Cervical Intraepithelial NeoplasiaPhase 2NCT02864147

Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3)

A Phase 2 study testing 9-valent HPV vaccine and Imiquimod in people with Cervical Intraepithelial Neoplasia and Cervical Dysplasia, run by Yale University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This is a randomized Phase II, three arm control trial in patients with Cervical Intraepithelial Neoplasia (CIN) 2/3 high grade cervical dysplasia. Patients with CIN 2/3 meeting eligibility criteria will have cervical biopsy specimens centrally reviewed by study pathologist to confirm diagnosis. Read more about this study

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Cervical Intraepithelial Neoplasia, Cervical Dysplasia
What is being tested?: 9-valent HPV vaccine and Imiquimod
Type of treatment: Vaccines
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 134 participants
Where: 1 siteUnited States
Study dates: Jul 2016to 22 Nov 2022
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

Patients must have untreated cervical biopsy-proven, CIN 2/3 ectocervical lesion(s).
Patients must have satisfactory colposcopy with visualization of the entire transformation zone or a negative endocervical curettage if colposcopy is unsatisfactory.
Patients must be high-risk HPV+ as determined by commercially available DNA hybridization test which tests for 13 high-risk HPV types.
All Patients must have a histologic diagnosis of CIN 2,3 cervical lesion(s) confirmed by a study pathologist within past 10 weeks.
Patients must have signed an approved informed consent.
Patients of childbearing potential must have a negative urine pregnancy test within 7 days prior to the study entry and be practicing an effective form of contraception.
Patients must be at least 18 years of age based on previous and current cervical cancer screening guidelines.
Patients must be fluent in speaking English or Spanish.

Who cannot join

Patients with unsatisfactory colposcopy* (unable to visualize entire transformation zone) or evidence of endocervical disease defined as CIN 2/3 diagnosed on endocervical curettage.
Patients with unsatisfactory colposcopy but negative endocervical curettage are eligible
Patients with a history of invasive cervical cancer
Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancers are excluded if there is any evidence of other malignancy being present within the last five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.
Patients with any unstable medical issue (including cardiac issues as above, active treatment for pulmonary embolism, CVA, renal or hepatic insufficiency, active infection/sepsis requiring IV antibiotics).
Patients who have an uncontrolled seizure disorder, or active neurological disease.

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Patients known to be seropositive for HIV and active hepatitis, even if liver function studies are in the normal range. Patients otherwise immunocompromised will also be excluded (chronic steroid use, taking immunosuppressive medications).
Pregnant or breastfeeding patients.
Patients who have had a total hysterectomy (removal of uterus and cervix) or trachelectomy (removal of cervix).
Patients with a known hypersensitivity to imiquimod. Patients with a known hypersensitivity to any prophylactic HPV vaccine or severe allergic reactions yeast (vaccine component).
Patients who have received their first dose of HPV vaccine < 4 weeks ago or their second dose < 12 weeks ago.
Known hypersensitivity or prior intravaginal treatment with Imiquimod

Trial locations and contacts

1 site in 1 country.

United States1 site

Smilow Cancer Hospital at Yale New Haven
New Haven, Connecticut, 06510

Other trials in United States

About this study

Official title: Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3) Using a Novel "Prime and Pull" Strategy

Patients who have CIN 2/3 with HPV+ disease will be enrolled in this study. Patients will be randomized to one of three arms: observation only (control), imiquimod only, imiquimod + 9-valent HPV vaccine.

Read the detailed description

The primary objectives of this study are as follows:

To determine treatment efficacy defined as histologic regression to CIN 1 or less at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the HPV Vaccine + Imiquimod group compared to control,
To determine treatment efficacy defined as histologic regression to CIN 1 or less at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the Imiquimod group compared to control.

The secondary objectives of this study are as follows:

To assess complete regression (i.e., histologic remission) at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in each group,
To assess HPV clearance in each group,
To assess treatment tolerability.

In addition to the primary and secondary objectives of this study, there additional exploratory/correlative objectives. The exploratory/correlative objectives are as follows:

To assess T cell infiltration in post-treatment cervical biopsies and endocervical cytobrush samples,
To assess HPV16 E7 immunity in CD4/CD8 T cells.

Conditions: Cervical Intraepithelial Neoplasia, Cervical Dysplasia
Being tested: 9-valent HPV vaccine, Imiquimod
Medical subject headings: Uterine Cervical Dysplasia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

9-valent HPV vaccineDrug
All women (regardless of age) will be administered a dose of the HPV vaccine on day of enrollment (regardless of previous HPV vaccination history). Women previously unvaccinated will receive an additional booster dose at 8 weeks.
ImiquimodDrug
At the baseline visit, this group will be instructed about the correct method of self-application of imiquimod 6.25mg as a vaginal suppository and receive a 16 week course of the drug.

Study groups in NCT02864147
Study group	Role	What they receive
imiquimod + 9-valent HPV vaccine	Experimental	Participants randomized to the imiquimod + 9-valent HPV vaccine group will receive instruction on imiquimod self application (16 week course) at the baseline visit. In addition, all women (regardless of age) will be administered a dose of the HPV vaccine on day of enrollment (regardless of previous HPV vaccination history). Women previously unvaccinated will receive an additional booster dose at 8 weeks. Receives: Drug: 9-valent HPV vaccine; Drug: Imiquimod
imiquimod only	Active comparator	Participants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit. Receives: Drug: Imiquimod
observation only (control)	No intervention	Participants randomized to the control group will only be observed and will receive no intervention.

What is being measured

The primary outcome is the main question the study is designed to answer.

Incidence of Objective Response
The major parameters of objective response to be assessed include treatment efficacy defined as histologic regression of cervical dysplasia to CIN 1 or less after the end of imiquimod treatment, HPV clearance and treatment tolerance. Objective response will be categorized as 'yes' or 'no' and included in the evaluations are the following criteria:
- Histologic regression (HR): Histologic regression of all index lesions to CIN 1 or less after end of imiquimod treatment period.
- Histologic remission (HM): Complete regression of cervical dysplasia at all index biopsy sites after end of imiquimod treatment period.
- Persistent Disease (PR): One or more index lesions persists with CIN 2,3 high grade dysplasia or new lesions are identified colposcopically and histologically confirmed to be CIN 2,3.
- Progressive Disease (PD): Worsening histology of an index lesion.
Measured: Between weeks 20 and 24 (approximately week 22)

Secondary outcomes (1)

Incidence of HPV Clearance
HPV Clearance will be categorized as 'yes' or 'no' and the evaluations are the following criteria: HPV clearance will be measured by both the Roche cobas HPV Test utilized by pathology concomitant with the pap test at final study visit which assesses for presence of 14 high risk HPV types as well as HPV 16/18 genotyping performed by Santin Lab.
Measured: Between weeks 20 and 24 (approximately week 22)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 201622 Nov 2022

First posted11 Aug 2016 (estimated)
Study startJul 2016
Primary completion24 May 2022
Study completion22 Nov 2022

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Cervical Intraepithelial NeoplasiaStudies of the same condition, open and under way.
More trials run by Yale UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Single blind
Who is masked: Participant
Enrolment: 134 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02864147
Sponsor's protocol ID: 1603017415
Other IDs: 000
Status last verified: Apr 2024
First submitted: 4 Aug 2016
Last updated: 2 May 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: Undecided

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Cervical Intraepithelial Neoplasia trials

Study at a glance

From the registry record, last updated by the sponsor on 2 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3) Using a Novel "Prime and Pull" Strategy
ClinicalTrials.gov ID: NCT02864147
Acronym / sponsor ID: 1603017415
Conditions: Cervical Intraepithelial Neoplasia, Cervical Dysplasia
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 134 participants (actual)
Lead sponsor: Yale UniversityUniversity, hospital or other
Study start: Jul 2016
Primary completion: 24 May 2022 (actual)
Study completion: 22 Nov 2022 (actual)
First posted: 11 Aug 2016 (estimated)
Results: Posted 2 May 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

The primary objectives of this study are as follows:

To determine treatment efficacy defined as histologic regression to CIN 1 or less at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the HPV Vaccine + Imiquimod group compared to control,
To determine treatment efficacy defined as histologic regression to CIN 1 or less at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the Imiquimod group compared to control.

The secondary objectives of this study are as follows:

To assess complete regression (i.e., histologic remission) at weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in each group,
To assess HPV clearance in each group,
To assess treatment tolerability.

In addition to the primary and secondary objectives of this study, there additional exploratory/correlative objectives. The exploratory/correlative objectives are as follows:

To assess T cell infiltration in post-treatment cervical biopsies and endocervical cytobrush samples,
To assess HPV16 E7 immunity in CD4/CD8 T cells.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Single blind (participant)
Number of arms: 3

Arm	Type	Receives
imiquimod + 9-valent HPV vaccine	Experimental	Drug: 9-valent HPV vaccine, Drug: ImiquimodParticipants randomized to the imiquimod + 9-valent HPV vaccine group will receive instruction on imiquimod self application (16 week course) at the baseline visit. In addition, all women (regardless of age) will be administered a dose of the HPV vaccine on day of enrollment (regardless of previous HPV vaccination history). Women previously unvaccinated will receive an additional booster dose at 8 weeks.
imiquimod only	Active comparator	Drug: ImiquimodParticipants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit.
observation only (control)	No intervention	–Participants randomized to the control group will only be observed and will receive no intervention.

Who may qualify

Ages: 18 years and older
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

Patients must have untreated cervical biopsy-proven, CIN 2/3 ectocervical lesion(s).
Patients must have satisfactory colposcopy with visualization of the entire transformation zone or a negative endocervical curettage if colposcopy is unsatisfactory.
Patients must be high-risk HPV+ as determined by commercially available DNA hybridization test which tests for 13 high-risk HPV types.
All Patients must have a histologic diagnosis of CIN 2,3 cervical lesion(s) confirmed by a study pathologist within past 10 weeks.
Patients must have signed an approved informed consent.

Key exclusion criteria (12 listed)

Patients with unsatisfactory colposcopy* (unable to visualize entire transformation zone) or evidence of endocervical disease defined as CIN 2/3 diagnosed on endocervical curettage.
Patients with unsatisfactory colposcopy but negative endocervical curettage are eligible
Patients with a history of invasive cervical cancer
Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancers are excluded if there is any evidence of other malignancy being present within the last five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.
Patients with any unstable medical issue (including cardiac issues as above, active treatment for pulmonary embolism, CVA, renal or hepatic insufficiency, active infection/sepsis requiring IV antibiotics).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
9-valent HPV vaccineAll women (regardless of age) will be administered a dose of the HPV vaccine on day of enrollment (regardless of previous HPV vaccination history). Women previously unvaccinated will receive an additional booster dose at 8 weeks.	Drug	imiquimod + 9-valent HPV vaccine
ImiquimodAt the baseline visit, this group will be instructed about the correct method of self-application of imiquimod 6.25mg as a vaginal suppository and receive a 16 week course of the drug.	Drug	imiquimod + 9-valent HPV vaccine, imiquimod only

Primary outcome

Incidence of Objective Response
Time frame: Between weeks 20 and 24 (approximately week 22)
The major parameters of objective response to be assessed include treatment efficacy defined as histologic regression of cervical dysplasia to CIN 1 or less after the end of imiquimod treatment, HPV clearance and treatment tolerance. Objective response will be categorized as 'yes' or 'no' and included in the evaluations are the following criteria: * Histologic regression (HR): Histologic regression of all index lesions to CIN 1 or less after end of imiquimod treatment period. * Histologic remission (HM): Complete regression of cervical dysplasia at all index biopsy sites after end of imiquimod treatment period. * Persistent Disease (PR): One or more index lesions persists with CIN 2,3 high grade dysplasia or new lesions are identified colposcopically and histologically confirmed to be CIN 2,3. * Progressive Disease (PD): Worsening histology of an index lesion.

1 secondary outcome

Incidence of HPV Clearance
Time frame: Between weeks 20 and 24 (approximately week 22)

Results and safety

Results posted to the registry on 2 May 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Observation Only (Control)	45	38
Imiquimod Only	45	38
Imiquimod + 9-valent HPV Vaccine	43	38

Primary outcome: Incidence of Objective Response

Time frame: Between weeks 20 and 24 (approximately week 22). Count of participants. Unit: Participants

Measure	Imiquimod + 9-valent HPV Vaccine n = 38	Imiquimod Only n = 38	Observation Only (Control) n = 38
Histologic regression (HR)	32	36	30
Histologic remission (HM)	0	0	0
Persistent Disease (PR)	6	2	8
Progressive Disease (PD)	0	0	0

Imiquimod Only vs Observation Only (Control): p = 0.043, Fisher Exact
Imiquimod + 9-valent HPV Vaccine vs Observation Only (Control): p = 0.384, Fisher Exact

Population analysed: Complete case analysis.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Up to 24 weeks. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Observation Only (Control)	0 of 45 (0%)	5 of 45 (11.1%)	0 of 45
Imiquimod Only	0 of 45 (0%)	38 of 45 (84.4%)	0 of 45
Imiquimod + 9-valent HPV Vaccine	1 of 43 (2.3%)	36 of 43 (83.7%)	0 of 43

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 May 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Alessandro D Santin, MD principal investigator

Yale University School of Medicine Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology

Sangini S Sheth, MD, MPH principal investigator

Yale University School of Medicine Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Specialties

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 9-valent HPV vaccine and Imiquimod in people with Cervical Intraepithelial Neoplasia and Cervical Dysplasia, run by Yale University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Objective Response (time frame: Between weeks 20 and 24 (approximately week 22)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02864147.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2024.