Methods
The study was designed as a Phase II, single-centre, double-blind,
randomised control trial. Inclusion criteria were all women were ≥ 18
years of age who presented with histologically proven uVIN on biopsy,
either as primary or recurrence disease. All uVIN lesions must be
measurable with at least one lesion that can be accurately measured in
one dimension with longest diameter ≥ 10mm. Patients with recurrence
disease were treatment free for at least 12 weeks and must be able to
provide a written consent to participate in the study. Exclusion
criteria were patients suspected or histological proven invasive
disease; pregnant, breast feeding or were trying to conceive; know
allergies to any of Veregen® or placebo components; underlying
immunosuppressive disease; unable to comply with protocol; severe liver
dysfunction or chronic liver disease; unable to provide written consent.
This study is approved by the East Midlands - Derby Research Ethics
Committee with study number 13/EM/0398. All patients provided a written
consent to participate in the study.
Patients who fulfilled the recruitment criteria were randomised 1:1 into
receiving Veregen® (experimental) or a placebo ointment. Veregen®
ointment, 10% EGCG concentration, and placebo were manufactured and
supplied by MediGene AG, Germany. Patients were to apply ointment thrice
daily for 16 weeks, and the frequency of application was recorded in a
diary. Follow up were scheduled at two weeks (telephone call), 4, 8, 16,
32 and 52 weeks after starting treatment. Baseline biopsy for
histological diagnosis was obtained prior to treatment and at 16 and 32
weeks after treatment. Recruitment to the trial was scheduled for 24
months. The study protocol is included in the supplementary information.
The primary objective was to evaluate whether application of Veregen®
could induce histological resolution of uVIN when assessed at 32 weeks
following the start of treatment. Histological resolution is defined as
the absence of uVIN lesion or invasive cancer. The secondary objectives
were to assess: clinical resolution (as measured by ≥30% reduction in
the sum of the longest diameter of all lesions when compared to
baseline), treatment compliance, safety and tolerability, and quality of
life using McGill pain questionnaire8 and Dermatology
Life Quality Index (DLQI)9 questionnaire. The primary
endpoint; best histological response observed across the 32 weeks as
established by blinded pathology review; was to be analysed as per
Jung’s design, an analogue of Simon’s design, for randomised phase II
trials. The trial was designed to have type I and type II error rates
less than or equal to 0.15. Assuming that the VIN resolution rate in the
control arm would be 10%, and that an improvement to 30% would be
clinically important, a required total of 28 patients were to be
randomised to each arm. At least 3 more cases of histological resolution
at 32 weeks on the experimental arm compared to the control arm of the
trial were required in order to conclude sufficient activity.
Clinical resolution was measured according to a protocol defined
evaluation criteria based on RECIST, the number of patients with
clinical resolution will be reported by treatment arm and proportions
will be compared using 2-sample test for equality of proportions with
continuity correction. Time to clinical resolution was measured as the
time from randomisation to clinical resolution, patients not having
resolution were censored at the date last seen, and this will be
presented in a Kaplan-Meier plot. Treatment compliance were summarised
at patient level taking into account both dose reductions and
interruptions. Adverse event data was collected as per Common
Terminology Criteria for Adverse Events (CTCAE v4.0), summary tables
were presented for this data. Quality of life questionnaire scores were
presented using informative plots over time.