Choice of Moisturiser for Eczema Treatment (COMET): study protocol for a randomized controlled trial

Design

COMET is a feasibility study of a pragmatic, single-masked, randomized clinical trial
to compare the clinical benefit and cost-effectiveness of leave-on emollients in the
treatment of children with eczema in primary care. The aim is to recruit 160 children,
randomly allocate them to one of four emollients and follow them up for 3 months.
The primary means of data collection are parent-completed daily diaries, monthly assessments,
and retrospective review of electronic medical records.

Setting

General practices located in Bristol, South Gloucestershire and North Somerset will
be invited to participate in the trial via the West of England Clinical Research Network..
We aim to recruit practices from a diversity of settings, using different computer
systems and with varying levels of research activity and experience. Criteria for
entry into the trial include having at least one GP trained in good clinical practice
and a willingness to undertake patient mail-outs and prescribe the study emollients.

Participants

Children are eligible if they: are aged from 1 month to under 5 years; have eczema
(diagnosed by a doctor or an appropriately qualified health care professional with
oversight from a medically qualified doctor); and are not known to be sensitive or
allergic to any of the study emollients or their constituents. An adult with parental
responsibility must consent for the child to participate. Throughout this paper, the
term ‘parent’ will be used to denote all carers or guardians.

Eligibility will be confirmed by an appropriately qualified health care professional
for patients referred by the practice, with oversight from a medically qualified doctor,
or by the chief investigator (or his deputy) for patients who self-refer. All those
making eligibility decisions will be trained in good clinical practice.

Recruitment

There are two recruitment methods: ‘self-referral’ or ‘in consultation’.

‘Self-referral’ is defined as when parents of potentially eligible children are invited
to contact the research team directly by means of a practice mailshot, practice waiting
room posters or study flyers. Parents who respond have their child’s eligibility and
understanding of the study checked by a researcher. Once confirmed, written informed
consent is received at the baseline visit.

‘In consultation’ is defined as when parents of eligible children are recruited by
a GP or practice nurse during a surgery visit (which need not be for the child’s eczema).
The GP or practice nurse establishes eligibility, receives written informed consent
and conducts the randomization. Practice nurses and GPs are asked to record all approaches
to potentially eligible participants in a recruitment log.

Intervention and assignment of intervention

Participants are randomly allocated to one of four emollients (Aveeno® lotion 400
ml, Diprobase® cream 500 g, Doublebase® gel 500 g, Hydromol® ointment 500g) to use
as their primary leave-on emollient with directions to ‘Use twice daily and when required.’
These were chosen because they represent each of the different formulations (lotion,
cream, gel and ointment), are among the most commonly prescribed and vary in cost.
In addition, Doublebase® and Diprobase® emerged as the most popular in a patient preference
study and mechanistic studies have shown that these emollients enhance skin barrier
function (Professor Hywel Williams, personal communication). Allocation is done by
the Bristol Randomised Trials Collaboration web-based system, using a simple randomization
process in a 1:1:1:1 allocation.

All study emollients are prescribed for the duration of the study by the participant’s
GP surgery as per normal care. For children recruited via the self-referral route,
randomization is conducted by the trial coordinator (or the trial coordinator’s deputy)
upon confirmation of eligibility and consent, who will then contact the practice to
arrange prescription of the study emollient. For children recruited in consultation,
the recruiting GP or practice nurse is responsible for randomization and prescribes
the allocated emollient at that visit. This process is kept secret from the researchers
who perform the assessment visits.

Therefore COMET is a single-masked study, where clinician, parent and trial coordinator
are unmasked but the researchers undertaking the baseline and follow-up visits are
masked. This is to ensure that the ‘objective’ assessments of eczema severity are
unbiased, that is are not influenced by researcher knowledge of the type of emollient
being used. To maintain masking, the following steps will be taken. First, researchers
undertaking the assessments do not have access to the randomization system and are
not able to identify which emollient has been assigned to which participant. Second,
clinicians and parents are asked not to disclose which treatment they are using. Third,
to minimize the risk of unmasking due to differences between emollients when applied
to the skin (their look, feel or smell), parents are asked to maximize the amount
of time between application and the assessment visits. Fourth, parents are also asked
to ensure that the emollient container is hidden from view.

Researcher masking will be assessed using the Bang blinding index 15], which takes a value between ?1 and +1: +1 indicates complete lack of masking and
0 is consistent with perfect masking. Negative values indicate that the respondent
is wrong more often than would be expected by chance, which can arise, for example,
if all participants are said to be on one particular treatment irrespective of what
they receive. The index can be presented with confidence intervals and can be used
as the basis of a test of the null hypothesis that the respondent is randomly guessing
each participant’s allocation.

Routine clinical care is not affected – children will attend appointments for their
eczema as normal and use other medications (for example, topical corticosteroids)
as normally directed. If, during the course of the study, children have a reaction
to the study emollient or parents wish to change for another reason, the clinicians
in charge are free to prescribe any alternative as per their normal clinical practice.
Co-prescribing of other leave-on emollients and bath additives will be discouraged,
but allowed.

Outcome measures

Participants will be followed up monthly (every 28 days) for 3 months (total 84 days).
As this is a feasibility study, the primary outcome is the proportion of children
approached who were randomized to a study emollient and used it for the duration.

Secondary outcome measures relate to the feasibility of the study:

Data completeness of daily, weekly and monthly measures, recorded by parents and
collected by research assistants.

The extent to which the research assistants were kept masked to intervention.

Preliminary data on the clinical effectiveness of the proposed study emollients,
including the quantity and frequency of emollient application, and evidence of any
effect on topical corticosteroid or calcineurin inhibitor use.

Qualitative feedback from parents of participants regarding the logistics and acceptability
of trial processes, procedures and paperwork.

Data collection

How, when and by whom the data are collected are summarized in Table 1.

Table 1. Type, timing and means of data collected about participants in COMET study

Parent-completed daily diary

At enrolment, parents are given the option of completing a paper or electronic (app)
version of the diary; and the option of automatic text reminders to encourage completion.
They are asked to record use of emollient and topical corticosteroid or calcineurin
inhibitor on a daily basis; detail contacts with healthcare professionals, eczema-related
costs and the Patient-Orientated Eczema Measure 16] weekly; and complete Dermatitis Family Impact 17], Quality of Life 18] and global assessment questionnaires monthly.

Assessment visits

At the baseline visit, the researcher collects sociodemographic information, data
on eczema diagnosis and treatments used, and asks the parents to complete the Dermatitis
Family Impact questionnaire. At baseline and monthly follow-up visits, researchers
undertake objective assessments of eczema severity (Eczema Area Severity Index; 19] Six Area, Six Sign Atopic Dermatitis severity score; 20] Three Item Severity score 21]) and measurements of skin hydration at the antecubital fossa and forearm (three measurements
in each area) using a corneometer (Corneometer® CM825, Courage Khazaka electronic
GmbH, Cologne, Germany). Standardized procedures written in accordance with guidelines
on biophysical skin measurements are followed 22].

At the final visit, parents are asked to complete an exit questionnaire. Parents who
choose to withdraw from the study at any point are asked to complete a withdrawal
questionnaire.

Review of electronic medical record

The primary care electronic medical records of consented children are reviewed for
the 3 months they are in the study. Data on relevant prescriptions (emollients, topical
and oral corticosteroids, topical calcineurin inhibitors) and health care use (number
of consultations with GP or practice nurse and of dermatology out-patient attendances)
are extracted.

Data management

Parents of all participating children will be asked to provide consent using paper
consent forms (Additional file 1). Consent forms and study questionnaires (case report forms) will be stored securely
and made accessible only to the research team and authorized personnel.

Data from case report forms completed on paper by the participant or research team
are entered in a study database, which incorporates data validation rules to reduce
data entry errors, and management functions to facilitate auditing and data quality
assurance. A random sample of 10% of diary and visit case report forms will be checked,
by the trial research team, against entries in the database for quality purposes.
At the end of the trial, the database will be cleaned and locked.

Patient identifiers will be kept in a separate system from the clinical data. The
database and randomization system will be designed to protect patient information,
in line with the UK Data Protection Act (1998). The research team will ensure that
participants’ anonymity is maintained through secure handling and storage of patient
information at the trial centre. Participants will be identified only by a patient
ID number on the case report form.

Analysis

Participant recruitment and follow-up via each of the two recruitment pathways will
be reported using a CONSORT flowchart showing the numbers of people approached, eligible,
recruited and randomized (with reasons for exclusions).

The proportion of children approached who were randomized to a study emollient and
used it for the duration of the study (the primary outcome measure) will be reported.
We will explore how participant recruitment and retention varies by recruitment pathway
and practice and participant characteristics.

We will report data completeness of daily, weekly and monthly measures, recorded by
parents and collected by the research team. In respect of the diary, we will compare
data completeness between paper, with or without text reminders, and app versions.
We will also, by referring to participants’ electronic medical record data, assess
accuracy and completeness of parent-recorded diary data.

The different outcome measures will be presented as summary statistics, to allow sensitivity
of each measure to change over time to be compared. The different emollients will
be compared in terms of these summary outcome measures, and in terms of parent-completed
questionnaires, to identify any early evidence of the inferiority of a particular
emollient, which would inform the choice of emollients to be included in the main
trial.

Feedback from parents of participants regarding satisfaction with the allocated emollient
and trial processes, procedures and paperwork will be presented. Bang blinding index
data will be presented to evaluate the success of keeping researchers masked to treatment
allocation.

We will test the feasibility of using data collected during the trial to carry out
a cost-effectiveness study from the perspectives of the NHS, parents, and the value
of lost productivity. Data on resource use collected via the patient diary will be
used to identify the level of missingness, by item, and which items are important
cost drivers. This information will be used in designing data collection for the economic
evaluation in the full trial. NICE recommends the use of quality-adjusted life years
as the preferred outcome measure in economic evaluations. However, no validated generic
measure of health-related quality of life is psychometrically and conceptually robust
enough for young children under the age of 3. We are therefore using a preference-based
measure of health in children with atopic dermatitis 18] in this feasibility study, which will indicate the value of using it to estimate
quality-adjusted life years in the full trial.

Sample size

Because this is a feasibility study, a formal sample size calculation for the estimation
of treatment effectiveness has not be made. We will aim for a target sample size of
160, 40 in each arm. With this number, a true consent rate of 50% (160 children participating
having invited 320 potentially eligible children) will be estimated, with a 95% confidence
interval of the order 44% to 56%. This is sufficiently precise to inform the design
of a definitive trial.

Monitoring

The University of Bristol will act as sponsor for the trial (reference UoB2009). Because
of the low risk nature of the study, it is being overseen by a joint Trial Steering
and Data Monitoring Committee (TS/DM-C). The overall role of the TS/DM-C, which is
independent of the sponsor, is to safeguard the interests of the trial’s participants,
potential participants, investigators and sponsor; and to monitor the trial’s overall
conduct, and protect its validity and credibility. No formal interim statistical analyses
are planned: it is expected that the study recruitment will terminate when the intended
sample size have been achieved. The committee will be masked to the identity of the
treatment arms unless unexpected numbers of adverse events warrant examination of
data by treatment allocation.

All adverse events will be recorded in participants’ study diaries. Expected adverse
reactions to study emollients (for example, pruritus or erythema) will be collated
and reviewed at Trial Management Group and TS/DM-C meetings. Expected non-serious
(for example, upper respiratory tract viral infections, diarrhoea or vomiting) and
serious (for example, lower respiratory tract infections or urinary tract infections)
adverse events that cannot be causally related to study participation will not be
reported. Expected serious adverse events that might be related to study participation
will be reported to the sponsor within 24 hours of knowledge of the event. All relevant
information about a suspected unexpected serious adverse reaction will be reported
within 7 days to the Medicines and Healthcare Products Regulatory Agency (MHRA) and
the ethics committee.

The chief investigator and study sites will allow monitors, persons responsible for
the audit, representatives of the ethics committee and of the regulatory authorities
to have direct access to source data and documents. Trial monitoring will be undertaken
on behalf of the Sponsor by University Hospitals Bristol NHS Foundation Trust following
their standard monitoring procedures.

Ethics

The study was approved by the Central Bristol Research Ethics Committee (reference:
13/SW/0297), clinical trial authorization was given by the MHRA (reference: 03299/0017/001-003)
and research governance approvals were obtained across all areas prior to recruitment.
The study will be conducted in accordance with the principles of good clinical practice,
UK Research Governance Framework and the Medicines for Human Use (Clinical Trial)
Regulations 2006.

The current protocol version is 1.3. Version 1.0 (October 2013) was the version submitted
for research ethics committee approval. Version 1.1 (November 2013) was the version
first approved by both the research ethics committee and MHRA. Version 1.2 (May 2013)
included minor wording and timeline changes and amendments to descriptions of study
procedures, including adverse event reporting. Version 1.3 (November 2014) included
revised eligibility criteria (from ‘child aged between 1 month and 3 years with doctor-diagnosed
eczema’ to ‘child aged between 1 month and 5 years of age with eczema (diagnosed by
a doctor or an appropriately qualified health care professional with oversight from
a medically qualified doctor)’) and recruitment of additional sites. All amendments
have been approved by the relevant regulatory bodies and communicated to relevant
parties.

Dissemination

Following a separate agreed publication policy, we will disseminate findings through
local and national networks, including key professional, public stakeholder and educational
organizations. Dissemination will also occur via oral presentations and posters to
national primary care and dermatological scientific conferences, and by publication
in peer-reviewed journals. For promotional and informative purposes, the study website
23] and on-line social media (Twitter 24] and Facebook 25]) are publically accessible. A summary of the main findings will be distributed via
these routes at the end of the study and specifically for the participants involved.