fred Hollows Foundation and MHMS. Due to the small population size of several provinces in the Solomon Islands
it was agreed to form three larger evaluation units for trachoma control activities. Choiseul province was therefore included in an evaluation unit with Western province. The prevalence of TF in
this new evaluation unit was above 10% and it was therefore recommended that MHMS conduct MDA in Choiseul province.
The problem of scabies
Scabies is a skin disease caused by a tiny mite (Sarcoptes scabiei) that burrows under the skin and is transmitted through close personal contact.3 Scabies and its complications particularly affect
young children especially in topical developing countries.3 The direct effect of scabies is debilitating itching leading to scratching which is in turn followed by complications due to bacterial
infection of the skin ranging from impetigo abscesses and cellulitis through to septicaemia renal failure and possibly rheumatic heart disease.3
The World Health Organization estimates that over 100 million people worldwide are affected by scabies each year. Countries of the Pacific region are recognised as having a particularly high burden
of scabies and its complications.4 Multiple published and unpublished studies in Fiji the most populous developing country of the Pacific apart from Papua New Guinea have systematically
documented scabies at minimum prevalence of 20%5-7 among the highest in the world. Scabies has been consistently neglected as a priority for health programs and research perhaps because its
impact is spread across a broad range of disciplines including dermatology infectious diseases and paediatrics. Endemic scabies is also primarily a disease of tropical developing countries where
resources for new health initiatives are scarce. However the recent addition of scabies to the list of WHO NTDs in 2013 demonstrates the increasing global interest in public health strategies for
scabies control.8
Scabies in the Solomon Islands
Scabies infestation in the Solomon Islands is common affecting over 15% of the population in a number of population-based studies. The most recent study conducted in August 2014 in Western
Province neighbouring Choiseul found an all ages prevalence of 19.2% (unpublished data Andrew Steer). This study found that the highest prevalence was in children aged less than 1 year (37.1%).
More than half of the participants in this study with scabies had moderate or severe scabies (>10 lesions). Impetigo was also very common with a prevalence of 32.7%.
Public health control of scabies
Given this burden of disease there is a need for effective public health control of scabies. Standard approaches to scabies control focus on people with symptoms and their immediate household
contacts. Guidelines used in Australia Fiji and most other countries call for treatment with topical cream (permethrin) and follow up review in 2 weeks. Treatment of the affected persons family
members is also recommended using the same regimen of permethrin 5 to reduce the chance of re-infestation. Currently topical benzyl-benzoate is the recommended first line treatment in the Solomon
Islands (Solomon Islands Standard Treatment Manual for Children 3rd Edition 2009). Apart from topical agents one oral agent ivermectin has been recommended for scabies treatment using a single
tablet for initial treatment with a repeated dose at 1 to 2 weeks because ivermectin kills the mite but not the eggs a single dose may be inadequate to eradicate the different stages of the
parasite.9 Ivermectin is listed as an alternative agent for the treatment of scabies in the Solomon Islands (Solomon Islands Standard Treatment Manual for Children 3rd Edition 2009). Ivermectin is
available in Australia and is listed on the Pharmaceutical Benefits Scheme for scabies treatment as second line treatment for scabies after failure of topical treatment and as first line for
crusted scabies.9 The strategy of treating clinical cases of scabies and their contacts has been in place for many years and although it has undoubtedly provided relief for many people with
scabies there is no published evidence to indicate success in reducing community prevalence long-term. There are two main reasons why an individual-based approach has been ineffective in
controlling endemic scabies. First adherence to treatment may be incomplete particularly among family members without symptoms for whom treatment is prescribed based on the presence of an index
case. As an example <50% of household contacts of children with scabies (<50%) were found to be adherent to treatment in a study in the Northern Territory of Australia.10 Second there is likely to be a substantial pool of infestation in households without symptomatic cases which acts as a source of re-infestation when members of these untreated households come in contact with people who have been recently treated. With the recent recognition of the inadequacy of individual-based treatment for scabies control attention has shifted to the potential role of MDA. Evidence for effectiveness of MDA using ivermectin for scabies We now have strong evidence that MDA is a highly effective and safe approach to the control of scabies in small populations. Studies in Panama had already shown the MDA with topical permethrin might be effective. 11 The earliest evidence that MDA with ivermectin was an effective control strategy comes from a study conducted in the Lau Lagoon Malaita Province by MHMS and collaborators from Australia. In a study conducted in 1997-2000 they found that mass treatment with ivermectin significantly reduced the prevalence of scabies in children. In Zanzibar an MDA program using ivermectin for lymphatic filariasis was implemented and the rate of clinical consultation for scabies fell by 90% as did requests for distribution of medication.12 None of these studies had a control group so in the recently concluded NHMRC funded Skin Health Intervention Fiji Trial (SHIFT) we randomly assigned three island communities to one of three different interventions for scabies control: standard care based on permethrin treatment of clinical cases and their contacts; permethrin-based MDA; or ivermectin-based MDA. In the ivermectin arm one dose of ivermectin was given to all participants with a second dose for those clinically diagnosed with scabies; pregnant women and children and others with a contra-indication for ivermectin received permethrin. The primary endpoint was the change in prevalence of scabies at one year. A total of 2051 participants were enrolled across the three arms and at baseline scabies prevalence was similarly high in all arms 36.6% 41.7% and 32.1% respectively (Table below). At 12 months scabies prevalence declined significantly in all arms with the greatest reduction in the ivermectin arm with relative risk reduction 94% compared to 62% and 49% in the permethrin and standard care arms respectively. The prevalence of impetigo declined similarly with the greatest reduction in the ivermectin arm (67%). Preliminary analysis of data at 24 months shows that the effect of ivermectin based MDA persists over 2 years with a prevalence of 3.7% in this group compared to 13.4% and 15.4% in the permethrin and standard care arms respectively. All adverse events were mild and reported more frequently in the ivermectin arm compared to the permethrin arm (15.6% vs 6.8%). We concluded that standard care for scabies when applied systematically under trial conditions could reduce the prevalence significantly and topical permethrin was even better. However the really impressive finding was the size and sustainability of the reduction in prevalence in the ivermectin-based MDA group. Study arm Baseline prevalence (95% CI) Prevalence at 12 months (95% CI) Relative Risk reduction (95% CI) Ivermectin MDA Scabies 32.1% (28.8 35.6) 1.9% (0.9 3.3) 94% (83 100) Impetigo 24.6% (21.6 27.9) 8.0% (6.1 -10.5) 67% (52 83) Permethrin MDA Scabies 41.7% (37.6 46.0) 15.8% (12.6 19.5) 62% (49 75) Impetigo 24.6% (21.2 28.5) 11.3% (8.8 14.6) 54% (35 73) Standard Care Scabies 36.6% (33.4 40.0) 18.8% (16.0 21.8) 49% (37 60) Impetigo 21.4% (18.7 24.4) 14.6% (12.3 17.3) 32% (14 -50) Findings from the SHIFT trial in Fiji are now the strongest evidence in favour of MDA for scabies and add to the earlier non-controlled studies that supported this approach. Azithromycin Azithromycin is an azalide antibiotic a subclass of the macrolides. After oral administration peak plasma concentration is reached in 2 to 3 hours. Tissue levels of azithromycin are greater than plasma levels (up to 50 times the maximum plasma concentration). Biotransformation occurs mainly in the liver with elimination mainly by the bile and partly by urine. The plasma terminal half-life is 2-4 days.13 Azithromycin is indicated for mild to moderate infections such as respiratory-tract infections otitis media skin and soft-tissue infections genital chlamydial infections and non-gonococcal urethritis caused by susceptible strains of microorganisms.13 Azithromycin is the treatment of choice for mass treatment of trachoma.1415 The recommended dose for the mass treatment of trachoma is a single-dose of azithromycin 20mg/kg up to a maximum of 1g.1415 Azithromycin is available as 250 mg or 500 mg tablets and as oral suspension.13 Safety of azithromycin The safety profile of single dose azithromycin monotherapy is well known.1617 Azithromycin is considered the standard treatment for trachoma both as therapy and in MDAs and has been employed for over 10 years in trachoma control programs.14 An active population-based surveillance of multiple communities in Ethiopia found a low prevalence of AEs after mass azithromycin distribution. The most frequently observed AEs (between 1 and 10%) were nausea vomiting and diarrhea. AEs were more common in persons who had recently received azithromycin treatment and in older persons. AEs appeared to cluster by household and perhaps by village. The authors concluded This study provides further evidence that community-wide azithromycin treatments for trachoma as advocated by the WHO are safe.16 The AE profile was similar to that seen in other populations given a single high dose of azithromycin.17-22 Ivermectin Ivermectin is an anthelminthic. Ivermectin is metabolized in the liver and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days with less than 1% of the administered dose excreted in the urine. After oral administration the apparent plasma half-life of ivermectin is approximately 16 hours. Ivermectin is indicated for the treatment of onchocerciasis or river blindness caused by Onchocerca volvulus and for strongyloidiasis caused by Strongyloides stercoralis.23 Ivermectin is licensed by the TGA in Australia for the treatment of crusted scabies and as second-line treatment for ordinary scabies when there is failure of first line topical treatment. The recommended dosage for treatment of scabies is two oral doses designed to provide approximately 200g of ivermectin per kg of body weight. The same dose is recommended in the Solomon Islands. Ivermectin is available in 3mg tablets. Safety of ivermectin The safety profile of ivermectin is very well known. Safety has been well studied through its usage therapeutically and in large scale MDA programs. In the past 21 years more than 1 billion doses of ivermectin tablets have been distributed for both onchocerciasis and lymphatic filariasis at doses of 100-200 g/kg with excellent safety.2425 A review of women accidentally given ivermectin while pregnant showed no evidence of teratogenicity.24 Although central nervous system toxicity due to ivermectin has been shown to occur in dogs it does not cross the intact bloodbrain barrier in humans.26 Nevertheless these studies have led to ivermectin being contra-indicated in children under 15kg because of the theoretical possibility that it may cross poorly-developed bloodbrain barriers leading to a risk of neurotoxicity. Although there are no data to support this restriction and despite anecdotal reports of ivermectin being well tolerated without serious adverse effects in young children when used for scabies4 further data are needed to clearly establish safety in young children before authorities will allow its use in this age group.26 Azithromycin and ivermectin combination treatment A pharmacokinetic study on the interaction of azithromycin ivermectin and albendazole in healthy volunteers showed minimal interaction between azithromycin and ivermectin and albendazole. Any interactions were not considered to be sufficient to result in any clinically significant alterations in efficacy or adverse event profile.2728 The conclusion by the authors of one of these studies was that the data support further study of co-administration of azithromycin with the widely used agents ivermectin and albendazole under field conditions in disease control programs. 28 Further results from a pharmacovigilance study involving more than 3000 participants on the adverse events associated with the triple co-administered combination therapy of azithromycin ivermectin and albendazole (AZIVAL AZithromycin IVermectin ALbendazole) in Mali found that triple combination therapy appears to be safe.4 There were no serious adverse events in this study. Overall the rate of adverse events was similar in the triple combination therapy group (18.7%) compared to the standard therapy group (16.0%). Taken together these studies support expert opinion that the combination of azithromycin and ivermectin is safe. 2.2 Research Question This study 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. 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 evaluate the effectiveness of ivermectin-based MDA for scabies in this population. 2.3 Rationale for Current Study A large-scale comprehensive trial of MDA for endemic scabies has been advocated as a global health need29 but never implemented. Resource limited settings faced with multiple neglected tropical diseases are asking how to scale up several MDA programs in an efficient and coordinated manner. The rationale for the co-administration strategy outlined in this proposal is to extend the benefit of the MDA infrastructure that is in place for delivery of azithromycin to enable the delivery of ivermectin-based MDA for scabies. While it is believed that co-administration of azithromycin and ivermectin is safe there is little knowledge about how feasible it is to deliver the two drugs at the same time using shared infrastructure. We will measure feasibility in this study as the primary outcome by measuring coverage and comparing this coverage to that of MDA for trachoma using azithromycin without ivermectin in the Solomon Islands. Although we have confidence that the co-administration of azithromycin and ivermectin is highly likely to be safe based on the individual safety and vast experience with the two agents their well-studied joint pharmacokinetics and experience from a prior randomised study of 3000 people we will nevertheless undertake safety monitoring. We propose to investigate safety using surveillance strategies that go beyond those that are used in routine MDA programmes. Specifically we will measure self-reported short-term adverse events and hospital admissions with serious illness. The third goal of the study relates to efficacy. By linking to the trachoma MDA infrastructure we wil be able to deliver ivermectin to a larger population than has ever been included in a scabies MDA. This will allow us to evaluate efficacy and duration of effect of ivermectin MDA on scabies and impetigo in a population exceeding 20000 people. 3. STUDY OBJECTIVES 3.1 Primary Objective 1. To assess the feasibility of conducting a joint MDA for trachoma and scabies control in a large population. 3.2 Secondary Objectives 1. To assess the safety of co-administration of azithromycin and ivermectin MDA for trachoma and scabies control. 2. To assess the effectiveness of ivermectin-based MDA for scabies in a large island population. 3. To assess the effectiveness of ivermectin-based MDA on the complications of scabies including impetigo and severe SSTI. 4. STUDY DESIGN 4.1 Type of Study This is a prospective community intervention trial to assess the feasibility safety and efficacy of co-administration MDA for trachoma and scabies in one province of the Solomon Islands. The MDA regimen will include a single dose of oral azithromycin (or topical tetracycline eye ointment if azithromycin is contraindicated) and 2 doses of oral ivermectin (or topical permethrin cream if ivermectin is contra-indicated). 4.2 Study Design Diagram Note: *The third medical illness check will be in a randomly selected group of participants only; skin examinations will be performed for participants in 10 randomly selected villages at baseline (day 1) and for participants in a further 10 randomly selected villages at 12 months (independent of the 10 baseline villages). 4.3 Number of Subjects Choiseul province has a population of approximately 26000 people. Assuming 80% response rate the total number of participants receiving MDA will be approximately 20800. Ten villages with an average population of 125 residents each will be randomly selected to receive a skin examination. Assuming 80% response rate the total number of participants receiving skin examination will be approximately 1000. 4.4 Expected Duration of Study The duration of the study is 12 months. For all participants for the active adverse event monitoring component of the study there will be a 15 day on-study period which will include two visits by the study team (day 1 for baseline medical illness assessment and delivery of azithromycin/tetracycline and ivermectin/permethrin and day 8 for second medical illness assessment and delivery of second dose of ivermectin/permethrin). A random sample will have a third visit at day 15 for medical illness assessment). For all participants passive monitoring for serious illnesses at hospitals and clinics will continue throughout the study period. For a subset of participants (residing in 10 villages randomly selected at baseline and then 10 independent villages randomly selected at 12 months) there will be a skin examination (see 7. Study Visit and Procedure Schedule). 4.5 Primary and Secondary Outcome Measures Primary Outcome Measures: -The coverage of the MDA in the study population separate for trachoma and scabies MDA. Coverage will be measured by doses distributed to individuals divided by total population. Secondary Outcome Measures -The incidence of serious illness occurring in the study population in the 12 month period after MDA compared to the 12 months prior Serious illness will be defined as any illness requiring admission to hospital. Serious illnesses will be categorised and rates per 100000 population calculated. Death will also be counted and death rates calculated. -Occurrence of self-reported short-term adverse events Further detailed information regarding definition of adverse events is included below under Section 9. -Prevalence of scabies and impetigo at months 12 months in 10 randomly selected villages compared to 10 independent randomly selected villages at baseline. Scabies and impetigo will be diagnosed clinically and further detail regarding these methods are included below. -The 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 100000 population will be calculated. -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 100000 population. 5. STUDY TREATMENTS 5.1 Treatment regimens This study investigates the safety of the co-administration of MDA with oral ivermectin (or topical permethrin for those with a contra-indication to ivermectin) and azithromycin (or topical tetracycline for those with a contra-indication to azithromycin). Oral ivermectin based MDA for scabies: Participants will be offered 2 doses of oral ivermectin (observed) separated by 7 days at 200 ug/kg unless contra-indicated. If a participant has a contra-indication for ivermectin they will be offered permethrin topical cream for 2 doses separated by 7 days. Contra-indications for Ivermectin are: 1) children under 15 kg 2) pregnant women 3) breastfeeding women 4) those who are seriously ill (unable to engage in the normal activities of daily living without assistance because of their illnesses) 5) people who have previously suffered from a serious adverse event thought to be caused by a reaction to ivermectin and 6) people taking warfarin.30 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). Permethrin cream is applied from neck to toe (and including the scalp in infants) and washed off after a minimum of 8 to 24 hours. For children aged 2 months or less it is washed off after 4 hours. MDA of oral azithromycin for trachoma: Participants will be offered 1 dose of oral azithromycin (single observed dose) at 20 mg/kg up to a maximum of 1 gm as per Solomon Islands guidelines for trachoma MDA. Pregnant women will be offered a choice of azithromycin or topical tetracycline. Individuals aged less than 6 months will be offered topical tetracycline. 5.1.1 Description Dosage Route of Administration and Dose Modification Ivermectin permethrin and azithromycin are registered and routinely manufactured and marketed drugs produced respectively by Merck Sharp & Dohme Johnson & Johnson and Pfizer (see APPENDIX ABC). Ivermectin 200g/kg Ivermectin (Stromectol) is a white to yellowish-white non-hygroscopic crystalline powder which is practically insoluble in water freely soluble in methanol and soluble in 95% ethanol. It also contains microcrystalline cellulose pregelatinised maize starch magnesium stearate butylated hydroxyanisole and citric acid anhydrous. Prepared as 3 mg tablets the product is packaged in a small cardboard box containing 4 tablets. Ivermectin will be taken orally as directly observed therapy either swallowed whole or crushed and mixed with yoghurt/custard. The recommended dose for scabies is 200 g/kg. The dose range of 160250 g/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 g/kg can be delivered. The ivermectin dosage per weight will be as follows: 1518 kg 3.0 mg 1927 kg 4.5 mg 2836 kg 6.0 mg 3755 kg 9.0 mg 5674 kg 12.0 mg 75100 kg 15.0 mg >100kg 18.0 mg
Topical 5% permethrin cream (Lyclear)
Topical 5% permethrin (Lyclear ) cream for scabies is supplied in a 30g tube. The cream is applied all over the body including from neck to toe and washed off after a minimum of 8 hrs. For
children aged 2 months or less permethrin should be washed off after 4 hours.
Azithromycin (Zithromax) and Topical tetracycline
Azithromycin and topical tetracycline will be dosed and administered as per the Solomon Islands Ministry of Health guidelines for trachoma MDA. Briefly MHMS guidelines state that azithromycin is
administered as a single dose of 20mg/kg (max 1/g) for the treatment of trachoma. Azithromycin is thought to be safe in pregnancy and breastfeeding and mothers are therefore offered azithromycin
treatment. Paediatric oral suspension is available as needed. Those who decline can be offered treatment with topical tetracycline eye ointment. Children aged less than 6 months are offered topical
tetracycline eye ointment instead.
For ease of administration weight bands are used to guide the dose of azithromycin.
Azithromycin 250mg Tablets
Patient Weight Dose Number of Tablets
12.5kg to <25kg 250mg 1 25kg to <37.5kg 500mg 2 37.5kg to <50kg 750mg 3 50kg or over 1000mg 4 Azithromycin Paediatric Oral Suspension 30mg/ml Patient Weight Dose Number of mL 3kg to <6kg 60mg 2ml 6kg to <9kg 120mg 4ml 9kg to <12kg 180mg 6ml 12kg to <15kg 240mg 8ml 15kg to <18kg 300mg 10ml 18kg to <21kg 320mg 12ml 21kg to <24kg 420mg 14ml 24kg 480mg 16ml 5.2 Preparation and administration of study drug For participants receiving ivermectin the dose will be determined according to body weight and treatment will be administered under direct supervision of the study team. Participants assigned to permethrin (due to contra-indication to ivermectin) will receive a tube of cream and will be asked apply the cream from neck to toes before they leave the clinic and under supervision of a study nurse and leave it on for a minimum of 8 hours maximum 24 hours if possible. For children aged 2 months or less cream will applied for a maximum of 4 hours. 5.3 Dispensing and Product Accountability Medications will arrive by plane and will reach the islands by boat at the provincial pharmacy / medical store. The order request will be checked with the supplies delivered. The delivery notice number delivery date and the medications batch number will be recorded in a log book. Medications will be taken out of the pharmacy in bulk by the study teams for dispensing in the community. Study teams will maintain a log of all medicines dispensed that can be cross-checked against participants study records. 5.4 Measurement of subject adherence All oral medicines will be delivered as directly observed treatment and this will be recorded in the relevant data collection form. For permethrin application will be directly observed where possible: for younger children parents will be asked to apply cream observed by study staff and older children and adults will be encouraged to apply the cream under observation but they will also be permitted to do this at home. The choice of directly observed or home treatment will be recorded in the relevant data collection form. 5.5 Excluded medications and treatments Ivermectin will be replaced by topical permethrin cream in the following cases: 1) children under 15 kg 2) pregnant women 3) breastfeeding women 4) those who are seriously ill (unable to engage in the normal activities of daily living without assistance because of their illnesses) 5) people who have previously suffered from a serious adverse event thought to be caused by a reaction to ivermectin and 6) people taking warfarin. Azithromycin will be replaced by topical tetracycline cream in the following cases: 1) infants under 6 months 2) pregnant women who decline azithromycin 4) those who are seriously ill (unable to engage in the normal activities of daily living without assistance because of their illnesses) 5) people who have previously suffered from a serious adverse event thought to be caused by a reaction to azithromycin or erythromycin 6. SUBJECT ENROLLMENT AND RANDOMISATION 6.1 Recruitment The entire province of Choiseul was selected to be included in the study. The study team has had extensive preliminary discussions with a number of key stakeholders in the Solomon Islands and is following an established process that is undertaken for the introduction of new community health initiatives. Following the initial endorsement granted for the overall concept by the Ministry of Health engagement at the community level will include discussion with senior district nurses who visit the island nurses at the island health centres and local community leaders and village leaders. Further detailed discussion will be undertaken between study investigators and community leaders and key stakeholders at a 1 day long dedicated study meeting before the beginning of the trial. 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. The study will also establish a parallel program of information dissemination to ensure that community members are aware of the study including by radio as has previously been conducted by MHMS for trachoma control activities in other provinces. 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. 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 written informed consent will be obtained for participation. The project coordinator and a study nurse will conduct the informed consent discussion and will check that the subject and their legally acceptable representative comprehend the information provided and answer any questions about the study. Consent will be voluntary and free from coercion. A copy of the consent form will be given to the subject or their legally acceptable representative and the fact that the subject has been consented to the study will be documented in the subjects record. Both written and verbal consent will be obtained in local dialect on all occasions. 6.2 Eligibility Criteria As a community-based study of mass drug administration all community members who have given informed consent to participate according to the described procedures are eligible for participation. 6.2.1 Inclusion Criteria All community members are able to be included in the study. 6.2.2 Exclusion Criteria The following are exclusion criteria for the study: 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 12312 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. 6.3 Randomisation Procedures Not applicable 6.4 Blinding Arrangements Not applicable. 6.5 Breaking of the Study Blind Not applicable. 6.6 Subject withdrawal 6.6.1 Reasons for withdrawal Study participation is voluntary and study participants can withdraw at any time. The number of withdrawals will be recorded and only data collected prior to withdrawal will be included in the analysis. 6.6.2 Handling of withdrawals and losses to follow-up Only data collected prior to withdrawal will be included in the analysis. 6.6.3 Replacements Not applicable 6.7 Trial Closure The trial is planned to run over a 12 month period. The trial will be complete at the end of this 12 month period. 6.8 Continuation of therapy Not applicable 7. STUDY VISIT AND PROCEDURE SCHEDULE VISIT NUMBER Visit 1 Visit 2 Visit 3 Visit 4* TIMING Day 1 Day 8 Day 15 12 months Informed Consent X Demographic Information X Medical History X Weight measurement X X Physical Examination* X* X* Contra-indication check X Study drug dispensing X X Medical illness / Adverse event check X X X *Only undertaken in a sample of 20 randomly selected villages (10 villages at visit 1 and 10 villages at 12 months) Adverse events will be monitored at hospitals in Choiseul province over a 3 month period. Surveillance for adverse events after the second dose of ivermectin by self-report will be conducted in a randomly selected subsample 8. CLINICAL AND LABORATORY ASSESSMENTS 8.1 Clinical assessment of scabies (relevant only for 10 randomly selected villages) In scabies endemic areas diagnosis based on clinical signs and symptoms has previously been demonstrated to be highly sensitive and specific.31 Scabies will be defined clinically without the use of microscopy or dermatoscopy on the basis of typical clinical findings that is pruritic inflammatory papules with a typical distribution of lesions. These include webs of the fingers hands wrists elbows knees trunk and ankles. Categories of scabies severity will be determined based on the nature and distribution of characteristic scabies lesions with specific differentiation of infected scabies and crusted scabies. Screening for scabies will be conducted in the community from visible skin and skin that the participant is comfortable to expose. Infected scabies will be identified as pus filled sores or crusted sores within the collection of scabies lesions. The severity of skin sores will be determined by the number of lesions identified. 8.2 Clinical assessment of skin sores (relevant only for 10 randomly selected villages) Impetigo is an infection by bacteria of the top layers of the skin. Impetigo starts as red or pimple-like sores surrounded by reddened skin. The sores can be anywhere on the body but mostly on the face arms and legs. They fill with pus then break open after a few days and form a crusted scab. Itching is common. Diagnosis of skin sores in endemic areas is based upon clinical findings of discrete sores/lesions with pus or crusts. 8.3 Assessment of contra-indications to ivermectin including pregnancy and contraindications to permethrin. All participants will be screened for contraindications for ivermectin. Children under 15kg will be offered permethrin cream. Participants will be asked whether they are pregnant (as described further below) and/or breastfeeding. If a participant is pregnant or unsure topical permethrin cream will be offered instead of oral ivermectin. Participants with a severe illness will be offered permethrin. All participants will be asked if they are taking medication. If they are taking warfarin they will be offered permethrin. If a patient is allergic or hypersensitive to any component of ivermectin or permethrin that medication will not be offered. 8.4 Measurement of weight Participants will have their weight measured using standardized methods. Calibrated digital scales will be used to weigh participants. Weight will be measured in kilograms. Participants will be asked to remove shoes. Records will be recorded on the appropriate form. There are no laboratory assessments in this study and no tissue samples of any kind are being collected. 9. ADVERSE EVENT REPORTING The Project Steering Committee will supervise and monitor the project at all times and if adverse events are experienced the committee will make sure that appropriate care is available. If present the committee will report side effects to the Data Safety Monitoring Committee (DSMC) and the ethics committees. 9.1 Definitions Adverse Event (AE): AE will be assessed using the following standard definition of AEs: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.32 An AE can be new or an exacerbation of an existing complaint after administration of the pharmaceutical product. Serious Adverse Event (SAE) Adverse events are classified as serious or non-serious. An SAE is defined as any AE that: results in death; or is immediately life threatening; or requires inpatient hospitalisation; or requires prolongation of existing hospitalisation; or results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect. Important medical events will be considered an SAE when based upon appropriate medical judgement they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Suspected Unexpected Serious Adverse Reaction (SUSAR): A SUSAR is any SAE that is both suspected to be related to the study treatment and is unexpected (i.e. not consistent with applicable product information). 9.2 Assessment and Documentation of Adverse Events An adverse event (AE) is any untoward medical occurrence experienced by the participant while undergoing treatment in a clinical trial. A SAE is defined as any event that is fatal or life threatening is permanently disabling to the participant or an event that requires admission to hospital. Other AEs include temporary moderate discomfort and disability to the participant. All SAEs should be reported to the Principal Investigator who will ensure that the DSMC is informed. The DSMC will assess the progress of the study for safety. Given the short duration of the on-study period of the study (15 days) and the well known adverse event profiles of single dose azithromycin and two dose ivermectin the DSMC will meet prior to the study in the first 3 months after the MDA intervention and at the end of the study. The DSMC will review subject enrolment AEs and address any problems within the study or any matter raised from a source external to the study. The DSMC will meet at additional timepoints if requested by a participating community or investigator. 9.3 Eliciting Adverse Event Information Each participant or participants parent/carer will be asked a set of questions that relate to known AE symptoms caused by ivermectin and/or permethrin. The questions will be asked prior to administration of medication (day 1 and day 8) and again at 7 days after administration (day 8 and day 15 respectively). If any participant seeks medical care within this 15 day time frame the information will be collected from their clinic records. Beyond this 2 week time period and up to 12 months any serious illnesses within the communities will be reported to the study team by the health centres. The overall AE rates will be calculated as follows: Any AE during the 15 day study period that was also present at baseline will only be counted if severity increases; for instance a severe headache on day 7 while a mild headache was present at baseline will be counted as one severe headache one AE; a mild headache on day 7 while a mild headache was already present at baseline will not be counted as an AE. Multiple episodes of the same AE during the 15 day study period will be counted as one AE and graded as the most severe of the episodes; for instance one severe headache and one mild headache will be counted as one severe headache one AE. Study participants can have different AEs during the 15 day study period; for instance headache itching and nausea. All three AEs would be accounted for in the overall AE rate. 9.4 Serious Adverse Event Reporting 9.4.1 SAEs Assessment of adverse events will be performed according to the Common Toxicity Criteria for Adverse Events (CTCAE v3.0).33 Adverse events will be graded according to severity Grade 1: Mild Grade 2: Moderate Grade 3: Severe requiring medical care or hospitalization Grade 4: Life-threatening or disabling Grade 5: Death Adverse events will be assessed for the likely relationship to treatment Not related to treatment Unlikely to be related to treatment Possibly related to treatment Probably related to treatment Definitely related to treatment Serious adverse events (SAE) will be reviewed by the DSMB. These will be defined as grade 3+ (irrespective of relationship to treatment) and grade 2 adverse events possibly related or related to treatment. Adverse events (AE) not categorized as serious will be documented and reported to the Principal Investigator and the Investigator responsible for trial site medical decisions. They will be compiled and reported to the DSMB at the next meeting date. 9.4.2 SUSARs All SUSARs occurring in a study participant will be reported to the DSMB (i.e. within 15 calendar days of first knowledge) or for fatal or life threatening events an initial or full report within 7 calendar days and a follow-up report if necessary within the 15 calendar day timeframe. An investigator will complete sign and submit the SUSAR report. 10. STATISTICAL METHODS 10.1 Sample Size Estimation Primary outcome The primary end point of the study is the coverage of co-administration of azithromycin and ivermectin. The coverage will be compared to coverage achieved for azithromycin MDA in other provinces of Solomon Islands in the most recent round of MDA (around 80%). With a population of over 20000 we expect to be able to measure coverage with very high precision (confidence intervals of less than 5% absolute width.) Secondary outcomes We will have sufficient sample size to be able to measure self-reported outcomes that have occur in 5% of the population with confidence intervals of 3% absolute width. On the basis of the SHIFT data and other previous research we expect that the overall prevalence of scabies will be approximately 20% at baseline and it will fall to under 5% using ivermectin based MDA.3435 Assuming 80% response rate of the total community of 1200 a total of 1000 surveyed participants at the two timepoints will allow detection of this change in prevalence such that the upper and lower bounds of the confidence intervals around these estimates will not cross. 10.2 Population to be analysed The study population will be all those residing in Choiseul at month 0 and 12 and consented to enroll in this study. 10.3 Statistical Analysis Plan 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 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 in 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. 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. 11. DATA MANAGEMENT 11.1 Data Collection Completed case report forms will be checked for completeness and accuracy by the study coordinator against the source data. Original case report forms will be used when entering information into the computer database. The database will be checked against the case report forms for accuracy. No investigation of the data will begin until an accurate database has been assured 11.2 Data Storage Data collected about the patients will be coded and de-identified and held in strict confidence. All results will be presented in a way which does not allow individuals to be identified. No information concerning the study or the data will be released to any unauthorized third party. Storage and access will be through a password-protected database held at Murdoch Childrens Research Institute. Data will be entered into EpiData and transferred into Oracle database with a restricted access to the data manager principal investigator and the study statistician. The paper data forms will be kept in a locked room. Only the investigators and the study staff will have access to the raw data during and after the study. A password protected copy of the full database will be provided to the Solomon Islands MHMS. 11.3 Study Record Retention The paper data forms will be kept in a locked room in a locked and secure filing system at our office in Honiara Solomon Islands. Only the investigators and the study staff will have access to the raw data during and after the study. Data from this study will be destroyed after 15 years as per local guidelines. If data are published only aggregate results will be analysed. Reports and publications will not disclose the identity of participants. 12. ADMINISTRATIVE ASPECTS 12.1 Confidentiality Subject confidentiality is strictly held in trust by the participating investigators research staff and the sponsoring institution and their agents. This confidentiality is extended to cover testing of biological samples and the clinical information relating to participating subjects. The study protocol documentation data and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsoring institution. Authorized representatives of the sponsoring institution may inspect all documents and records required to be maintained by the Investigator including but not limited to medical records (office clinic or hospital) and pharmacy records for the subjects in this study. The clinical study site will permit access to such records. All evaluation forms reports and other records that leave the site will be identified only by the Subject Identification Number (SID) to maintain subject confidentiality. Clinical information will not be released without written permission of the subject except as necessary for monitoring by HREC or regulatory agencies. 12.2 Independent HREC Approval This protocol and the informed consent document and any subsequent modifications will be reviewed and approved by the human research ethics committee (HREC). A letter of protocol approval by HREC will be obtained prior to the commencement of the study as well as approval for other study documents subject to HREC review. This protocol is being considered by the MCRI/RCH HREC and the National Research Ethics Review Committee Solomon Islands. 12.3 Modifications of the protocol Modifications from the original protocol is not anticipated however if this does occur approval will be sought for amendments to the protocol and these will be described in the final reports. Protocol modifications will be reported to study investigators in accordance with standard GCP processes. 12.4 Protocol Deviations Deviation from the original protocol and statistical plan is not anticipated however if this does occur approval will be sought for amendments to the protocol and these will be described in the final reports. Protocol deviations will be reported to study investigators in accordance with standard GCP processes. 12.5 Participant Reimbursement Not applicable 12.6 Financial Disclosure and Conflicts of Interest There are no relevant financial or other conflict of interest to be to disclosed. 12.7 Trial Registration This study will be registered at The Australian New Zealand Clinical Trials Registry. 13. USE OF DATA AND PUBLICATIONS POLICY Publication and reporting of results and outcomes of this study will be accurate and honest undertaken with integrity and transparency. Publication of results will be subjected to fair peer- review. Authorship will be given to all persons providing significant input into the conception design and execution or reporting of the research. No person who is an author consistent with this definition will be excluded as an author without their permission in writing. Authorship will be discussed between researchers prior to study commencement (or as soon as possible thereafter) and reviewed whenever there are changes in participation. All conflicts arising through disputes about authorship will be reviewed by the director. Acknowledgement will be given to collaborating institutions and hospitals and other individuals and organisations providing finance or facilities. Individual data will not be made available publicly but de-identified data may be made available for further analysis. Results of the study will be presented locally (including to the community) and made available to health policy decision makers and clinical staff. 14. REFERENCES 1. Solomon AW Zondervan M DCW. M. Trachoma control: a guide for program managers. Geneva Switzerland: World Health Organization; 2006. 2. Mabey DC Solomon AW Foster A. Trachoma. Lancet 2003;362:223-9. 3. Heukelbach J Feldmeier H. Scabies. Lancet 2006;367:1767-74. 4. Lawrence G Leafasia J Sheridan J et al. Control of scabies skin sores and haematuria in children in the Solomon Islands: another role for ivermectin. Bull World Health Organ 2005;83:34 -42. 5. Steer AC Tikoduadua LV Manalac EM Colquhoun S Carapetis JR Maclennan C. Validation of an Integrated Management of Childhood Illness algorithm for managing common skin conditions in Fiji. Bull World Health Organ 2009;87:173-9. 6. Thomas M Woodfield G Moses C Amos G. Soil-transmitted helminth infection skin infection anaemia and growth retardation in schoolchildren of Taveuni Island Fiji. N Z Med J 2005;118:U1492. 7. Steer AC Jenney AW Kado J et al. High burden of impetigo and scabies in a tropical country. PLoS Negl Trop Dis 2009;3:e467. 8. Neglected Tropical Diseases. 2015. (Accessed 16/3/2015 at http://www.who.int/neglected_diseases/diseases/en/.) 9. Ivermectin (Stromectol) for typical and crusted scabies2014. 10. La Vincente S Kearns T Connors C Cameron S Carapetis J Andrews R. Community management of endemic scabies in remote aboriginal communities of northern Australia: low treatment uptake and high ongoing acquisition. PLoS Negl Trop Dis 2009;3:e444. 11. Taplin D Meinking TL Porcelain SL Castillero PM Chen JA. Permethrin 5% dermal cream: a new treatment for scabies. J Am Acad Dermatol 1986;15:995-1001. 12. Mohammed KA Deb RM Stanton MC Molyneux DH. Soil transmitted helminths and scabies in Zanzibar Tanzania following mass drug administration for lymphatic filariasisa rapid assessment methodology to assess impact. Parasit Vectors 2012;5:299. 13. Pfizer. ZITHROMAX (azithromycin tablets) and (azithromycin for oral suspension) Package Insert. Revised January 2013. Reference ID: 3263750 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039050711s036050784s023lbl.pdf. 2013. 14. Evans JR Solomon AW. Antibiotics for trachoma. Cochrane Database Syst Rev 2011:CD001860. 15. Mabey D Bailey R. Eradication of trachoma worldwide. The British journal of ophthalmology 1999;83:1261-3. 16. Ayele B Gebre T House JI et al. Adverse events after mass azithromycin treatments for trachoma in Ethiopia. The American journal of tropical medicine and hygiene 2011;85:291-4. 17. Martin DH Mroczkowski TF Dalu ZA et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study Group. N Engl J Med 1992;327:921-5. 18. Law C Amsden GW. Single-dose azithromycin for respiratory tract infections. The Annals of pharmacotherapy 2004;38:433-9. 19. West SK West ES Alemayehu W et al. Single-dose azithromycin prevents trichiasis recurrence following surgery: randomized trial in Ethiopia. Archives of ophthalmology 2006;124:309-14. 20. Cochereau I Goldschmidt P Goepogui A et al. Efficacy and safety of short duration azithromycin eye drops versus azithromycin single oral dose for the treatment of trachoma in children: a randomised controlled double-masked clinical trial. The British journal of ophthalmology 2007;91:667-72. 21. Tabbara KF Abu-el-Asrar A al-Omar O Choudhury AH al-Faisal Z. Single-dose azithromycin in the treatment of trachoma. A randomized controlled study. Ophthalmology 1996;103:842-6. 22. Solomon AW Akudibillah J Abugri P et al. Pilot study of the use of community volunteers to distribute azithromycin for trachoma control in Ghana. Bulletin of the World Health Organization 2001;79:8-14. 23. Merck. STROMECTOL (IVERMECTIN) Package Insert http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s026lbl.pdf. 2009. 24. Pacque M Munoz B Poetschke G Foose J Greene BM Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet 1990;336:1486-9. 25. Task Force for Global Health. 2015. (Accessed 12 January 2015 at Available from: http://www.mectizan.org/.) 26. Fox LM . Ivermectin: uses and impact 20 years on. Curr Opin Infect Dis 2006;19:588-93. 27. Amsden GW Gregory TB Michalak CA Glue P Knirsch CA. Pharmacokinetics of azithromycin and the combination of ivermectin and albendazole when administered alone and concurrently in healthy volunteers. The American journal of tropical medicine and hygiene 2007;76:1153-7. 28. El-Tahtawy A Glue P Andrews EN Mardekian J Amsden GW Knirsch CA. The effect of azithromycin on ivermectin pharmacokineticsa population pharmacokinetic model analysis. PLoS neglected tropical diseases 2008;2:e236. 29. Currie BJ McCarthy JS. Permethrin and ivermectin for scabies. N Engl J Med 2010;362:717-25. 30. Orkin M E. Epstein and H.I. Maibach. Treatment of todays scabies and pediculosis. JAMA 1976:1136-9. 31. Mahe A Faye O NDiaye HT et al. Definition of an algorithm for the management of common skin diseases at primary health care level in sub-Saharan Africa. Trans R Soc Trop Med Hyg 2005;99:39-47. 32. Edwards IR Aronson JK. Adverse drug reactions: definitions diagnosis and management. Lancet 2000;356:1255-9. 33. Fawcett RS. Ivermectin use in scabies. Am Fam Physician 2003;68:1089-92. 34. Strong M Johnstone PW. Interventions for treating scabies. Cochrane Database Syst Rev 2007:CD000320. 35. Romani L Koroivueta J Steer AC et al. Scabies and impetigo prevalence and risk factors in fiji: a national survey. PLoS Negl Trop Dis 2015;9:e0003452.

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