Cervical Intraepithelial Neoplasia
Conditions
Keywords
CIN
Brief summary
An effective and safe medical therapy would be most welcome to reduce the need for surgical interventions and related adverse events and psychological impact on patients with cervical cancer precursors. In this clinical trial, the investigators propose to evaluate the efficacy and safety of photodynamic therapy (PDT) using hexaminolevulinate (HAL) for mild to moderate-grade CIN (grade 1-2).
Interventions
Treatment with a singe dose of 2g, HAL 5% ointment followed by photoactivation
DRUGHAL 1% with illumination
Treatment with a singe dose of 2g, HAL 1% ointment followed by photoactivation
DRUGHAL 0.2% with illumination
Treatment with a singe dose of 2g, HAL 0.2% ointment followed by photoactivation
DRUGPlacebo ointment without illumination
Treatment with a singe dose of 2g placebo ointment, no photoactivation
Sponsors
Photocure
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with ectocervical CIN1 or CIN2 as verified by local pathology (biopsy) obtained within the last month * Satisfactory colposcopy examination including: * visibility of entire transformation zone including the squamocolumnar junction and * visibility of entire lesion margin * Negative endocervical os by colposcopy * Colposcopical visible lesion at visit 2, before treatment * Patients with an average sized uterine cervix (approximately 27mm diameter) suitable for application of the Klemcap * Age 18 or above * Written informed consent signed
Exclusion criteria
* Previous treatment of CIN or invasive disease * Lesion(s) extending to the vaginal vault * Atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) on cytology, malignant cells on cytology or histology or other suspicion of either micro-invasive or invasive disease * Suspicion of endocervical disease on colposcopy * Current severe pelvic inflammatory disease, severe cervicitis, or other severe gynaecological infection as per colposcopy and clinical examination * Undiagnosed vaginal bleeding * History of toxic shock syndrome * Known or suspected porphyria * Known allergy to hexaminolevulinate or similar compounds (e.g. methyl aminolevulinate or aminolevulinic acid) * Pregnancy, or intention to become pregnant during the study period * Nursing * Childbirth or miscarriage within six weeks of enrolment * Use of heart pacemaker * Participation in other clinical studies either concurrently or within the last 30 days * Risk of poor protocol compliance. Patient participation should be considered with respect to living far away from the hospital, plans for moving to another city/state, frequent travelling, planning to become pregnant, drug abuse/alcoholic, difficult working hours, family obligations, other illness (e.g. psychiatric), etc. * Unwillingness to use adequate birth control (not abstinence) from screening until last PDT * Patient is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 3 months after last treatment | Lesion response was defined by three variables: Histology, cytology and HPV. Patient response at three months required histology regression to CIN1 or normal, cytology of LSIL or less severe, and HPV negative. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 3 months after treatment | HPV response was defined as clearance of baseline HPV infection, asssessed by genotype |
Countries
Germany, Norway
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HAL 5% With Illumination Cervical PDT using Hexaminolevulinate: Treatment with a singe dose of 2g HAL 5% ointment followed by photoactivation | 65 |
| HAL 1% With Illumination Cervical PDT using Hexaminolevulinate: Treatment with a singe dose of 2g HAL 1% ointment followed by photoactivation | 67 |
| HAL 0.2% With Illumination Cervical PDT using Hexaminolevulinate: Treatment with a singe dose of 2g HAL 0.2% ointment followed by photoactivation | 62 |
| Placebo Ointment Without Illumination Cervical PDT using Hexaminolevulinate: Treatment with a singe dose of 2g placebo ointment, no photoactivation | 68 |
| Total | 262 |
Baseline characteristics
| Characteristic | HAL 1% With Illumination | HAL 0.2% With Illumination | HAL 5% With Illumination | Placebo Ointment Without Illumination | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 67 Participants | 62 Participants | 65 Participants | 68 Participants | 262 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 65 Participants | 61 Participants | 64 Participants | 68 Participants | 258 Participants |
| Sex: Female, Male Female | 67 Participants | 62 Participants | 65 Participants | 68 Participants | 262 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 65 | 29 / 67 | 23 / 62 | 33 / 68 |
| serious Total, serious adverse events | 2 / 65 | 1 / 67 | 0 / 62 | 0 / 68 |
Outcome results
Primary
Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment.
Lesion response was defined by three variables: Histology, cytology and HPV. Patient response at three months required histology regression to CIN1 or normal, cytology of LSIL or less severe, and HPV negative.
Time frame: 3 months after last treatment
Population: Patients with CIN2 at baseline, based on central histology review
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HAL 5% With Illumination | Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 95 percentage of patients |
| HAL 1% With Illumination | Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 69 percentage of patients |
| HAL 0.2% With Illumination | Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 63 percentage of patients |
| Placebo Ointment Without Illumination | Comparison of Lesion Response Rates of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 57 percentage of patients |
Secondary
Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment.
HPV response was defined as clearance of baseline HPV infection, asssessed by genotype
Time frame: 3 months after treatment
Population: Patients with CIN2 at baseline, based on central histology read, and HPV positive at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HAL 5% With Illumination | Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 62 percentage of patients |
| HAL 1% With Illumination | Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 38 percentage of patients |
| HAL 0.2% With Illumination | Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 41 percentage of patients |
| Placebo Ointment Without Illumination | Comparison of HPV Response of Three Different Doses of HAL PDT and Placebo at 3 Months After Treatment. | 28 percentage of patients |
Post Hoc
Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 6 Months After First Treatment.
Response was defined as absence of HSIL, and absence of oncogenic HPV if LSIL.
Time frame: 6 months after first treatment
Population: Patients diagnosed with HSIL histology by a panel of pathologists were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HAL 5% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 6 Months After First Treatment. | 76 percentage of participants |
| HAL 1% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 6 Months After First Treatment. | 45 percentage of participants |
| HAL 0.2% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 6 Months After First Treatment. | 43 percentage of participants |
| Placebo Ointment Without Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 6 Months After First Treatment. | 28 percentage of participants |
Post Hoc
Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 9 Months After First Treatment
Response was defined as absence of HSIL, and absence of oncogenic HPF if LSIL
Time frame: 9 months after first treatment
Population: Patients diagnosed with HSIL histology by a panel of pathologists were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HAL 5% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 9 Months After First Treatment | 76 percentage of participants |
| HAL 1% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 9 Months After First Treatment | 50 percentage of participants |
| HAL 0.2% With Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 9 Months After First Treatment | 43 percentage of participants |
| Placebo Ointment Without Illumination | Comparison of Response Rates of Three Different Doses of HAL PDT and Placebo at 9 Months After First Treatment | 33 percentage of participants |