E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HPV-16 and/or HPV-18 related high grade squamous intraepithelial lesion (HSIL) of the cervix |
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E.1.1.1 | Medical condition in easily understood language |
Precancerous cells on the cervix caused by human papillomavirus (HPV) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064328 |
E.1.2 | Term | Human papilloma virus test positive |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066237 |
E.1.2 | Term | Cervical high grade squamous intraepithelial lesion |
E.1.2 | System Organ Class | 100000004872 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Among baseline biomarker-positive women determine the efficacy of VGX-3100 compared with placebo with respect to combined histopathologic regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 |
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E.2.2 | Secondary objectives of the trial |
1.Among i) baseline biomarker-positive women and ii) all women, evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP with CELLECTRA™ 5PSP. 2. Among all women, determine the efficacy of VGX-3100 compared with placebo with respect to combined histopathologic regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18. 3. Among i) baseline biomarker-positive women and ii) all women, determine VGX-3100 efficacy compared to placebo as measured by histopathologic regression of cervical HSIL. 4. Among i) baseline biomarker-positive women and ii) all women, determine VGX-3100 efficacy compared to placebo as measured by virologic clearance of HPV-16 and/or HPV-18. 5. Among i) baseline biomarker-positive women and ii) all women, determine VGX-3100 efficacy compared to placebo as measured by complete histopathologic regression of cervical HSIL to normal. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Women aged 18 years and above that meet the minimum age of consent per local regulations; 2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobas™ HPV test; 3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects must be willing and able to provide voluntary consent to participate and sign a Consent Form prior to study-related activities; 6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified procedure(s) required at Week 36; 7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-white epithelium or suspected CIN disease; 8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 10. Must meet one of the following criteria with respect to their reproductive capacity: a) Post-menopausal as defined by spontaneous amenorrhea for more than 12 months; b) Surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion performed more than 12 months prior to screening; c) Women of Child Bearing Potential (WOCBP) are 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. The following methods are acceptable : - Hormonal contraception: either combined or progestin-alone including oral contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); - Abstinence from penile-vaginal intercourse when this is the subject’s preferred mode of sexual activity; - Intrauterine device or intrauterine system; - Male partner sterilization at least 6 months prior to the female subject’s entry into the study, and this male is the sole partner for that subject 11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by the investigator
* Use of condoms alone or condoms with spermicide does not have a failure rate of <1% per year and is therefore not an acceptable form of contraception. |
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E.4 | Principal exclusion criteria |
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal (inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical canal at screening; 3. ECC that shows a potentially untreated carcinoma, untreated HSIL, indeterminate, or insufficient for diagnosis (ECC is not required to be performed as part of study screening); 4. Treatment for cervical HSIL within 4 weeks prior to screening; 5. Pregnant, breastfeeding or considering becoming pregnant through week 36; 6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, e.g. Gardasil™, Cervarix™); 7. Presence of any unresolved abnormal clinical screening laboratory values of Grade 1 or greater per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 and deemed clinically significant by the investigator 60 days prior to Day 0; 8. Immunosuppression as a result of underlying illness or treatment including: a) History of or positive serologic test for HIV at screening (performed within 30 days prior to Day 0) b) Primary immunodeficiencies c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) e) History of solid organ or bone marrow transplantation f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed autoimmune disease that may jeopardize the safety of the subject or require therapy that would interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results. g) Subjects who are malnourished based on screening labs, medical history (e.g. clinically significant unintentional weight loss) and physical exam, as determined by investigator's clinical judgement 9. Receipt of any non-study, non-live vaccine within 2 weeks of Day 0; 10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 11. Current or history of clinically significant, medically unstable disease which, in the judgment of the investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, or clinically significant arrhythmias) 12. Malignancy or systemic treatment for malignancy within 2 years of screening (locally treated ano-genital malignancy and superficial skin cancers are allowed); 13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate intramuscular IM injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at screening or Day 0; 17. Prior major surgery within 4 weeks of Day 0; 18. Participation in an interventional study with an investigational compound or device within 30 days of signing informed consent; participation in an observational study is permitted; 19. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral quadriceps muscles; 20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 22. Metal implants or implantable medical device within the electroporation area; 23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements; 24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (i.e. infectious disease) illness; 25. Active military service personnel; 26. Study-related staff or family member of study-related staff; 27. Any illness or condition that in the opinion of the investigator may affect the safety of the subject or the evaluation of any study endpoint |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of baseline biomarker-positive women with no evidence of cervical HSIL on histology sample and no evidence of HPV-16 and/or HPV-18 in cervical samples by type specific HPV testing at Week 36 visit |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1a. Incidence and severity of local and systemic events for 7 and 28 days following each investigational treatment and for the duration of the study (i.e., 40 weeks). 1b. Incidence and severity of all adverse events including Serious adverse events (SAEs) (e.g., Serious unexpected serious adverse reaction (SUSAR), Unexpected adverse device effect (UADE) and other unexpected AEs) for the duration of the study (through Week 40 visit). 2. Proportion of all women with no evidence of cervical HSIL on histology sample and no evidence of HPV-16 and/or HPV-18 in cervical samples by type specific HPV testing at Week 36 visit. 3. Proportion of women with no evidence of cervical HSIL on histology sample at Week 36 visit. 4. Proportion of women with no evidence of HPV-16 and/or HPV-18 in cervical samples by type specific HPV testing at Week 36 visit. 5.Proportion of women with no evidence of Low grade squamous intraepithelial lesion (LSIL) or HSIL (i.e., no evidence of CIN1, CIN2 or CIN3) on histology sample at Week 36 visit. 6.Proportion of women with no evidence of LSIL or HSIL (i.e., no evidence of CIN1, CIN2 or CIN3) on histology sample and no evidence of HPV-16 and/or HPV-18 by type specific HPV testing at Week 36 visit. 7. Proportion of women with no progression of cervical HSIL to cervical carcinoma from baseline on histology sample at Week 36 visit. 8. Proportion of women 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. 9a. Levels of serum anti-HPV-16 and anti-HPV-18 antibody concentrations at Weeks 15 and 36 visits 9b. Interferon-γ ELISpot response magnitudes at baseline, Weeks 15 and 36 visits 9c. Flow Cytometry response magnitudes at baseline and Week 15 visits. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a. For 7 and 28 days following each investigational treatment and for the duration of the study 40 weeks 1b. Through Week 40 visit 2. At Week 36 visit 3. At Week 36 visit 4. At Week 36 visit 5. At Week 36 visit 6. At Week 36 visit 7. At Week 36 Visit 8a. At Weeks 15 and 36 visits 8b. At Weeks 15 and 36 visits 8c. At baseline and Week 15 visits |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
Mexico |
Peru |
Philippines |
Puerto Rico |
South Africa |
Thailand |
United States |
Estonia |
Finland |
Lithuania |
Poland |
Spain |
Germany |
Italy |
Belgium |
Portugal |
Slovakia |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |