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Trial registered on ANZCTR


Registration number
ACTRN12617000902392
Ethics application status
Approved
Date submitted
14/06/2017
Date registered
20/06/2017
Date last updated
20/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploring a tea tree oil-based treatment option for scabies in Aboriginal and Torres Strait Islander children living in remote Australia
Scientific title
Exploring a better treatment option for scabies using tea tree oil-based gel formulation in remote-dwelling Aboriginal and Torres Strait Islander children – Protocol for a pilot, randomised, permethrin controlled trial
Secondary ID [1] 292006 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Scabies infestation 303394 0
Condition category
Condition code
Infection 302807 302807 0 0
Other infectious diseases
Skin 302808 302808 0 0
Dermatological conditions
Alternative and Complementary Medicine 302895 302895 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test group - treatment of scabies infestation with a topical 5% v/w Tea Tree Oil (TTO) gel, applied twice (day 1 and day 7)

The test medication (5% v/w TTO gel) will be applied on days 1 and 7 of the trial, and the treatment will be left on the body for 8 to 12 hours, after which children will shower with non-medicated soap and water.

The treatment formulations (for both the test and control group participants) will be applied chin down by the patient or carer wearing plastic gloves and gowns. Patients will be bathed (as usual) and bed linen changed before applying the treatment. The formulations will be applied to every square inch of skin, from the posterior ear folds down over the entire body. This includes intergluteal cleft, umbilicus, skin folds, palms and soles, and webs between fingers and toes. The area behind the ears will be given special attention while avoiding eyes and mouth. Fingernails and toenails will be clipped and the scabies formulations applied under nails. Clean clothing will be put on after applying the treatment.

The study participants and carers will be given additional personal protective equipment such as disposable, long sleeve gowns and gloves for direct patient care to prevent reinfestation. Participants will be instructed to wash contaminated clothing and linens in the hot cycle of the washing machine and dry in the hot cycle of the dryer for 10-20 minutes or dried under hot sunlight. If trial medication is washed off during hand washing, toileting, or perineal care, it will be reapplied. The formulation will be applied at night after the evening bath (with a non-medicated soap). Treatment will be overseen by a group of senior GPs at the Wurli-Wurlinjang Health Service.

In order to prevent and contain spread of scabies, all other family contacts will be offered standard first-line scabies treatment (Lyclear, permethrin 5% cream) with instructions for use at home. The permethrin cream will be provided in visually distinguishable containers with clear instructions using coloured labels to prevent medication errors. Crusted scabies-infested house contacts will be treated with a combination of standard oral and topical therapy by the physician. Participants will be advised not to use or mix any other scabies treatment with trial medications. Patients living in a house with crusted scabies-infested house mates will be given ACTELLIC 50 EC (pirimiphos methyl, insecticide), with labelled instructions for use to clean the house (e.g. floors and walls). Test formulations (5% v/w TTO gel in an aqueous base) will be prepared following WHO Good Manufacturing Practices (GM, IDT Australia, VIC) and all formulations will be supplied in appropriate child-safe medicine containers, labelled with the child’s identifiers and dosing (application) instructions.


Compliance:
Innovative strategies will be employed to motivate trial participants’ compliance to the treatment protocol. These include providing each trial participant with a tablet with pre-set alarms to remind them and pre-loaded engaging video tutorials in relevant Aboriginal languages to facilitate the correct and easy application of trial medications. Further, a limited supply of washing machines (n=30) will be provided to appropriate participating communities to better control the scabies infestation in the local communities and to facilitate the accomplishment of long-term treatment goals.
Healthcare home visits by Indigenous health workers (every week during the course of study) will be organised to enhance patients’ adherence to the treatment protocol. Further, gift vouchers (e.g. prepaid telephone cards and grocery vouchers) will be given to participants to compensate for patient transport to the study centre for follow-up assessments. An experienced and appropriately qualified study nurse (employed at the trial site) will review each patient by phone to record any apparent adverse effects and to assess adherence to treatment protocol. During the treatment phase, the participant/parent/carer will also receive daily SMS alerts in the morning to remind them about the treatment application. Further, patient compliance to the treatment protocols will be assessed (subjectively) by weighing the tubes of medications prior to the supply and at the end of treatment. Parents/carers will be reminded by nursing staff to return the formulations and tablets at the end of week 1. As a bush medicine used in Aboriginal healing practices for centuries, TTO is likely to be accepted by study participants.
Intervention code [1] 298139 0
Treatment: Drugs
Comparator / control treatment
Control group - treatment of scabies infestation with topical 5% permethrin cream, single application only (day 1) followed by application of placebo treatment (day 7).

Participants in the control group will be treated with an active comparator, permethrin 5% cream (Lyclear, Registered Trademark), which is the standard first-line treatment against scabies. This treatment will be applied at night once only over the entire body from the chin down (as described previously). The permethrin cream will be left on the body for 8-12 hours after which time the children will shower with non-medicated soap and water. Permethrin treatment will be given on day 1 of the trial followed by placebo treatment (i.e. identical standard formulation minus permethrin) on day 7. Treatment will be overseen by a group of senior GPs at the Wurli-Wurlinjang Health Service.
Control group
Active

Outcomes
Primary outcome [1] 302192 0
Rate of clinical cure (i.e. complete resolution or improvement) of scabies skin lesions.
Digital endpoint will be recorded (i.e. images demonstrating clinical change/improvement in scabies presentation). Cure is defined as the absence of new lesions, and all old lesions healed at week 4 (residual, dry, non-inflammatory papules will not be considered to be active). Differences in cure rate between test and control treatment groups will be presented with a corresponding 95% confidence interval and one-sided p-value.
Timepoint [1] 302192 0
4 weeks after intervention commencement (day 29)
Secondary outcome [1] 335147 0
Extent of relief (percentage improvement) of pruritus as reported by the participant (or their parent/caregiver).
After one week follow-up, each participant will be asked to quote 0/25/50/75/100%, on a visual analogue scale about the 'percentage of remaining pruritus', considering the pruritus at first visit as 100%. Antipruritic medication, if needed, will be given after this period.
Timepoint [1] 335147 0
1 week, 2 weeks and 4 weeks after intervention commencement (days 8, 15 and 29)
Secondary outcome [2] 335379 0
The proportion of children with secondary bacterial complications.
Aboriginal health workers will be trained to identify skin sores (clinical signs of bacterial complication) and grade their severity. Severity will be stratified into mild impetigo (one purulent or crusted sore and fewer than five sores in total) or severe impetigo (two or more purulent or crusted sores or five or more sores in total) as per the reference below.
Additionally, skin lesions will be photographed and assessed by researchers.

Reference: Asha C Bowen, Steven Y C Tong, Ross M Andrews, Irene M O'Meara, Malcolm I McDonald, Mark D Chatfield, Bart J Currie, Jonathan R Carapetis, Short-course oral co-trimoxazole versus intramuscular benzathine benzylpenicillin for impetigo in a highly endemic region: an open-label, randomised, controlled, non-inferiority trial, The Lancet, Volume 384, Issue 9960, 2014, Pages 2132-2140,
Timepoint [2] 335379 0
1 week, 2 weeks and 4 weeks after intervention commencement (days 8, 15 and 29)
Secondary outcome [3] 335382 0
The proportion of children with side effects (adverse events).
At follow-up assessments, subjects will be shown informed lists of local adverse events (e.g. swelling, stinging, itch, rash, erythema and tingling) and systemic adverse events (e.g. fever, nausea, vomiting, headache, dizziness) and asked to record or report any they have experienced as well as any others not on the lists. Carers of participants will also be given a diary card to record ongoing solicited adverse events
Timepoint [3] 335382 0
1 week, 2 weeks and 4 weeks after intervention commencement (days 8, 15 and 29)
Secondary outcome [4] 335383 0
Compliance to treatment protocol..
An experienced and appropriately qualified study nurse will interview each patient by phone (daily in the afternoon during the first week post randomisation and once weekly post treatment phase) to assess adherence to treatment protocol. Compliance to the treatment protocols will be objectively assessed by weighing the tubes of medications prior to supply and at the end of treatment (1 week post intervention).
Timepoint [4] 335383 0
Subjective assessment - daily during treatment phase and weekly post treatment phase until 4 weeks post intervention commencement (days 1-8, 15, 22, 29)
Objective assessment - 1 week post intervention commencement (day 8)
Secondary outcome [5] 335384 0
Patient acceptability of treatment protocol.
Participants and/or caregivers will be interviewed and asked to rate the acceptability of the treatment protocol on a 0-5 visual analogue scale.
Timepoint [5] 335384 0
1 week and 2 weeks post intervention commencement (days 8 and 15)

Eligibility
Key inclusion criteria
1) Presence of typical scabietic lesions, for example papules, nodules, or vesicles at classical sites (including but not limited to the following sites of predilection: face, head, palms, interdigit, sides of fingers, upper and lower extremities, wrists, elbows, axilla, nipple, umbilical area and/or lower abdomen, genitalia, inguinal, buttocks and back area);
2) Presence of classical burrows on clinical examination;
3) Nocturnal pruritus;
4) History of similar symptoms among family members or close contacts.
Minimum age
5 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Treatment with any topical scabicidal therapy in the month before entry into the study;
2) Use of any topical or systemic therapy in the week before entry;
3) Confirmed or suspected immunosuppressive or immunodeficient conditions, including human immunodeficiency virus (HIV) infection;
4) Presence of scabies with an atypical presentation, like crusted scabies or scabies incognito;
5) Presence of any other skin disease which could alter the picture of scabies;
6) Known history of allergy to any of the study medications (permethrin, tea tree oil or other essential oils);
7) Receipt of more than 2 weeks of immuno-suppressants or immune modifying drugs, (e.g. prednisolone >0.5 mg/kg/day).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be performed with sealed opaque envelopes. After confirmation that the inclusion criteria have been met, an appropriately qualified and experienced research coordinator will ascribe participants to either the intervention or control group using a pre-determined, site-specific, age- stratified sequential serial number. He/she will then open the matched, sequentially numbered opaque envelope containing the treatment allocation instructions.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using computerised sequence generation. The randomisation sequence will use varying block sizes and be stratified by participant age and site (clinic and/or location). The randomisation will be kept secure by an independent statistician and concealed from all investigators and research staff.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size:
The study sample size was calculated using expectations based on previous observational studies, in vitro data of TTO and findings from similar trials. Calculations are based on the assumptions that permethrin 5% cream will have a 90% cure rate and TTO 5% formulation will have an 80% cure rate at 15 days. Given an estimated 10% difference in cure rate in favour of the comparator permethrin arm, a sample of 69 patients per arm (138 in total) is required to be 80% sure that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the permethrin arm of more than 25%, thus establishing non-inferiority between TTO and permethrin. A larger sample would have permitted us to detect a smaller non-inferior difference (e.g. 15%, 10%) which makes it easier to argue the case for non-inferiority. However, it may not be practical to recruit a larger cohort for a pilot RCT without presenting preliminary clinical safety efficacy data, especially in children. The results will be considered significant if P= 0.05. The current study will recruit 200 patients (100 in each arm, to allow for up to 30% attrition, based on our previous studies).

Statistical analysis:
Data will be reported in accordance with the Consolidated Standards of Reporting Trial (CONSORT) guidelines. For each outcome, the number of evaluable children in each treatment group will be presented. Categorical variables will be summarised using frequency and percentage. Continuous variables will be first assessed for significant departures from normality using a Shapiro-Wilk test and summarised using mean and standard deviation (SD) or median and inter-quartile range (IQR) as appropriate. Significantly skewed variables will be further assessed for transformation and analysed parametrically or non-parametrically as appropriate. Differences in cure rate between treatment arms groups will be presented with a corresponding 95% confidence interval and one-sided p-value. Kaplan-Meier estimates and a log-rank test will be used to compare time-to-event outcomes by treatment arm. Cox proportional hazards regression will be used to adjust the association between treatment arm and time-to-event outcomes for known or suspected baseline confounders. The baseline comparability of groups will be further assessed, using the centre as an adjustment factor. Hazard proportionality will be assessed through analysis of scaled Schoenfeld residuals. All analysis will be based on an "intention to treat" (ITT) approach analysis, including all patients randomised, whether treated or not, and including all patients who have withdrawn prematurely. This approach reduces any bias that may occur when participants not receiving assigned treatments are excluded from analysis. A priori sub-group analysis will be performed by age group (<12 years vs. 12–16 years) and the recruitment site. A test for interaction will be performed to assess for the presence of a differential treatment effect by subgroup. Sensitivity analyses will be conducted to compare: 1) the available data analysis with alternative assumptions about any missing data; and 2) the 'treatment allocated' approach with 'treatment received' approach.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/06/2017
Actual
Date of last participant enrolment
Anticipated
30/12/2018
Actual
Date of last data collection
Anticipated
28/02/2019
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NT

Funding & Sponsors
Funding source category [1] 296531 0
University
Name [1] 296531 0
University of Canberra
Country [1] 296531 0
Australia
Primary sponsor type
University
Name
University of Canberra
Address
University Dr
Bruce ACT 2617
Country
Australia
Secondary sponsor category [1] 295486 0
None
Name [1] 295486 0
Address [1] 295486 0
Country [1] 295486 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297747 0
University of Canberra Human Ethics Committee
Ethics committee address [1] 297747 0
Ethics committee country [1] 297747 0
Australia
Date submitted for ethics approval [1] 297747 0
23/05/2016
Approval date [1] 297747 0
16/12/2016
Ethics approval number [1] 297747 0
Ethics committee name [2] 297834 0
Wurli-Wurlinjang Health Service Indigenous subcommittee
Ethics committee address [2] 297834 0
Ethics committee country [2] 297834 0
Australia
Date submitted for ethics approval [2] 297834 0
Approval date [2] 297834 0
23/03/2017
Ethics approval number [2] 297834 0
Ethics committee name [3] 297835 0
Aboriginal Medical Services Alliance Northern Territory (AMSANT) reference group
Ethics committee address [3] 297835 0
Ethics committee country [3] 297835 0
Australia
Date submitted for ethics approval [3] 297835 0
Approval date [3] 297835 0
29/05/2017
Ethics approval number [3] 297835 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75006 0
Dr Jackson Thomas
Address 75006 0
Faculty of Health
University of Canberra
Building 12 Level D Office 36
Kirinari Street
Bruce ACT 2601
Country 75006 0
Australia
Phone 75006 0
+61 2 62068928
Fax 75006 0
+61 2 62015727
Email 75006 0
Jackson.Thomas@canberra.edu.au
Contact person for public queries
Name 75007 0
Jackson Thomas
Address 75007 0
Faculty of Health
University of Canberra
Building 12 Level D Office 36
Kirinari Street
Bruce ACT 2601
Country 75007 0
Australia
Phone 75007 0
+61 2 62068928
Fax 75007 0
+61 2 62015727
Email 75007 0
Jackson.Thomas@canberra.edu.au
Contact person for scientific queries
Name 75008 0
Jackson Thomas
Address 75008 0
Faculty of Health
University of Canberra
Building 12 Level D Office 36
Kirinari Street
Bruce ACT 2601
Country 75008 0
Australia
Phone 75008 0
+61 2 62068928
Fax 75008 0
+61 2 62015727
Email 75008 0
Jackson.Thomas@canberra.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTreatment of scabies using a tea tree oil-based gel formulation in Australian Aboriginal children: Protocol for a randomised controlled trial.2018https://dx.doi.org/10.1136/bmjopen-2017-018507
N.B. These documents automatically identified may not have been verified by the study sponsor.