Proactive against reactive treatment for lichen sclerosus

ISRCTN	ISRCTN72275160
DOI	https://doi.org/10.1186/ISRCTN72275160
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	1008267
Protocol serial number	23055, IRAS 1008267, CPMS 61122
Sponsor	Nottingham Clinical Trials Unit
Funder	Health Technology Assessment Programme

Submission date: 09/01/2024
Registration date: 08/03/2024
Last edited: 27/03/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Skin and Connective Tissue Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Lichen sclerosus (LS) is a long-term, itchy and distressing condition affecting vulval skin (the skin around the outside of the vagina). It needs ongoing treatment with steroid creams to manage flares of symptoms. If untreated, it may lead to scarring causing the labia minora (inner lips) to fuse together or the entrance to the vagina to narrow. People with LS are at higher risk of developing vulval cancer. Vulval LS can affect everyone, but most commonly children and women of any age, particularly women who have gone through the menopause and children before puberty. This study will try to find out what is the best way to manage future flares of LS: using a steroid treatment regularly (e.g. twice a week), even when symptoms are controlled OR using a steroid cream only during a flare.

Who can participate?
Female patients with LS aged 5 years and over

What does the study involve?
Participants are randomly allocated to either use their steroid cream twice a week or to only use it if they experience symptoms. The researchers will compare how many people in each group develop LS flares. With the optional consent of the participant/parent/guardian, photographs will be taken at baseline to check if scarring worsens during the trial. The researchers will follow patients for 2 years to gather data. With participants’ consent (optional), the researchers will check their medical records at a later stage (after the trial ends) to see how many patients in each treatment group develop cancer. They will conduct an optional qualitative study and interview patients (those who consented to participate in qualitative sub-study) to explore how they feel about the trial and the different ways of treating LS that we are testing. The researchers will also compare the costs and outcomes of the two treatments used in the trial to see if one is better value for money for the NHS. If successful, the study results will be used to change clinical practice for the treatment of patients with LS.

What are the possible benefits and risks of participating?
The study treatment involves topical steroid ointment/cream, which is normally prescribed to patients as their routine care for LS. The only difference between the study treatment and the routine care may be the treatment regimen. It is, therefore, believed that the risk associated with the study due to the intervention is negligible. Participants will be asked to attend research appointments. Every effort will be made to coincide these appointments with participants' clinical appointments.
Safety data will be collected for the duration of participation and will be reported as per sponsor guidelines. Although the steroid treatment can be safely applied to the whole body in a single dose with minimal risk of adverse reactions, there is however a risk of adverse reactions following long-term use of topical corticosteroid on localised areas of skin (e.g. skin thinning, telangiectasia). These will be monitored during clinical examination at follow-up visits (or at an unscheduled trial visit, as necessary).

Where is the study run from?
Nottingham Clinical Trials Unit (UK)

When is the study starting and how long is it expected to run for?
March 2023 to March 2028

Who is funding the study?
NIHR Health Technology Assessment Programme (UK)

Who is the main contact?
PEARLS study team, PEARLS@nottingham.ac.uk

Contact information

Dr Rosalind Simpson
Scientific, Principal investigator

Centre of Evidence-Based Dermatology
Applied Health Research Building
University Park
Nottingham
NG7 2RD
United Kingdom

Email	rosalind.simpson@nottingham.ac.uk

Dr PEARLS Study Team
Public

NCTU
University of Nottingham
University Park
Nottingham
NG7 2RD
United Kingdom

Email	PEARLS@nottingham.ac.uk

Study information

Primary study design	Interventional
Study design	Open randomized controlled parallel-group trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Proactive against reactive therapy for the prevention of lichen sclerosus exacerbation and progression of disease – a pragmatic, parallel group randomised controlled trial with embedded economic evaluation and process evaluation
Study acronym	PEARLS
Study objectives	Primary objective: Compare the clinical and cost-effectiveness of a twice-weekly topical corticosteroid maintenance strategy (proactive therapy) with as-required treatment (reactive therapy) in the management of vulval lichen sclerosus (LS) Secondary objectives: 1. Assess the effectiveness of proactive versus reactive use of topical corticosteroids (TCSs) over 24 months in reducing disease progression 2. Assess the clinical effectiveness of proactive versus reactive strategies for the management of vulval LS for up to 24 months 3. Assess the safety of using potent and superpotent TCSs in the vulval area over 24 months 4. Assess the cost-effectiveness of the two treatment strategies 5. Understand the acceptability of reactive and proactive long-term treatment strategies and the barriers and facilitators to continuing with prescribed treatment
Ethics approval(s)	Approved 27/02/2024, South West – Central Bristol Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8197, +44 (0)207 104 8269, +44 (0)207 104 8061; centralbristol.rec@hra.nhs.uk), ref: 24/SW/0016
Health condition(s) or problem(s) studied	Vulval lichen sclerosis
Intervention	In the intervention group participants will be asked to apply potent or superpotent topical corticosteroid (TCS) on two non-consecutive days per week even in the absence of symptoms (proactive treatment). In the comparator group participants will be asked to apply potent or superpotent TCS as required to treat a LS flare (reactive treatment). Eligible patients will be individually allocated in a 1:1 ratio to either proactive or reactive use of TCS. Treatment will be assigned randomly using a minimisation algorithm with a random element, balancing across groups on the recruiting site, age, time since last flare and strength of prescribed TCS. The choice of TCS will be according to the patient’s usual care. PEARLS is a pragmatic trial, and the researchers will test the strategy of proactive vs reactive treatment using the potency of topical corticosteroid recommended by the treating clinician (potent or superpotent). There are several generic names available for these prescribed TCSs and all available brands and forms can be prescribed. The examples of the most commonly prescribed brands/products of the TCS class are: 1. Dermovate ointment - superpotent TCS 2. Elocon® 0.1% w/w ointment - potent TCS The topical dosage of TCSs for both trial groups will be recommended in Fingertip Units (FTU) depending upon the area affected by LS (typically 0.5-1 FTU). FTU is the amount of topical steroid (ointment or cream) that is applied along an adult’s fingertip to the first crease in the finger. One FTU is sufficient to treat an area of skin twice the size of the flat of an adult’s hand with the fingers together (i.e. a ‘handprint’). FTU is also used to treat an area of skin on a child. The treating physician will advise on the dosage for adults or children.
Intervention type	Drug
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Topical Corticosteroid (TCS)
Primary outcome measure(s)	Number of flares over 12 months. Flare is defined as the worsening of symptoms requiring increased application of TCS, measured via text/app/email reminders every 2 weeks for 12 months.
Key secondary outcome measure(s)	Clinical effectiveness: 1. Progression of scarring, assessed by a blinded assessor at 12 and 24 months by comparing the post-randomisation assessment to baseline photographs (if patients consented), or assessed clinically if consent has not been given for photographs: 1.1. Adults: scarring worsened (yes/no). 1.2. Children and adolescents: failure of normal vulval development (clinical assessment) and/or evidence of scarring (yes/no) 2. Vulval Architectural Severity Scale (VASS) at 12 and 24 months post-randomisation, assessed clinically 3. Time to first flare, measured via text/app/email reminders at the point of first flare 4. Clinician global severity assessment of LS using a 5-point ordinal scale at 3, 6, 12, 18 and 24 months. Also assessed by a blinded assessor at 12 and 24 months. This will be measured via clinical assessment. 5. Condition-specific quality of life (QoL) measured at 3, 6, 12, 18 and 24 months using: 5.1. Vulvar Quality Life Index (VQLI) (adults) 5.2. Children’s Dermatology Life Quality Index (CDLQI) (adolescents and children) 5.3. Sexual function (adults only) assessed using the Female Sexual Function Index at 12 and 24 months Safety: 1. Adverse reactions (e.g. stinging, skin thinning) measured throughout the trial by patient-reported symptoms and clinical examination from randomisation over 24 months 2. Development of vulval intraepithelial neoplasia or vulval squamous cell carcinoma at 24 months, measured by clinical assessment and/or medical notes Treatment acceptability and potential barriers/facilitators to treatment: 1. Acceptability of treatment strategy measured using a Likert scale at 12 and 24 months 2. Adherence to treatment measured using a bespoke questionnaire completed by participants at 3, 6, 12, 18 and 24 months 3. Qualitative interview sub-study at 12 months Cost-effectiveness: 1. Generic utility instrument to measure QoL at 3, 6, 12, 18 and 24 months with EQ-5D-5L (adolescents and adults) and Child Health Utility Instrument - Nine Dimensions (CHU-9) (children) 2. Resource use including prescription, direct and indirect healthcare and out-of-pocket costs associated with vulval LS at 3, 6, 12, 18 and 24 months, measured via a bespoke questionnaire
Completion date	01/03/2028

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	5 Years
Sex	Female
Target sample size at registration	400
Key inclusion criteria	1. Clinical or biopsy confirmed diagnosis of vulval LS 2. Currently controlled disease (asymptomatic with minimal clinical evidence of active disease) at baseline 3. Age ≥5 years 4. Able to give consent/child assent plus parental consent
Key exclusion criteria	1. Previous vulval intraepithelial neoplasia (VIN) or vulval squamous cell carcinoma (SCC) 2. Contraindications to topical steroids 3. Concomitant use of other topical anti-inflammatory vulval treatments 4. Using systemic immunosuppressants (for any indication) 5. Using systemic treatment for LS 6. Patients with surgical alteration of vulval skin as part of gender reaffirming surgery, or patients not born with a vulva 7. Pregnant and breastfeeding women
Date of first enrolment	01/04/2024
Date of final enrolment	28/02/2026

Locations

Countries of recruitment

United Kingdom
England
Scotland

Study participating centres

Axess Sexual Health, Royal Liverpool University Hospital

Mount Vernon St
Liverpool
L7 8XP
United Kingdom

Liverpool Women's Hospital

Liverpool Womens Hospital
Crown Street
Liverpool
L8 7SS
United Kingdom

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

Royal Blackburn Hospital

Haslingden Road
Blackburn
BB2 3HH
United Kingdom

The James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

St Mary's Hospital

Oxford Road
Manchester
M13 9WL
United Kingdom

Market Street Health Centre, Oxleas

16-20 Market Street
Woolwich
London
SE18 6QR
United Kingdom

Whipps Cross University Hospital

Whipps Cross Road
Leytonstone
London
E11 1NR
United Kingdom

Queen Elizabeth Hospital

Sheriff Hill
Gateshead
NE9 6SX
United Kingdom

Florence Nightingale Community Hospital

London Road
Derby
DE1 2QY
United Kingdom

Royal Derby Hospital

Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Churchill Hospital

Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Leicester Royal Infirmary

Infirmary Square
Leicester
LE1 5WW
United Kingdom

Nottingham City Hospital

Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Princess Royal Hospital

Apley Castle
Grainger Drive
Apley
Telford
TF1 6TF
United Kingdom

East Surrey Hospital

Canada Avenue
Redhill
RH1 5RH
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets analysed during the current trial will be available upon request from the NCTU (ctu@nottingham.ac.uk), a minimum of 6 months after publication of the main results paper. Access to the data will be subject to review of a data sharing and use request by a committee including the CI and sponsor and will only be granted upon receipt of a data sharing and use agreement. Any data shared will be anonymised which may impact on the reproducibility of published analyses.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 2.0	05/02/2024	01/08/2024	No	No

Additional files

44852_PROTOCOL_V2.0_05Feb24.pdf: Protocol file

Editorial Notes

27/03/2025: The recruitment end date was changed from 01/09/2025 to 28/02/2026.
01/08/2024: Protocol uploaded. The recruitment start date was changed from 01/03/2024 to 01/04/2024.
05/04/2024: Internal review.
11/03/2024: The public title was changed from 'Treatment therapies with topical corticosteroids for the prevention of progression of lichen sclerosus in patients aged 5 years and older' to 'Proactive against reactive treatment for lichen sclerosus'. Ethics approval added.
08/03/2024: ISRCTN received notification of combined HRA/MHRA approval for this trial on 08/03/2024.
09/01/2024: Study's existence confirmed by the HRA.