Cervical High Grade Squamous Intraepithelial Lesion
Conditions
Keywords
HSIL, CIN, HPV, HPV vaccination, gardasil, HIV, cervical dysplasia, LEEP, cervical cancer
Brief summary
Cervical cancer occurs commonly in HIV-infected women in South Africa. These women have poor response to treatment of cervical cancer precursors. This study will test whether giving the quadrivalent vaccine to women prior to surgical treatment of the cervical cancer precursor will improve outcomes. We hypothesize that pre-treatment HPV vaccine will result in a reduced occurrence or cervical cancer precursors in follow-up.
Detailed description
This is a single-center, randomized, double-blinded, placebo-controlled, phase II trial of the quadrivalent human papillomavirus vaccine (qHPV) in HIV-infected women to prevent occurrence of cervical HSIL after LEEP/LLETZ. Participants will undergo colposcopy with directed biopsies, cervical cytology, and stored HPV testing prior to vaccination. Participants will be randomized to the quadrivalent vaccine or saline placebo to be given at entry, week 4, and week 26. Women will have LEEP treatment at week 4. Participants will be seen in follow-up for cervical cytology, colposcopy with directed biopsies at weeks 26 and 52, and stored HPV specimens. Treatment assignment will be unblinded after study follow-up is completed for the last study participant. Women aged 45 or less randomized to placebo will be offered open label HPV vaccine after the study is concluded..
Interventions
BIOLOGICALHuman Papillomavirus vaccine
The participants receive the qHPV vaccine at entry, week 4 and week 26
Sponsors
Merck Sharp & Dohme LLC
University of Witwatersrand, South Africa
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
1. HIV infection 2. Women aged ≥ 18 years. 3. Cervical HSIL on biopsy (i.e. CIN2 and/or CIN3) 4. For participants of reproductive potential, negative serum or urine pregnancy test 5. All study participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or in vitro fertilization) during study participation (from the time of study entry until week 52).
Exclusion criteria
1. History or current biopsy diagnosis of invasive or microinvasive cervical, vaginal, vulvar, anal or oropharyngeal cancer 2. Prior hysterectomy 3. Cervical cryotherapy or LEEP/LEETZ within one year of entry. 4. Cervical, vulvar, or vaginal lesions suspicious for cancer, unless biopsies show no invasive cancer 5. Prior receipt of one or more doses of an HPV vaccine. 6. Receipt of anticoagulants other than aspirin or nonsteroidal anti-inflammatory drugs (NSAIDS) within 14 days prior to entry. 7. Known allergy/sensitivity or any hypersensitivity to yeast or any of the components of the study product or its formulation (see section 5.2 for a list of components). 8. Hemophilia or other bleeding diatheses. 9. Use of any systemic antineoplastic or immunomodulatory treatment, systemic corticosteroids, other than inhaled corticosteroids or prednisone ≤ 10 mg (or equivalent) , investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry. 10. Breastfeeding 11. Less than 3 months post-partum
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cervical HSIL | up to 52 weeks | For this trial, the primary endpoint is high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells suggestive of HSIL found on cervical cytology, or HSIL found on cervical biopsy specimens at either the week 26 or week 52 visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cervical Cytology | Week 26 | Cervical cytology abnormalities according to the Bethesda scale. The Bethesda scale classifies cytologic abnormalities. We have dichotomized the outcomes into high grade squamous intraepithelial lesions (HSIL)/atypical squamous cells suggestive of HSIL, or no evidence of intraepithelial lesions or malignancy (NILM)/atypical squamous cells of unknown significance (ASC-US)/low grade squamous intraepithelial lesions (LSIL). We report the number of women in each category. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Human Papillomavirus Vaccine Participants receive the quadrivalent Human Papillomavirus vaccine at entry, week 4 and week 26. | 90 |
| Saline Placebo The participants receive saline placebo at entry, week 4 and week 26. | 90 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | basaloid cervical cancer | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Human Papillomavirus Vaccine | Saline Placebo | Total |
|---|---|---|---|
| Age, Continuous | 40.1 years | 39.1 years | 39.2 years |
| CD4 | 511 cells/mm^3 | 483 cells/mm^3 | 489 cells/mm^3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 90 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HSIL/ASC-H cervical cytology | 86 Participants | 83 Participants | 169 Participants |
| Nadir CD4 | 125 cells/mm3 | 108 cells/mm3 | 116 cells/mm3 |
| Plasma HIV-1 RNA <200 copies/mL | 77 Participants | 76 Participants | 153 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 90 Participants | 86 Participants | 176 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment South Africa | 90 participants | 90 participants | 180 participants |
| Sex: Female, Male Female | 90 Participants | 90 Participants | 180 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 90 | 0 / 90 |
| other Total, other adverse events | 0 / 90 | 0 / 90 |
| serious Total, serious adverse events | 2 / 90 | 0 / 90 |
Outcome results
Primary
Cervical HSIL
For this trial, the primary endpoint is high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells suggestive of HSIL found on cervical cytology, or HSIL found on cervical biopsy specimens at either the week 26 or week 52 visit.
Time frame: up to 52 weeks
Population: Six participants did not have cytologic or histologic samples available for the primary endpoint
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Human Papillomavirus Vaccine | Cervical HSIL | 46 Participants |
| Saline Placebo | Cervical HSIL | 39 Participants |
p-value: 0.2995% CI: [0.87, 1.6]Chi-squared
Secondary
Cervical Cytology
Cervical cytology abnormalities according to the Bethesda scale. The Bethesda scale classifies cytologic abnormalities. We have dichotomized the outcomes into high grade squamous intraepithelial lesions (HSIL)/atypical squamous cells suggestive of HSIL, or no evidence of intraepithelial lesions or malignancy (NILM)/atypical squamous cells of unknown significance (ASC-US)/low grade squamous intraepithelial lesions (LSIL). We report the number of women in each category.
Time frame: Week 26
Population: Comparison of cytologic outcomes between arms at week 26. Nine participants are missing due to a missed visit, loss to follow-up, or unsatisfactory cytology result.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Papillomavirus Vaccine | Cervical Cytology | HSIL or ASC-H | 34 Participants |
| Human Papillomavirus Vaccine | Cervical Cytology | NILM/ASCUS/LSIL | 52 Participants |
| Saline Placebo | Cervical Cytology | HSIL or ASC-H | 26 Participants |
| Saline Placebo | Cervical Cytology | NILM/ASCUS/LSIL | 59 Participants |
p-value: 0.2295% CI: [0.85, 1.95]Chi-squared