Impact of Combined Azithromycin and Ivermectin Mass Drug Administration for Yaws and Scabies - Impact on Impetigo and Skin Microbiology
Phase: PHASE4
Conditions: Scabies, Yaws, Impetigo
Sponsor: London School of Hygiene and Tropical Medicine

 
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AIM-Skin 
 
 
 
Impact of Single-Dose Azithromycin in Impetigo and Skin Microbiology 
 
 
ISRCTN 
NCT (clinicaltrials.gov) 
 
 
 
V1.0 
17th February 2016 
 
 
 
 
 
 
SPONSOR: London School of Hygiene & Tropical Medicine  
FUNDERS: Wellcome Trust 
STUDY COORDINATION CENTRE: LSHTM 
 
LSHTM ethics reference: Pending 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol authorised by: 
 
Name:  
Michael Marks 
Role: Chief Investigator 
Signature: 
 
Date:   
 
 
  
Name: 
Rowena Asugeni 
Role: Co-Investigator, AAH 
Signature: 
 
Date:   
 
 
  
Name: 
 
Role: Sponsor Representative 
Signature: 
 
Date:   
 
 
  
Main Contacts 
 
Trial Management Group 
 
Chief Investigator:  
Michael Marks 
Clinical Research Department 
London School of Hygiene & Tropical Medicine 
Michael.marks@lshtm.ac.uk 
 
Co-investigators:  
Rowena Asugeni 
Atoifi Adventist Hospital 
Atoifi 
Solomon Islands 
rowenaasugeni@gmail.com 
 
Statistician:  
Christian Bottomley 
London School of Hygiene & Tropical Medicine 
Christian.bottomley@lshtm.ac.uk 
 
Trial Coordination Centre 
For general queries, supply of trial documentation, and collection of data, please contact: 
 
Michael Marks 
Clinical Research Department 
London School of Hygiene & Tropical Medicine 
Michael.marks@lshtm.ac.uk 
 
 
 
Clinical Queries 
Clinical queries should be directed to Michael Marks who will direct the query to the appropriate person. 
 
Sponsor 
 
 
London School of Hygiene & Tropical Medicine is the main research sponsor for this study.  For further 
information regarding the sponsorship conditions, please contact the Research Governance and Integrity 
Office: 
 
 
 

 
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London School of Hygiene & Tropical Medicine 
Keppel Street 
London WC1E 7HT 
Tel: +44 207 927 2626 
Email:  
 
Funder 
This study is funded as part of a Wellcome Trust Research Fellowship held by Michael Marks. 
 
This protocol describes the AIM-Skin study and provides information about procedures for entering participants. The 
protocol should not be used as a guide for the treatment of other participants; every care was taken in its drafting, 
but corrections or amendments may be necessary. These will be circulated to investigators in the study, but centres 
entering participants for the first time are advised to contact the trials centre to confirm they have the most recent 
version.  
 
Problems relating to this trial should be referred, in the first instance, to the study coordination centre.  
 
This trial will adhere to the principles outlined in the International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) guidelines, protocol and all applicable local regulations.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
1. INTRODUCTION 
8 
1.1 
BACKGROUND 
8 
2.  STUDY OBJECTIVES 
9 
3.  STUDY DESIGN 
10 
3.1 
STUDY OUTCOME MEASURES 
11 
3.2 
RISKS AND BENEFITS 
12 
4. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
13 
4.1 
PRE-RANDOMISATION OR PRE-REGISTRATION EVALUATIONS 
13 
4.2 
INCLUSION CRITERIA 
13 
4.3 
EXCLUSION CRITERIA. 
13 
4.4 
WITHDRAWAL CRITERIA 
13 
5. RANDOMISATION AND ENROLMENT PROCEDURE 
14 
5.1 
RANDOMISATION OR REGISTRATION PRACTICALITIES 
14 
5.2 
BLINDING 
14 
6. TRIAL MEDICATION 
15 
7. SAFETY REPORTING FOR DRUG TRIALS 
19 
7.1 
DEFINITIONS 
19 
7.2 
CAUSALITY 
19 
7.3 
REPORTING PROCEDURES 
20 
8. ASSESSMENT AND FOLLOW-UP 
22 
8.1 
LOSS TO FOLLOW-UP 
23 
8.2 
TRIAL CLOSURE 
23 
9. STATISTICS AND DATA ANALYSIS 
24 
10. MONITORING 
25 
10.1 
RISK ASSESSMENT 
25 
10.2 
MONITORING AT STUDY COORDINATION CENTRE 
25 
10.3 
MONITORING AT LOCAL SITE 
25 
11. REGULATORY ISSUES 
26 
11.1 
ETHICS APPROVAL 
26 
11.2 
CONSENT 
26 
11.4 
CONFIDENTIALITY 
26 
11.5 
INDEMNITY 
27 
11.6 
SPONSOR 
27 
11.7 
FUNDING 
27 

 
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11.8 
AUDITS AND INSPECTIONS 
27 
12. TRIAL MANAGEMENT 
28 
13. PUBLICATION POLICY 
29 
14. REFERENCES 
30 
APPENDICES 
31 
 
 
 

 
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GLOSSARY OF ABBREVIATIONS 
AAH 
Atoifi Adeventist Hospital 
AE 
Adverse Event 
MDA 
Mass Drug Administration 
SAE 
Serious Adverse Event 
SUSAR 
Serious Unexepected Event 
 
KEYWORDS 
Yaws 
Scabies 
Azithromycin 
Ivermectin 
Impetigo 
MDA 
 
 

 
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STUDY SUMMARY 
 
TITLE Impact of Single-Dose Azithromycin in Impetigo and Skin Microbiology 
 
DESIGN A prospective community intervention trial to assess the impact of community 
mass treatment with azithromycin for yaws and ivermectin for scabie, on non-
yaws bacterial skin infections.  
AIMS Assess the impact of single dose azithromycin, given for yaws, on other 
prevalent bacterial skin infections. 
Assess the impact of single dose azithromycin on antimicrobial resistance 
patterns in isolates of S.pyogenes and S.aureus. 
 
OUTCOME MEASURES Primary Outcome 
a) Difference in the change in prevalence of impetigo between baseline and 12-
months between the parallel and the sequential treatment arms. 
 
Secondary Outcomes 
b) Change in the proportion of swab samples from which S. pyogenes is cultured 
between baseline and follow-up in the two arms  
c) The proportion of samples from which a drug-resistant isolate of S.pyogenes 
is cultured in the two arms 
 
POPULATION Parallel Treatment Arm: Sample size of 637 
Sequential Treatment Arm: Sample size of 637 
 
ELIGIBILITY All residents of selected communities are eligible to participate in the study 
TREATMENT Treatment of yaws: 
Single dose of Azithromycin (30mg/kg, max 2G). 
 
Treatment of scabies: 
Either an oral dose of Ivermectin (200μg/kg) or permethrin cream for those 
with a contraindication to Ivermectin (WT<15kg, pregnant or breastfeeding 
women) given in 2 doses 7-14 days apart.  
 
DURATION 12 months 
 
 
 
 
 
 
 
 
 
 

 
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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
 
Both trachoma, caused by Chalmydia trachomatis, and yaws, caused by Treponema pallidum subsp. 
pertenue, are endemic in many Pacific countries including the Solomon Islands[1,2]. Mass treatment with 
azithromycin is the cornerstone of the WHO strategy for the elimination and eradication of these two 
diseases resepectively[3,4]. Mass treatment with azithromycin has been shown to have beneficial off-
target effects including decreased malaria transmission and some evidence to support a reduction in 
infant mortality [5,6]. Conversely, mass treatment with azithromycin has been associated with changes in 
the resistance patterns of nasopharyngeal isolates of Streptococcus pneumoniae[7]. 
 
Scabies is also a significant public health problems in the Pacific[8]. Scabies is associated with secondary 
bacterial infections (impetigo) which are most commonly caused by Streptococcus pyogenes and 
Staphylococcus aureus[9]. Recently community mass treatment with Ivermectin has been shown to be an 
effective strategy for reducing the prevalence of both scabies and associated bacterial complications[10].  
Recent surveys conducted in the Solomon Islands have shown that the prevalence of scabies is between 
18-25% and the prevalence of impetigo between 25-40% (A Steer, personal communication). 
 
 
1.2 
RATIONALE FOR CURRENT STUDY 
 
Current WHO recommendations for yaws are for community mass treatment with single dose 
azithromycin[3]. The impact of this treatment on other bacterial skin diseases is unknown. 
 
Azithromycin has activity against both S. pyogenes and S. aureus and mass treatment with azithromycin, 
for either yaws or trachoma control, might have additional impacts on both the prevalence of impetigo 
and the potential emergence of resistant organisms. These issues may be of particular relevance in the 
Pacific where mass treatment for yaws or trachoma is likely to be conducted in the near future and where 
scabies and impetigo are also both common. 
 
Understanding the impact of azithromycin mass treatment on impetigo will inform whether integrated 
control programmes for yaws, trachoma and scabies could be considered in the Pacific where all three 
diseases are endemic. 
 
 
 
 
 
 

 
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2.  STUDY OBJECTIVES 
 
Study Aims: 
Assess the impact of single dose azithromycin, given for yaws, on other prevalent bacterial skin infections. 
Assess the impact of single dose azithromycin on antimicrobial resistance patterns in isolates of 
S.pyogenes and S.aureus. 
 
 
Primary Objective: 
The primary objective is to see whether a single dose of azithromycin, given as treatment for yaws, has an 
additional impact on impetigo.  
 
Secondary Objectives:  
The secondary objective is to assess whether treatment with a single dose of azithromycin results in 
change in the anti-microbial susceptibility of clinical skin swab isolates . 
 
 

 
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3.  STUDY DESIGN 
 
 
This is an open-label prospective community intervention trial to assess the impact of community mass 
treatment with azithromycin for yaws and ivermectin for scabies, on non-yaws bacterial skin infections. 
 
Study Site 
This study will be conducted within communities residing in the catchment area of Atoifi Adventist 
Hospital (AAH), Malaita Province, Solomon Islands. Both yaws and scabies are known to be endemic 
across the whole of the Solomon Islands[1]. 
  
Duration 
The duration of the study is 12 months. For all participants, there will be a 15 day on-study period 
which will include two visits by the study team  
 
Day 1 for baseline medical assessment and delivery of azithromycin/tetracycline and 
ivermectin/permethrin  
 Day 8-15 for delivery of second dose of ivermectin/permethrin  
 
 
 
 

 
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Treatment 
 
No investigational medications or indications are being assessed. Both study sites will receive standard 
treatment for both yaws and scabies either in parallel (site 1) or in sequence (site 2). 
 
Treatment of yaws: 
Single dose of Azithromycin (30mg/kg, max 2G). 
 
Treatment of scabies: 
Either an oral dose of Ivermectin (200μg/kg) or permethrin cream for those with a contraindication to 
Ivermectin (WT<15kg, pregnant or breastfeeding women) given in 2 doses 7-14 days apart.  
 
Site 1- Parallel Treatment Arm 
Single dose azithromycin (for yaws) and Ivermectin/Permethrin (for scabies) will be offered on D1. A 
second dose of Ivermectin/Permethrin will be offered 7-14 days later. 
 
Site 2- Serial Treatment Arm 
Ivermectin/Permethrin (for scabies) will be offered on D1 with a second dose of Ivermectin/Permethrin 
offered 7-14 days later.. 
Single dose azithromycin (for yaws) will be offered at the twelve month follow-up visit. 
 
3.1 
STUDY OUTCOME MEASURES 
 
Primary Outcome 
a) Difference in the change in prevalence of impetigo between baseline and 12-months between the 
parallel and the sequential treatment arms. 
 
Secondary Outcomes 
b) Change in the proportion of swab samples from which S. pyogenes is cultured between baseline and 
follow-up in the two arms  
c) The proportion of samples from which a drug-resistant isolate of S.pyogenes is cultured in the two arms 
 
 

 
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3.2 
RISKS AND BENEFITS 
Mass treatment with azithromycin is the standard of care for yaws endemic communities. Several 
studies have demonstrated a reduction in both active and latent cases of infection[11,12]. Mass 
treatment for scabies with both Ivermectin and Permethrin has been shown to be an effective 
intervention at reducing the prevalence of scabies at a community level[10,13]. 
 
The safety profile of single dose azithromycin is well known. Azithromycin is considered the standard 
treatment for trachoma and yaws, both as therapy and in MDAs, and has been employed for over 10 
years in trachoma control programs. 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.  
The safety profile of ivermectin is also 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. A review of women accidentally given ivermectin while 
pregnant showed no evidence of teratogenicity.  
Co-Administration of Azithromycin and Ivermectin was shown to be safe in the Azival study[14]. 
There was no difference in the number of adverse events in individuals who received combined 
treatment compared to those who received treatment one week apart. The safety of co-
administration has recently been confirmed in the AIM study in which the rate of adverse events 
following combined Azithromycin and Ivermectin treatment was <5% and no SAEs were noted (A 
Steer, Personal Communication). 
Benefits to Communities 
Communities will benefit from receiving treatment for both scabies and yaws as part of these studies. 
These are both major public health problems in the Solomon Islands and participating communities will 
therefore gain benefit from receiving the best available treatment for these two conditions which it is 
believed will result in improvements in their health and well being. 
 
 
 

 
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4. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS  
 
4.1 
PRE-RANDOMISATION OR PRE-REGISTRATION EVALUATIONS  
Mass treatment of the whole community with azithromycin is recommended for the purpose of yaws 
control. Mass treatment of the whole community with Ivermectin and Permethrin is the best available 
treatment for the purpose of scabies control.  Both treatment are offered to all individuals regardless 
of the presence/absence of clinical features of either disease – which is in line with the best evidence 
on how community mass treatment for these diseases should be conducted. 
 
 
4.2 
INCLUSION CRITERIA 
All consenting individuals in the participating communities will eligible to participate 
 
4.3 
EXCLUSION CRITERIA. 
Individuals not consenting to participate in the study. 
Individuals who are unwell on the day that study medications are administered. 
 
 
4.4 
WITHDRAWAL CRITERIA 
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.  Only data collected prior to withdrawal will be included in the analysis.   
 
 
 
 

 
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5. 
RANDOMISATION AND ENROLMENT PROCEDURE 
 
5.1 
RANDOMISATION OR REGISTRATION PRACTICALITIES 
 
Randomisation will be done at the level of the community by drawing sealed envelopes. 
All individuals within a community will be offered treatment in line with the randomisation of that 
community. All residents of the selected communities will be invited to participate in the study. 
 
Community Awareness 
Prior to the study commencing we will engage community leaders and local health staff from communities 
in the catchment area of AAH. A research training workshop will be held at AAH and which will be 
attended by AAH and other study staff as well as key community leaders. This meeting will provide an 
opportunity for explanation of the study aims and methodologies and for study staff to answer questions 
about the study design and implementation. 
 
Eligibility Criteria: 
All individuals within a community will be offered treatment in line with the randomisation of that 
community. All residents of the selected communities will be invited to participate in the study. 
 
Inclusion Criteria: 
All residents of the selected communities will be invited to participate in the study. 
 
Exclusion Criteria: 
Individuals with a contra-indication to treatment. 
Individuals not consenting to participate. 
 
 
 
5.2 
BLINDING  
 
This is an open-label study 
 
 
 
 

 
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6. 
TRIAL MEDICATION  
 
6.1 
Name and description of investigational medicinal product(s) 
 
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. Azithromycin is indicated for mild to moderate infections such as respiratory-tract infections, 
otitis media, skin and soft-tissue infections and genital chlamydial infections Azithromycin is the 
treatment of choice for mass treatment of both yaws and trachoma. The recommended dose for the 
mass treatment of yaws is a single- dose of azithromycin 30mg/kg up to a maximum of 2g. 
Azithromycin is available as 250 mg or 500 mg tablets and as oral suspension. 
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. The recommended dosage for treatment of scabies is two oral doses 
designed to provide approximately 200μg of ivermectin per kg of body weight. The same dose is 
recommended in the Solomon Islands. Ivermectin is available in 3mg tablets.  
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.  
 
6.2 
Legal status of drug 
Azithromycin is licensed for use in the UK. It is listed on the essential medicines list of the Solomon 
Islands and is the WHO recommended drug for community mass treatment for yaws eradication. 
 
Permethrin is licenced in the UK for the treatment of scabies. It is listed as on the essential medicines 
list for the Solomon Islands and recommended as a potential treatment for scabies. 
 

 
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Ivermectin is not licenced for the treatment of scabies in the UK although NICE has provided guidance 
on its use (https://www.nice.org.uk/advice/esuom29/resources/ivermectin-for-difficulttotreat-
scabies-17546902981). Ivermectin is widely used in control programmes for both Onchocerciasis 
and Lymphatic Filariasis.   Ivermectin is listed as on the essential medicines list for the Solomon 
Islands and recommended as a potential treatment for scabies.  
 
 
6.3 
Summary of Product Characteristics (SmPC) or Investigator Brochure (IB) 
Product Characteristics Sheets are attached in the Appendix. 
 
6.4 
Drug Storage and Supply 
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.  
 
 
 
 
6.5 
Preparation and labelling of IMP 
For participants receiving ivermectin and azithromycin, the dose will be determined according to body 
weight and treatment will be administered under direct supervision of the study team. Drug 
administration will be recorded in a standardized record form. 
 
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.  
 
6.6 
Dosage schedules/modifications 
In line with standard treatment the dosing of both Azithromycin and Ivermectin will use the following 
weight bands 
 
 
 
 
 

 
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Permethrin will be used instead of Ivermecitn in the following circumstances 
 
Pregnancy 
 
Breastfeeding 
 
Child <6 months age 
 
Child <12.5kg15kg 
 
Where permethrin is indicated the following standard dosing protocol will be used: 
 
Full tube for adults. 
 
Half tube for children. 
 
Apply to whole body and leave on for 1 day before washing off 
 
 
6.7 
Known drug reactions and interaction with other therapies 
 
The safety profile of both azithromycin and ivermecitn is well established from large mass treatment 
campagins where >100 million doseases have been adminsted. The most commonly reported side 
effects are for Ivermectin are headache, dizziness, itch. For Azithromycin the most commonly 
reported side effects are abdominal pain, nausea, vomiting and diarrhoea. For both drugs adverse 
events are normally mild and self-limiting with no specific therapy required.  
 
Results from a pharmacovigilance study involving more than 3,000 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[14]. 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.  
 
6.8 
Concomitant medication 
WEIGHT 
AZITHROMYCIN 
TABLETS 
(250mg Tabs) 
IVERMECTIN 
TABLETS 
(3mg Tabs) 
<15KG12.5KG 
1 
PERMETHRIN 
CREAM 
12.515 – 25 KG 
1 
1 
25 – 37.5 KG 
2 
2 
37.5 – 50 KG 
3 
3 
50-75 KG 
4 
4 
>75 KG 
4 
5 
Formatted: Font: Bold
Formatted: Font: Bold

 
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Individuals receiving Warfarin may not receive treatment with Ivermectin due to potential 
interactions. 
No individuals outside of the capital of the Solomon Islands (Honiara) are receiving Warfarin due to a 
lack of INR monitoring facilities and therefore it is not anticipated that nay individuals in the study 
will be receiving a contra-indicated concomitant medication.  
 
6.9 
Trial restrictions 
There are no trial restrictions.  
As noted above pregnant and breast feeding women and children <15kg will be offered permethrin 
rather than ivermecitn but will still be allowed to participate in the study. 
 
6.10 
Assessment of compliance 
Drugs will be delivered as a single observed treatment and therefore compliance will be assessed at 
the time of drug distribution. 
 
 
 
 

 
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7. 
SAFETY REPORTING FOR DRUG TRIALS  
 
7.1 
DEFINITIONS   
 
Term 
Definition 
Adverse 
Event 
(AE) 
Any untoward medical occurrence in a participant to whom a medicinal product 
has been administered, including occurrences which are not necessarily caused 
by or related to that product. 
 
An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP), whether or not considered 
related to the IMP. 
Adverse Reaction 
(AR) 
Any untoward and unintended response in a participant to an investigational 
medicinal product which is related to any dose administered to that participant. 
 
The phrase “response to an investigational medicinal product” means that a 
causal relationship between a trial medication and an AE is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as adverse reactions. 
Serious 
Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Results in persistent or significant disability/incapacity 
 Consists of a congenital anomaly or birth defect 
 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the above 
consequences.   
 
Serious 
Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
investigator, believed with reasonable probability to be due to one of the trial 
treatments, based on the information provided. 
Suspected 
Unexpected 
Serious 
Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the information about the medicinal product in question set out: 
 
 In the case of a product with a marketing authorisation, in the summary of 
product characteristics (SmPC) for that product 
 In the case of any other investigational medicinal product, in the investigator 
brochure (IB) relating to the trial in question. 
 
7.2 
CAUSALITY 
Most adverse events and adverse drug reactions that occur in this study, whether they are serious or not, 
will be expected treatment-related side effects due to the drugs used in this study.  The assignment of  
causality should be made by the investigator responsible for the care of the participant using the 
definitions in the table below. 
 
If any doubt about the causality exists the local investigator should inform the study coordination centre 
who will notify the Chief Investigators.  The pharmaceutical companies and/or other clinicians may be 
asked to advise in some cases. 
 

 
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In the case of discrepant views on causality between the investigator and others, all parties will discuss 
the case.  In the event that no agreement is made, both points of view are to be reported.  
 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the trial medication).  
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because the event 
occurs within a reasonable time after administration of the trial medication).  
However, the influence of other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant treatments). 
Probable 
There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
Not assessable 
There is insufficient or incomplete evidence to make a clinical judgement of the 
causal relationship. 
 
7.3 
REPORTING PROCEDURES 
Depending on the nature of the event the reporting procedures below should be followed.  Any questions 
concerning adverse event reporting should be directed to the study coordination centre in the first 
instance.   
 
7.3.1 Non serious Adverse Reactions (ARs)/Adverse Events (AEs) 
Given the established safety profile of the drugs being used in this study and the fact that they are being 
used for established indications we will only collect data on SAEs and SUSARs. 
 
 
7.3.2 Serious Adverse Reactions (SARs)/Serious Adverse Events (SAEs) 
Serious Adverse Events (SAEs) and Serious Adverse Reactions (SARs) should be reported to the study 
coordination centre within 24 hours of the local site being made aware of the event.   
 
An SAE form should be completed and submitted to the study coordination centre with as much detail of 
the event that is available at that time.  If awaiting further details, a follow up SAE report should be 
submitted promptly upon receipt of any outstanding information.  The CI (for a single-centre trial) or PI 
(for a multi-centre trial) must record the event with an assessment of seriousness, causality and 
expectedness. 
 
Any events relating to a pre-existing condition or any planned hospitalisations for elective treatment of a 
pre-existing condition do not need reporting as SAEs. 
 
 
7.3.3 SUSARs  
 
All SAEs assigned by the PI or delegate as both suspected to be related to IMP-treatment and unexpected 
will be classified as SUSARs and will be subject to expedited reporting to the Regulatory Authority, in the 
UK: Medicines and Healthcare Products Regulatory Agency (MHRA).  The Sponsor (or delegate) will 
inform the MHRA, and the ethics committee of UK-relevant SUSARs within the required expedited 
reporting timescales (as per LSHTM Standard Operating Procedure for recording, managing and reporting 
of adverse events for IMP studies). 
 
For blinded trials, all SUSARs must be reported assuming the active compound is involved.   
 

 
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In the case of a suspected, unexpected, serious adverse reactions (SUSAR), the staff at the site should:  
 
1. Contact the study coordination centre immediately by phone or email to inform them of the event.   
2. Submit a completed SAE form (signed and dated) within 24 hours, together with relevant 
treatment forms and anonymised copies of all relevant investigations. 
3. Submit any additional information promptly upon request.   
 
 
Contact details for reporting SAEs and SUSARs 
Telephone: +677 7738438 / +44 7984 643424 
Email: michael.marks@lshtm.ac.uk 
 
 
 
 
 
 
 

 
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8. 
ASSESSMENT AND FOLLOW-UP  
 
Baseline Data Collection 
At baseline (D1) all individuals will undergo a standardized examination to collect data on the presence of 
skin lesions consistent with yaws, scabies and impetigo. Following examination a finger-prick sample will 
be obtained from all individuals on to filter paper. In individuals with skin lesions consistent with yaws 
the same finger prick sample will be used for a rapid diagnostic test for yaws. In individuals with skin 
lesions consistent with yaws or impetigo two sterile lesion swabs will be obtained. 
Following examination individuals will be weighed and directly observed treatment will be dispensed in 
line with standard treatment guidelines (see above). On D8 study teams will return to each community 
and offer a second dose of medication for scabies.  
Interim Visit 
At Month 3 an interim visit will be made. Individuals will be re-examined and swabs collected from those 
with clinical evidence of impetigo. Data from previous studies indicates that scabies and impetigo 
continue to decline between month 3 to month 12 following community mass treatment for scabies 
therefore treatment will not routinely be offered at this time point. 
 
Follow-Up Data Collection 
At follow-up all individuals will undergo again undergo a standardized examination to collect data on the 
presence of skin lesions consistent with yaws, scabies and impetigo. Following examination a finger-prick 
sample will be obtained from all individuals on to filter paper. In individuals with skin lesions consistent 
with yaws the same finger prick sample will be used for a rapid diagnostic test for yaws. In individuals 
with skin lesions consistent with yaws the same finger prick sample will be used for a rapid diagnostic test 
for yaws. In individuals with skin lesions consistent with yaws or impetigo two sterile lesion swabs will be 
obtained. 
In communities where azithromcycin mass treatment was not conducted at baseline (sequential 
treatment arm 2) this will be offered at the follow-up visit.  
Laboratory Work 
 
Dried blood spots will be eluted at tested using the Treponema Pallidum Haemagglutination 
Assays. 
 
From each pair of lesion swabs, one swab will be tested using culture and anti-microbial 
sensitivity testing for S. pyogenes and S. aureus..  

 
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 
The second lesion swab will  tested using molecular techniques to assess the microbiological flora 
of the lesions. 
 
8.1 
LOSS TO FOLLOW-UP 
This is not an individually randomised clinical trial but allowance has been made for loss to follow-up in 
the sample size calculation. 
 
8.2 
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.   
 
 
 
 

 
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9. 
STATISTICS AND DATA ANALYSIS 
 
Sample Size 
The sample size required for our primary outcome was estimated as follows: 
• Pre-MDA prevalence of impetigo of 25-30% 
• Impetigo prevalence to fall to about 10% in the Ivermectin only arm  
• Impetigo prevalence to fall to about 5% in the combined arm  
• Enrolment 80%  
• Loss to follow-up 10% 
• 90% power to detect a difference between the two arms 
 
Primary Outcome: 
a) Prevalence of impetigo at months 12 months in parallel treatment communities compared to 
sequential treatment communities. 
Secondary outcomes: 
b) Change in the proportion of swab samples from which S. pyogenes is cultured between baseline 
and follow-up in the two arms  
c) Proportion of samples from which a drug-resistant isolate is cultured. 
 
Data and all appropriate documentation will be stored for a minimum of 5 years after the completion 
of the study, including the follow-up period.   
 
 
 
 

 
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10. 
MONITORING 
 
10.1 
RISK ASSESSMENT 
This is considered a low risk study. 
All the drugs being used are being prescribed for routine indications and have well established safety 
profiles. As such only passive monitoring for adverse events will be undertaken during the study.  
 
10.2 
MONITORING AT STUDY COORDINATION CENTRE 
Data will be entered directly into an electronic database at the time of the study.  
 
10.3 
MONITORING AT LOCAL SITE 
Site visits will take place at D1 (treatment for yaws and scabies), D8 (second treatment for scabies) 
and month 12 (assessment of outcome).  
 
 
 

 
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11. 
REGULATORY ISSUES 
 
11.1 
ETHICS APPROVAL 
 
The Study Coordination Centre has obtained approval from the LSHTM Research Ethics Committee, as 
well as the Atoifi Adventist Hospital Ethics Committee. 
 
Substantial protocol amendments will not be implemented until a favourable opinion has been granted 
from both the LSHTM and AAH ethics committee.  
Correspondence from both ethics committees will be maintained in the trial master file. 
As the duration of the study is 1 year the annual progress report will accompany the notification of the 
end of the study.  
 
 
11.2 
CONSENT  
 
Prior to the study commencing a research training workshop will be held at AAH and which will be 
attended by AAH and other study staff as well as key community leaders. This meeting will provide an 
opportunity for explanation of the study aims and methodologies and for study staff to answer questions 
about the study design and implementation. 
 
Prior to performing any study specific procedure, written informed 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 provide consent. Written consent will be 
obtained in local dialect on all occasions.   
 
11.4 
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.  
 
 

 
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11.5 
INDEMNITY 
London School of Hygiene & Tropical Medicine holds Public Liability ("negligent harm") and Clinical Trial 
("non-negligent harm") insurance policies which apply to this trial. 
 
11.6 
SPONSOR 
London School of Hygiene & Tropical Medicine will act as the main sponsor for this study.  Delegated 
responsibilities will be assigned locally.   
 
11.7 
FUNDING 
This study is funded as part of a Wellcome Trust Research Fellowship held by Michael Marks.  
No payments will be made to patients participating in this study.  
 
11.8 
AUDITS AND INSPECTIONS  
The study may be subject audit by the London School of Hygiene & Tropical Medicine under their remit as 
sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.  
 
 
 
 

 
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12. 
TRIAL MANAGEMENT 
 
A Trial Management Group (TMG) will be appointed and will be responsible for overseeing the progress of 
the trial.  The day-to-day management of the trial will be co-ordinated by Michael Marks and Jason Diau.  
 
All treatments in the study are being given for standard indications and the drugs have known safety 
profiles including in the setting of co-administration. A DSMB will therefore not be appointed.  
 
All data will be held jointly by LSHTM and AAH. Data will be stored on an encrypted password protected 
server at both LSHTM and AAH.  
 
 
 
 

 
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13. 
PUBLICATION POLICY 
 
All publications and presentations relating to the study will be authorised by the Trial Management Group.  
The first publication of the trial results will be in the name of the Trial Management Group, if this does not 
conflict with the journal’s policy.  If there are named authors, these will include at least the trial’s Chief 
Investigator, Statistician and Trial Coordinator.  Members of the TMG and the Data Monitoring Committee 
will be listed and contributors will be cited by name if published in a journal where this does not conflict 
with the journal’s policy.  Authorship of parallel studies initiated outside of the Trial Management Group 
will be according to the individuals involved in the project but must acknowledge the contribution of the 
Trial Management Group and the Study Coordination Centre. 
 
 
 

 
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14. 
REFERENCES 
 
1  Marks M, Vahi V, Sokana O, et al. Mapping the Epidemiology of Yaws in the Solomon Islands: A Cluster 
Randomized Survey. Am J Trop Med Hyg 2015;92:129–33. doi:10.4269/ajtmh.14-0438 
2  International Association for the Prevention of Blindness. Trachoma Mapping in the Pacific. 2013.  
3  The World Health Organisation. Eradication of yaws - the Morges Strategy. Wkly Epidemiol Rec 
2012;87:189–94. 
4  Emerson PM, Burton MJ, Solomon AW, et al. The SAFE strategy for trachoma control: using 
operational research for policy, and implementation. Bull World Health Organ 2006;84:613–9. 
5  Sadiq ST, Glasgow KW, Drakely CJ, et al. Effects of azithromycin on malariometric indices in The 
Gambia. The Lancet 1995;346:881–2. doi:10.1016/S0140-6736(95)92712-3 
6  Keenan JD, Ayele B, Gebre T, et al. Childhood Mortality in a Cohort Treated With Mass Azithromycin 
for Trachoma. Clin Infect Dis 2011;52:883–8. doi:10.1093/cid/cir069 
7  Coles CL, Mabula K, Seidman JC, et al. Mass distribution of azithromycin for trachoma control is 
associated with increased risk of azithromycin-resistant Streptococcus pneumoniae carriage in young 
children 6 months after treatment. Clin Infect Dis Off Publ Infect Dis Soc Am 2013;56:1519–26. 
doi:10.1093/cid/cit137 
8  Romani L, Steer AC, Whitfeld MJ, et al. Prevalence of scabies and impetigo worldwide: a systematic 
review. Lancet Infect Dis 2015;15:960–7. doi:10.1016/S1473-3099(15)00132-2 
9  Heukelbach J, Feldmeier H. Scabies. The Lancet 2006;367:1767–74. doi:10.1016/S0140-
6736(06)68772-2 
10  Romani L, Whitfeld MJ, Koroivueta J, et al. Mass Drug Administration for Scabies Control in a 
Population with Endemic Disease. N Engl J Med 2015;373:2305–13. doi:10.1056/NEJMoa1500987 
11  Marks M, Vahi V, Sokana O, et al. Impact of Community Mass Treatment with Azithromycin for 
Trachoma Elimination on the Prevalence of Yaws. PLoS Negl Trop Dis 2015;9:e0003988. 
doi:10.1371/journal.pntd.0003988 
12  Mitjà O, Houinei W, Moses P, et al. Mass Treatment with Single-Dose Azithromycin for Yaws. N Engl J 
Med 2015;372:703–10. doi:10.1056/NEJMoa1408586 
13  Taplin D, Porcelain SL, Meinking TL, et al. Community control of scabies: a model based on use of 
permethrin cream. Lancet 1991;337:1016–8. 
14  Coulibaly YI, Dicko I, Keita M, et al. A cluster randomized study of the safety of integrated treatment of 
trachoma and lymphatic filariasis in children and adults in Sikasso, Mali. PLoS Negl Trop Dis 
2013;7:e2221. doi:10.1371/journal.pntd.0002221 
 
 
 
 

 
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APPENDICES 
1. Informed Consent Form 
2. Assent Form 
3. Study Information Sheet 
4. MDA Record Form 
5. Skin Examination Record Form 
6. SAE Report Form 
7. Summary of Product Characteristics for Azithromycin 
8. Summary of Product Characteristics for Ivermectin 
9. Summary of Product Characteristics for Permethrin