Primary Objectives- To evaluate disease related characteristics in patients with different vulvar conditions compared to healthy volunteers - To evaluate the variability of the selected biomarkers between subjects, and within subjects over time.…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Punch biopsies: histology (e.g. H&E and HPV typing), IHC (e.g. p16 and p53),
mRNA extraction
* Vulvar pH*
* Hormonal status (FSH, LS, estrogen)
* DermaToolbox:
- 2D photography* (photo documentation)
- 3D photography* (lesion dimensions)\ - Dermoscopy* (erythema + roughness
scores)
- Optical Coherence Tomography* (skin morphology, skin layer thickness, blood
perfusion)
- Confocal Microscopy* (skin morphology)
- Ultrasonography* (skin morphology, skin layer thickness, tumour penetration
up to 4cm)
- Trans Epidermal Water Loss* (skin barrier function)
* Clinical scores (e.g. Günthert, RECIST, PROVOKE)
* Patient reported outcomes* (this may include, but is not limited to: NRS
pruritus, NRS burning sensation, NRS pain, sleeplessness QoL, patient
satisfaction scores of imaging tools)
Secondary outcome
* Vulvar, vaginal and anal swabs* for microbiome
Background summary
A wide spectrum of benign and (pre)malignant lesions may occur in the
anogenital region. For example, lichen sclerosis (LS) is a chronic inflammatory
dermatitis with a predilection for the anogenital area. This disease can cause
severe atrophy in this area and lead to deformities of the vulvar structures.
It is mainly a pruriginous condition but can also be asymptomatic. The median
age at time of LS diagnosis is around 65 years and the prevalence is increasing
with age up to 1:30 women. Most important, LS is associated with an enormous
morbidity and an increased risk of vulvar premalignancy (dVIN) and subsequent
cancer (4-6%).
The cornerstone of treatment for vulvar (pre)cancers is surgery. Surgical
treatment in the vulvar area is frequently associated with significant
morbidity due to damage to vital structures like urethra, vagina, clitoris and
anus. Correct distinction between healthy and (pre)malignant tissue is one of
the major challenges for the clinician. Incorrect identification of
(pre)cancerous lesions results in re-excisions, recurrences, metastases and
worse prognosis. This underlines the high unmet medical need for clinicians to
better discriminate vulvar (pre)cancers.
In addition, most clinical trials within the vulvar cancer field make use of
clinical outcomes, as physician-evaluated scores, in the assessment of drug
efficacy. These outcomes can give a crude estimation of the disease *severity*
and potential improvement during the clinical trials. However, these clinical
endpoints have disadvantages as limited objectivity due to a possible response
quantification bias by the scoring physician, potential inter-rater variability
and lack of sensitivity needed to quantify smaller effects of a novel drug.
Unfortunately, there is little research on the mechanisms underlying the
development of and the response to treatment in vulvar (pre)cancers. Therefore,
more objective endpoints are needed to support unbiased objective evaluation of
drug efficacy in this field.
In this study a multi-modal and in-depth approach will be used, which consist
of different measurement methods and imaging techniques to acquire
non-physician based disease-related outcomes of vulvar (pre)malignancies. For
example, invasive punch biopsy will be compared to different non-invasive
techniques such as 2D/3D photography, dermoscopy, optical coherence thomography
(OCT), ultrasonography and trans-epidermal waterloss (TEWL) (Figure 1). By
integrating data from different domains such as biophysical, imaging,
molecular, cellular and microbial, a so-called *systems dermatology* approach
is used. The biomarkers created by these different technologies will describe
the pathophysiology in high detail and support a holistic view on vulvar
disease and potential drug mechanisms.
Therefore, a two-part study is proposed. Part 1: a non-interventional clinical
study to characterize different vulvar conditions, including lichen sclerosus
and (pre)cancerous lesions (HSIL), in comparison to healthy controls. Part 2:
an interventional clinical study in vulvar lichen sclerosus (LS) patients
treated with topical clobetasol, to observe whether different sampling methods
and non-invasive imaging techniques can discriminate the responsiveness to
change in disease activity. The results/endpoints from this study can be used
in the future for research into new treatments for these different vulvar
conditions. The results will be analysed and integrated with a novel machine
learning approach.
Study objective
Primary Objectives
- To evaluate disease related characteristics in patients with different vulvar
conditions compared to healthy volunteers
- To evaluate the variability of the selected biomarkers between subjects, and
within subjects over time.
Secondary Objectives
- To evaluate the feasibility, suitability and potential use of the skin
microbiome as biomarker for early phase clinical drug development in patients
with different vulvar conditions and to compare with healthy individuals.
Exploratory Objectives
- To design a machine learning model for diagnosis of vulvar (pre)malignant
disease by combining individual biomarker assessments.
Study design
This is an prospective two-part (observational and intervention), open label,
non-comparative and exploratory phase I study to evaluate the applicability and
integration of novel biomarkers in patients with vulvar (pre)malignancies.
Part A. This is an observational study in up to 40 patients with different
benign and (pre) malignant vulvar conditions (vulvar HSIL (n=10), vulvar LS
(n=10), VSCC (n=10) and 10 healthy volunteers. All participants will visit CHDR
for a screening and 5 short visits (day 1 (baseline), 2 and 8 (end of study)).
Part B. This is an interventional and open label study with a topical steroid
in vulvar LS patients (the LS patients from part A roll over to part B). 10
Patients with vulvar LS will treat their lesion(s) from day 8 until day 36.
Hereafter, a follow-up visit will take place at Day 22 and a final follow-up
visit will take place at day 36.
Intervention
Clobetasol propionate ointment
Study burden and risks
The overall aim of this study is to evaluate objectively measured disease
related characteristics in patients with different vulvar conditions compared
to healthy volunteers.
Benefit
No medical benefit can be expected during the observational part of this study
for the participating subjects.
Risks
- Although it is a minimal invasive procedure, participants can experience pain
and/or a haematoma in rare cases during and after biopsy of the vulvar area
and/or venepuncture.
- Patients could experience a (temporary) flare-up of their disease related
symptoms due to interruption or postponement of their standard treatment.
- LS patients will apply clobetasol for two weeks. Clobetasol is an
EMA-approved ointment for treatment of LS. For LS patients treated with
clobetasol no long-term benefits are expected if only treated for 2 weeks. On
short term, a reduction in itch and pain could be observed. Possible although
rare local adverse effects are local burning sensation and itching during
application. For a structured risk assessment see the SmPC of Clobetasol
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Non-pregnant female subjects, 25-95 years of age (inclusive); in general,
stable good health as per judgment of the investigator based upon the results
of a medical history, physical examination (BMI * 30) and vital signs.
2. BMI of * 30
3. If female of childbearing potential, have a negative urine pregnancy test at
Day 0.
4. Willing to give written informed consent and willing and able to comply with
the study protocol.
5. Ability to communicate well with the investigator in the Dutch or English
language.
6. Subject is willing to undergo vulvar biopsies.
7. Subject is willing to refrain from washing (including bathing, swimming,
showering and excessive sweating) the vulva counting from midnight of every
study visit day.
8. Subject is willing to refrain from application of products (e.g. ointments,
crème or wash) on the vulva 24 hours prior to every study visit day.
9. Subject is willing to refrain from sexual intercourse less than 24 hours
prior to every study visit.
10. Subject is willing to refrain from shaving, waxing or other hair removing
treatments in the perineal area in the 24 hours prior to every study visit.
11. Willing to refrain from any active treatment for vulvar HSIL and LS as from
14 days prior to Day 0.
Eligible HSIL patients must meet all of the following inclusion criteria at
screening:
12. At least one sharply marginated lesion (plaque) that can be accurately
measured (using RECIST criteria), in at least one dimension with a smallest
diameter of *15 mm, with confirmed HSIL diagnosis by histologic confirmation.
This histologic diagnosis does not necessarily have to be performed close to
inclusion.
Eligible LS patients must meet all of the following inclusion criteria at
screening:
13. Clinically and/or histologically diagnosed with LS and under topical
treatment with topical corticosteroids or willing to start topical steroid
treatment during study participation.
Eligible VSCC patients must meet all of the following inclusion criteria at
screening:
14. Histologically confirmed primary or local recurrent VSCC.
Exclusion criteria
1. Significant, uncontrolled or unstable disease in any organ system as per
judgment of the investigator (regardless of association with the
immunosuppressing disorder/therapy), including but not limited to: psychiatric,
neurologic, cardiovascular, pulmonary, gastrointestinal, hepatic, renal,
endocrine, hematologic or respiratory disease.
2. History of immunological abnormality (e.g., immune suppression) that may
interfere with study objectives, in the opinion of the investigator.
3. Known infection requiring (topical or oral) antibiotic therapy within 28
days prior to Day 0;
4. The use of any oral/systemic medication (e.g. immunomodulatory,
immunosuppressive, acetylsalicylic acid) within 28 days prior to Day 0, if the
investigator judges that it may interfere with the study objectives. The use of
paracetamol (up to 4 g/day) is allowed;
5. Pregnant, a positive pregnancy test, intending to become pregnant, or
breastfeeding;
6. Self-reported: (a) immunocompromised state, (b) sexually transmitted
disease, (c) AIDS and/or (d) hepatitis.
7. Have any current and / or recurrent clinically significant or subject
reported skin condition in the vulvar area other than the (absence of) vulvar
disease wherefore subject is included in the study.
Eligible vulvar patients must meet none of the following exclusion criteria at
screening:
8. Have any current relevant (inflammatory) skin infections in the treatment
area other than the observational disease (vulvar LS, vulvar HSIL of VSCC),
inclusively, but not limited to atopic dermatitis, herpes, candidiasis or
psoriasis.
9. Have used or received any topical vulvar HSIL treatment, laser therapy or
surgery in the anogenital area within 28 days prior to Day 0
10. Have used or received any topical corticosteroids or other topical immune
suppressive treatment for LS within 14 days prior to Day 0
11. Have used or received chemo-or radiotherapy or surgery in the anogenital
area within 3 months prior to enrolment.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002201-25-NL |
| CCMO | NL73964.058.20 |