A double blind, prospective, randomized, placebo controlled, multi-center phase 3 study to evaluate efficacy and safety of Cevira® in patients with cervical histologic high-grade squamous intraepithelial lesions (HSIL)

Cervical high-grade squamous intraepithelial lesion (HSIL) is a cervical
epithelial disease also referred to as cervical intraepithelial neoplasia
(CIN). HSIL is caused by persistent oncogenic human papilloma virus (HPV)
infection. HPV infection is common among sexually active women, with a lifetime
risk of about 75%. Most HPV infections are in a latent form and are
spontaneously cleared in about 90% of affected individuals within three years.
In individuals who fail to clear, persistent oncogenic HPV infection may lead
to HSIL and invasive cancer of the cervix.
According to the latest version (2019) of the ACS guideline for cervical cancer
screening, the priority treatments include excision (preferred) and ablation.
Women at the age of 25 through 65 years (preferred) should attend the cervical
cancer screening program and should be subjected to primary HPV testing every 5
years; when it is not available cervical cytology testing needs to be done
every 3 years or co-testing (HPV testing in combination with cytology) every 5
years. Histology HSIL is suspected from abnormal cytology and/or persistent
oncogenic HPV, and the diagnosis is confirmed from a colposcopically guided
biopsy specimen.
HSIL is generally managed by removing or destroying the abnormal cervical
tissue, using excision (laser, loop electrosurgical excisional procedure
(LEEP), cold knife conization) or ablation (cryotherapy, laser vaporization)
treatment modalities. Both office ablative and excisional treatments provide
for 80% (single treatment) and 95% (multiple treatments) complete response,
however, recurrence rates occur in up to 15% of the cases treated. Current
treatment methods may carry risk of vaginal cramping, discharge, bleeding, and
infections. LEEP is also associated with increased risk of preterm delivery.
Due to the untoward side effects, particularly the risk for future pregnancies,
it is important to avoid overtreatment in young women of reproductive age.
Cevira® is targeting treatment of patients with HSIL histology and adequate
colposcopy. The treatment is ablative, selectively removing cervical
intraepithelial lesions and potentially inducing regression of oncogenic HPV.
The treatment preserves the underlying stroma and thereby the competence of the
cervix, avoiding the side effects associated with surgical procedures.
Cevira® for vaginal use is prepared as an ointment formulation. The drug is
administered vaginally to the cervix by the gynecologist using a drug delivery
device which includes an integrated light source used in photoactivation of the
photosensitizer, the Cevira CL7 device. The intended dosing regimen is one
treatment, and one re-treatment after three months if clinically indicated. The
dose and regimen are based on the results of the phase 2b study, which
concluded that Cevira® (HAL HCl 5%) was the most effective dose.
Photodynamic therapy (PDT) is based on the accumulation of a photosensitizer or
its precursor in the target cells, which upon illumination generate reactive
oxygen species that eradicate the diseased cells by apoptosis and necrosis. HAL
is the hexyl ester of aminolevulinic acid, an endogenous substance converted to
intermediate photoactive porphyrins in the heme biosynthesis. Exogenous HAL is
taken up by the cervical epithelial cells, entering into the heme biosynthesis
pathway resulting in a selective accumulation of photoactive porphyrins in HSIL
cells. Therefore, upon photoactivation with red light (~635 nm), HSIL lesions
are selectively targeted preserving underlying normal stroma. The reason for
the selective accumulation of photoactive porphyrins (PAP) in HSIL is not fully
understood but includes changes in metabolic activity of diseased compared to
normal cells.
The potential benefits of the Cevira® treatment over existing modalities are
significant. Cevira® is an integrated drug- device treatment which is easily
applied in the office setting. It is a local, non-invasive procedure which
preserves cervical function. The treatment has few local side effects, and the
patient is free to resume normal daily activities immediately after
application. The treatment can easily be repeated, and it may be a
tissue-sparing alternative to observation and surgery in patients with CIN.

The purpose of the study is to evaluate the efficacy and safety of Cevira®
compared to placebo in treatment of patients with cervical histologic HSIL.

The study is designed as a double blind, prospective, randomized, placebo
controlled, multi-center study in patients with an adequate colposcopy and
histology diagnosis of HSIL. Patients will be randomized to Cevira® or placebo
(2:1). Inclusion will be based on histology diagnosis determined by a panel of
pathology experts from central laboratories in each region (China, US, and
Europe). The randomization will be stratified by CIN diagnosis (CIN2 or CIN3)
and HPV status (HPV-, HPV16+ or HPV18+Oth+).

The Cevira® treatment is an integrated combination of drug and device; Cevira®
5% HAL HCl ointment and Cevira® CL7 device. The device is a single-use,
disposable, LED-based red-light source. The device will automatically switch on
the light 5 hours after administration and provide continuous photoactivation
of 125 J/cm2 over 4.6 hours before automatically shutting down.

The placebo ointment contains only vehicle and is similar in appearance and
consistence as the Cevira® ointment. The placebo device is identical in
appearance as the Cevira® device but does not provide light.

The device and ointment are administered by a gynecologist at the clinic. The
patient removes the device herself after at least 11 hours, but no more than 24
hours after administration.

Patients will receive one or two treatments; a second treatment will be
administered in patients who at 3 months have a cytology of LSIL or more severe
(HSIL). The re-treatment visit (Visit 5) should be within 1 month of the
three-month assessment visit (Visit 4). All patients will have an assessment
visit at 6 months for primary and secondary efficacy/performance and safety
evaluation (Visit 7). All patients (placebo and active treatment group) will
participate for 6 months in the study for the primary and secondary
efficacy/performance and safety assessment. Additionally, the device-related
AEs (ISO 14155 and MPSV) and device deficiencies will be evaluated to access
the impact on the risk-benefit profile of the medical device. To minimize the
risk to patients in the placebo group, these patients will be unblinded at the
6 months visit to complete the study. Afterwards, these patients will be
followed according to the local standard of care.

All patients in the active treatment group will be followed for an additional 6
months in an open-label extension of the study. Additional efficacy and safety
data will be collected at 12 months (Visit E1) to assess the study extension
endpoints.

Safety (adverse events) will be assessed at treatment visit(s), and at the 3-,
6- and 12-month.

The device and ointment are administered by a gynecologist at the clinic. The
patient removes the device herself after at least 11 hours, but no more than 24
hours after administration.
Patients will receive one or two treatments; a second treatment will be
administered in patients who at 3 months have a cytology of LSIL or more severe
(HSIL).
The Cevira® treatment is an integrated combination of drug and device; Cevira®
5% HAL HCl ointment and Cevira® CL7 device. The device is a single-use,
disposable, LED-based red-light source. The device will automatically switch on
the light 5 hours after administration and provide continuous photoactivation
of 125 J/cm2 over 4.6 hours before automatically shutting down.
The placebo ointment contains only vehicle and is similar in appearance and
consistence as the Cevira® ointment. The placebo device is identical in
appearance as the Cevira® device but does not provide light.

Number of doctor/investigator visits: 6 on site visits and 2 follow up phone
calls. On site visits include colposcopy (4), biopsy (3), HPV testing (3),
Cytology (3), Urine pregnancy test (5)
Number and type questionnaires and/or diaries: patient diary includes
information about the device, possible side effects. The patient has to
complete the information about the removal time of the device, and light signal
on the device after removal. Additionally, the patient is asked to describe any
problem and discomfort experienced during of after the treatment.
Possible harmful side effects of the treatment: none
Foreseeable AEs/ physical or psychological discomfort: abdominal and cervical
discomfort/pain, vaginal discharge and bleeding during and after the treatment
procedure. These AEs typically resolve within a few days after the treatment.
No unacceptable AEs are anticipated.
Benefit: Cevira® is a local, non-invasive procedure which preserves cervical
function. The treatment has few local side effects, and the patient is free to
resume normal daily activities immediately after application. The treatment can
easily be repeated, and it may be a tissue-sparing alternative to observation
and surgery in patients with CIN.