REVEAL 2 Trial (Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical HSIL)
- Conditions
- Cervical DysplasiaHSILCervical High Grade Squamous Intraepithelial Lesion
- Interventions
- Registration Number
- NCT03721978
- Lead Sponsor
- Inovio Pharmaceuticals
- Brief Summary
HPV-303 is a prospective, randomized, double-blind, placebo-controlled study of VGX-3100 delivered intramuscularly (IM) followed by electroporation (EP) delivered with CELLECTRA™ 5PSP in adult women with histologically confirmed high-grade squamous intraepithelial lesions (HSIL) (cervical intraepithelial neoplasia grade 2 \[CIN2\] or grade 3 \[CIN3\]) of the cervix, associated with human papillomavirus (HPV-16) and/or HPV-18.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 203
- Women aged 18 years and above
- Confirmed cervical infection with HPV types 16 and/or 18 at screening
- Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for diagnosis scheduled to be collected within 10 weeks prior to anticipated date of first dose of study drug
- Confirmed histologic evidence of cervical HSIL at screening
- Must be judged by Investigator to be an appropriate candidate for the protocol-specified procedure required at Week 36
- With respect to their reproductive capacity must be post-menopausal or surgically sterile or willing to use a contraceptive method with failure rate of less than 1% per year when used consistently and correctly from screening until Week 36
- Normal screening electrocardiogram (ECG)
- Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal, or anal intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening
- Cervical lesion(s) that cannot be fully visualized on colposcopy
- History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, or insufficient for diagnosis
- Treatment for cervical HSIL within 4 weeks prior to screening
- Pregnant, breastfeeding or considering becoming pregnant during the study
- History of previous therapeutic HPV vaccination
- Immunosuppression as a result of underlying illness or treatment
- Receipt of any non-study, non-live vaccine within 2 weeks of Day 0
- Receipt of any non-study, live vaccine within 4 weeks of Day 0
- Current or history of clinically significant, medically unstable disease or condition which, in the judgment of the investigator, would jeopardize the safety of the participant, interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results
- Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM injections, or use of blood thinners within 2 weeks of Day 0
- Participation in an interventional study with an investigational compound or device within 30 days of signing informed consent
- Less than two acceptable sites available for IM injection
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description VGX-3100 + EP VGX-3100 Participants received 3 IM injections of 6 mg (in 1 mL) VGX-3100 followed by EP using the CELLECTRA™-5PSP device on Day 0, Week 4, and Week 12. VGX-3100 + EP CELLECTRA™-5PSP Participants received 3 IM injections of 6 mg (in 1 mL) VGX-3100 followed by EP using the CELLECTRA™-5PSP device on Day 0, Week 4, and Week 12. Matched Placebo + EP Matched Placebo Participants received 3 IM injections of 1 mL VGX-3100 matching placebo followed by EP using the CELLECTRA™-5PSP device on Day 0, Week 4, and Week 12. Matched Placebo + EP CELLECTRA™-5PSP Participants received 3 IM injections of 1 mL VGX-3100 matching placebo followed by EP using the CELLECTRA™-5PSP device on Day 0, Week 4, and Week 12.
- Primary Outcome Measures
Name Time Method Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Histologic Evidence of Cervical HSIL on Histology Sample and No Evidence of HPV-16 and/or HPV-18 in Cervical Samples At Week 36 Baseline biomarker-positive participants with no histologic (i.e., biopsies or excisional treatment) evidence of cervical HSIL, no evidence of HPV-16 and/or HPV-18 at Week 36, and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of HSIL was defined by histology as negative, squamous atypia, or low-grade intraepithelial lesion (LSIL). Cervical samples for HPV-16 and/or HPV-18 were collected using the ThinPrep™. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
- Secondary Outcome Measures
Name Time Method mITT Population: Serum Concentrations of Anti-HPV-16 and Anti-HPV-18 Antibody At Week 15 and Week 36 A standardized binding ELISA was performed to measure the anti-HPV-16/18 antibody response induced by VGX-3100. E7 is a viral protein produced by cells infected by HPV-16/18.
Baseline Biomarker-positive Participants for Safety Population: Number of Participants With Any Local and Systemic Adverse Events (AEs) From Baseline to Week 40 An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as AEs. Nausea, fatigue, injection site bruising, injection site erythema, injection site haematoma, injection site induration, injection site pain, injection site pruritus, injection site swelling, malaise, pyrexia, arthralgia, myalgia, headache and erythema were considered as local and systemic AEs for baseline biomarker-positive participants for safety population.
Baseline Biomarker-positive Participants for mITT Population: Change From Baseline in Interferon-Gamma Response Magnitude at Week 15 and 36 Baseline; Week 15 and Week 36 Assessment of cellular immune activity occurred via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot). Peripheral blood mononuclear cells (PBMCs) isolated from whole blood sample were used for analysis. E6 and E7 are viral proteins produced by cells infected by HPV-16/18.
Safety Population: Number of Participants With Local and Systemic AEs From Baseline to Week 40 An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as AEs. Nausea, chills, fatigue, injection site bruising, injection site erythema, injection site haematoma, injection site haemorrhage, injection site induration, injection site oedema, injection site pain, injection site paraesthesia, injection site pruritus, injection site swelling, malaise, pain, pyrexia, temperature regulation disorder, arthralgia, myalgia, headache and erythema were considered as local and systemic AEs for safety population.
Baseline Biomarker-positive Participants for Safety Population: Number of Participants With Any Treatment Emergent AEs (TEAEs) and Serious TEAEs (Including Suspected Unexpected Serious Adverse Reaction [SUSAR] and Unexpected Adverse Device Effect [UADE]) From Baseline to Week 40 AE is any untoward medical occurrence in a participant administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. Serious AE (SAE) is any experience that suggested significant hazard, contraindication, side effect/precaution, \& fulfilled any of the following: fatal, life-threatening, required in-patient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant/required intervention to prevent other outcomes. TEAEs are any AEs starting on or after the first administration of any investigational product (IP). TEAEs included both serious and non-serious TEAEs. UADE is any SAE on health/safety or any life-threatening problem/death caused by, or associated with a device, if that effect, problem/death was not previously identified in nature, severity/degree of incidence in the investigational plan or application.
Safety Population: Number of Participants With Any TEAEs and Serious TEAEs (Including SUSAR and UADE) From Baseline to Week 40 AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. SAE is any experience that suggested significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal, life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent other outcomes. TEAEs are defined as AEs starting on or after the first administration of any IP. TEAEs included both serious and non-serious TEAEs. UADE is any SAE on health/safety or any life-threatening problem/death caused by, or associated with a device, if that effect, problem/death was not previously identified in nature, severity/degree of incidence in the investigational plan or application.
ITT Population: Percentage of Participants With No Histologic Evidence of Cervical HSIL on Histology Sample and No Evidence of HPV-16 and/or HPV-18 in Cervical Samples At Week 36 Participants with no histologic (i.e., biopsies or excisional treatment) evidence of cervical HSIL, no evidence of HPV-16 and/or HPV-18 at Week 36, and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of HSIL was defined by histology as negative, squamous atypia, or low-grade intraepithelial lesion (LSIL). Cervical samples for HPV-16 and/or HPV-18 were collected using the ThinPrep™. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Histologic Evidence of Cervical HSIL on Histology Sample At Week 36 Baseline biomarker-positive participants with no histologic (i.e., biopsies or excisional treatment) evidence of cervical HSIL at Week 36 and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
ITT Population: Percentage of Participants With No Histologic Evidence of Cervical HSIL on Histology Sample At Week 36 Participants with no histologic (i.e., biopsies or excisional treatment) evidence of cervical HSIL at Week 36 and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Evidence of HPV-16 and/or HPV-18 in Cervical Samples by Type Specific HPV Testing At Week 36 Baseline biomarker-positive participants with no evidence of HPV-16 and/or HPV-18 at Week 36 time frame and participants in whom an excision or biopsy sample was not obtained between the initial dose up to Week 36 were considered to be responders. Cervical samples for HPV-16 and/or HPV-18 were collected using the ThinPrep™. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
mITT Population: Change From Baseline in Interferon-Gamma Response Magnitude at Week 15 and 36 Baseline; Week 15 and Week 36 Assessment of cellular immune activity occurred via the application of the IFN-γ ELISpot. PBMCs isolated from whole blood sample were used for analysis. E6 and E7 are viral proteins produced by cells infected by HPV-16/18.
ITT Population: Percentage of Participants With No Evidence of HPV-16 and/or HPV-18 in Cervical Samples by Type Specific HPV Testing At Week 36 Participants with no evidence of HPV-16 and/or HPV-18 at Week 36 and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. Cervical samples for HPV-16 and/or HPV-18 were collected using the ThinPrep™. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Histologic Evidence of LSIL or HSIL on Histology Sample At Week 36 Baseline biomarker-positive participants with no histologic evidence of cervical HSIL, squamous atypia, or LSIL at Week 36 and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of LSIL was defined as no evidence of cervical squamous intraepithelial neoplasia 1 (CIN1), CIN2, or CIN3 on biopsies or excisional treatment. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
ITT Population: Percentage of Participants With No Evidence of Histologic LSIL or HSIL on Histology Sample At Week 36 Participants with no histologic evidence of cervical HSIL, squamous atypia, or LSIL at Week 36 and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of LSIL was defined as no evidence of CIN1, CIN2, or CIN3 on biopsies or excisional treatment. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Evidence of LSIL or HSIL on Histology Sample and No Evidence of HPV-16 and/or HPV-18 by Type Specific HPV Testing At Week 36 Baseline biomarker-positive participants with no histologic evidence of cervical HSIL, squamous atypia, or LSIL, no evidence of HPV-16 and/or HPV-18 by type specific HPV testing at Week 36, and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of LSIL was defined as no evidence of CIN1, CIN2, or CIN3 on biopsies or excisional treatment. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
ITT Population: Percentage of Participants With No Evidence of LSIL or HSIL on Histology Sample and No Evidence of HPV-16 and/or HPV-18 by Type Specific HPV Testing At Week 36 Participants with no histologic evidence of cervical HSIL, squamous atypia, or LSIL, no evidence of HPV-16 and/or HPV-18 by type specific HPV testing at Week 36, and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. No evidence of LSIL was defined as no evidence of CIN1, CIN2, or CIN3 on biopsies or excisional treatment. No evidence of HSIL was defined by histology as negative, squamous atypia, or LSIL. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants With No Progression of Cervical HSIL to Cervical Carcinoma From Baseline at Week 36 Baseline biomarker-positive participants with no histologic evidence of cervical adenocarcinoma in situ (AIS) or cervical carcinoma at Week 36 relative to baseline and participants in whom an excision or biopsy sample was not obtained between initial dose up to Week 36 were considered as responders. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
ITT Population: Percentage of Participants With No Progression of Cervical HSIL to Cervical Carcinoma From Baseline at Week 36 Participants with no histologic evidence of cervical AIS or cervical carcinoma at Week 36 relative to baseline and participants who did not have unscheduled excision or biopsy sample obtained between the initial dose up to Week 36 were considered to be responders. The efficacy time frame is defined by a biopsy or surgical excision at any time starting from 14 days prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.
Baseline Biomarker-positive Participants for ITT Population: Percentage of Participants Who Have Cleared HPV-16 and/or HPV-18 in Non-cervical Anatomic Locations From Baseline at Week 36 Percentage of baseline biomarker-positive participants who have cleared HPV-16 and/or HPV-18 on specimens from non-cervical anatomic locations (oropharynx, vagina and intra-anal) at Week 36 Visit compared to baseline were reported.
ITT Population: Percentage of Participants Who Have Cleared HPV-16 and/or HPV-18 in Non-cervical Anatomic Locations From Baseline at Week 36 Percentage of participants who have cleared HPV-16 and/or HPV-18 on specimens from non-cervical anatomic locations (oropharynx, vagina, and intra-anal) at Week 36 Visit compared to baseline were reported.
Baseline Biomarker-positive Participants for mITT Population: Serum Concentrations of Anti-HPV-16 and Anti-HPV-18 Antibody At Week 15 and Week 36 A standardized binding enzyme-linked immunosorbent assay (ELISA) was performed to measure the anti-HPV-16/18 antibody response induced by VGX-3100. E7 is a viral protein produced by cells infected by HPV-16/18.
Baseline Biomarker-positive Participants for mITT Population: Change From Baseline in Flow Cytometry Response Magnitude at Week 15 Baseline, Week 15 Assessment of cellular immune activity was measured using the application flow cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay examines the following external cellular markers: CD3, CD4, CD8 (T cell identification), CD137, CD38, and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). Here, changes from baseline in the percentage of CD8+CD137+Perforin+, CD8+CD38+Perforin+, and CD8+CD69+Perforin+ are reported.
mITT Population: Change From Baseline in Flow Cytometry Response Magnitude at Week 15 Baseline, Week 15 Assessment of cellular immune activity was measured using the application flow cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay examines the following external cellular markers: CD3, CD4, CD8 (T cell identification), CD137, CD38, and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). Here, changes from baseline in the percentage of CD8+CD137+Perforin+, CD8+CD38+Perforin+, and CD8+CD69+Perforin+ are reported.
Trial Locations
- Locations (53)
Nuvance Health
🇺🇸Danbury, Connecticut, United States
ClinOhio Research Services
🇺🇸Columbus, Ohio, United States
Storks Research
🇺🇸Sugar Land, Texas, United States
Group For Women - Tidewater Clinical Research Inc.
🇺🇸Virginia Beach, Virginia, United States
Altus Research
🇺🇸Lake Worth, Florida, United States
HUS Naistentaudit ja synnytykset
🇫🇮Helsinki, Uusimaa, Finland
Lynette Reynders Private Practice
🇿🇦Centurion, Gauteng, South Africa
DIM Clinica Privada
🇦🇷Ramos Mejía, Argentina
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
Associação Obras Sociais Irmã Dulce Hospital Santo Antônio
🇧🇷Salvador, Bahia, Brazil
Visions Clinical Research- Tucson
🇺🇸Tucson, Arizona, United States
Christiana Care Health System
🇺🇸Newark, Delaware, United States
Unified Women's Clinical Research - Hagerstown
🇺🇸Hagerstown, Maryland, United States
Affinity Clinical Research Institute
🇺🇸Oak Brook, Illinois, United States
Praetorian Pharmaceutical Research, LLC
🇺🇸Marrero, Louisiana, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Precision Clinical Research, LLC
🇺🇸Sunrise, Florida, United States
Salom and Tangir LLC
🇺🇸Miramar, Florida, United States
Meridian Clinical Research Norfolk
🇺🇸Norfolk, Nebraska, United States
Saginaw Valley Medical Research Group LLC
🇺🇸Saginaw, Michigan, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Suffolk Obstetrics and Gynecology
🇺🇸Port Jefferson, New York, United States
Unified Women's Clinical Research - Greensboro
🇺🇸Greensboro, North Carolina, United States
Unified Women's Clinical Research - Morehead City
🇺🇸Morehead City, North Carolina, United States
Lyndhurst Clinical Research
🇺🇸Winston-Salem, North Carolina, United States
Obstetrics & Gynecology Associates, Inc.
🇺🇸Fairfield, Ohio, United States
Women's Physician Group Suite 203
🇺🇸Memphis, Tennessee, United States
Frontier Clinical Research-Smithfield
🇺🇸Smithfield, Pennsylvania, United States
Venus Gynecology, LLC
🇺🇸Myrtle Beach, South Carolina, United States
Instituto de Ginecología
🇦🇷Rosario, Santa Fe, Argentina
Hospital Italiano de Buenos Aires
🇦🇷Ciudad Autonoma de Buenos Aires, Argentina
Hospital Erasto Gaertner
🇧🇷Curitiba, Paraná, Brazil
Hospital Amaral Carvalho
🇧🇷Jaú, São Paulo, Brazil
Hospital das Clinicas de Goiânia
🇧🇷Goiânia, Goiás, Brazil
Tartu University Hospital
🇪🇪Tartu, Estonia
Vilnius District Central Outpatient Clinic
🇱🇹Vilnius, Lithuania
East Tallinn Central Hospital Womens Clinic
🇪🇪Tallinn, Estonia
Hospital Das Clinicas da Faculdade de Medicina de Ribeirão Preto - USP
🇧🇷Ribeirao Preto, São Paulo, Brazil
Pärnu Hospital
🇪🇪Pärnu, Pärnumaa, Estonia
Northern Savo Hospital District Muncipal Federation
🇫🇮Kuopio, Finland
Vilnius University Hospital Santaros Klinikos
🇱🇹Vilnius, Lithuania
Niepubliczny Zakład Opieki Zdrowotnej Profimed
🇵🇱Lublin, Lubelskie, Poland
Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
🇵🇱Lublin, Lubelskie, Poland
Centrum Medyczne Angelius Provita
🇵🇱Śląskie, Poland
University of Cape Town
🇿🇦Cape Town, Western Cape, South Africa
Hospital Universitario de Bellvitge
🇪🇸L'Hospitalet de Llobregat, Barcelona, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Puerto Rico Translational Research Center (PRTRC)
🇵🇷Rio Piedras, Puerto Rico
New Jersey Medical School
🇺🇸Newark, New Jersey, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States