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    Summary
    EudraCT Number:2018-004114-17
    Sponsor's Protocol Code Number:HPV-303
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-12-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedLithuania - SMCA
    A.2EudraCT number2018-004114-17
    A.3Full title of the trial
    REVEAL 2: A Prospective, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly Followed by Electroporation with CELLECTRA™ 5PSP for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous Intraepithelial Lesion (HSIL) of the Cervix
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A drug and a device used together to treat women with precancerous cells on the cervix caused by human papillomavirus (HPV)
    A.3.2Name or abbreviated title of the trial where available
    REVEAL 2 (Randomized Evaluation of VGX-3100 and Electroporation for Treatment of Cervical HSIL)
    A.4.1Sponsor's protocol code numberHPV-303
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03721978
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/367/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInovio Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInovio Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInovio Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address660 W. Germantown Pike, Suite 110
    B.5.3.2Town/ cityPlymouth Meeting
    B.5.3.3Post codePA 19462
    B.5.3.4CountryUnited States
    B.5.6E-mailHPV303ClinicalTeam@inovio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVGX-3100
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpGX3001
    D.3.9.1CAS number 1977487-95-8
    D.3.9.4EV Substance CodeSUB167139
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpGX3002
    D.3.9.1CAS number 1977488-08-6
    D.3.9.4EV Substance CodeSUB167140
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Yes
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberThe EMA/CAT considers that the product falls within the definition of a gene therapy medicinal product.; The reference number is EMA/706959/2016.
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HPV-16 and/or HPV-18 related high grade squamous intraepithelial lesion (HSIL) of the cervix
    E.1.1.1Medical condition in easily understood language
    Precancerous cells on the cervix caused by human papillomavirus (HPV)
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064328
    E.1.2Term Human papilloma virus test positive
    E.1.2System Organ Class 10022891 - Investigations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066237
    E.1.2Term Cervical high grade squamous intraepithelial lesion
    E.1.2System Organ Class 100000004872
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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
    E.2.2Secondary objectives of the trial
    1. Evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP with CELLECTRA™ 5PSP
    2. Determine VGX-3100 efficacy compared to placebo as measured by histopathologic regression of cervical HSIL
    3. Determine VGX-3100 efficacy compared to placebo as measured by virologic clearance of HPV-16 and/or HPV-18
    4. Determine VGX-3100 efficacy compared to placebo as measured by complete histopathologic regression of cervical HSIL to normal
    5. Determine VGX-3100 efficacy compared to placebo as measured by both complete histopathologic regression of cervical HSIL to normal and virologic clearance of HPV-16 and/or HPV-18
    6. Determine VGX-3100 efficacy compared to placebo as measured by histopathologic non-progression
    7. Describe the clearance of HPV-16 and/or HPV-18 infection from non-cervical anatomic locations
    8. Determine the humoral and cellular immune response of VGX-3100 compared with placebo at post dose 3 and week 36 visit as assessed relative to baseline
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (i.e. excision, 4 quadrant biopsy with ECC, or 4-quadrant biopsy) 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) is 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
    E.4Principal 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. History of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis (ECC is not 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 abnormal clinical screening laboratory values greater than Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 or less than Grade 1 but deemed clinically significant by the investigator within 30 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 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 treatment for malignancy within 2 years of screening, with the exception of superficial skin cancers that only require local excision;
    13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate 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
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects with no evidence of cervical HSIL on histology (i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or HPV-18 in cervical samples by type specific HPV testing at Week 36 visit
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Week 36 visit
    E.5.2Secondary 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 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 subjects with no evidence of cervical HSIL on histology (i.e. biopsies or excisional treatment) at Week 36 visit
    3. Proportion of subjects with no evidence of HPV-16 and/or HPV-18 in cervical samples by type specific HPV testing at Week 36 visit
    4. Proportion of subjects with no evidence of Low grade squamous intraepithelial lesion (LSIL) or HSIL (i.e. no evidence of CIN1, CIN2 or CIN3) on histology (i.e. biopsies or excisional treatment) at Week 36 visit
    5. Proportion of subjects with no evidence of LSIL or HSIL (i.e. no evidence of CIN1, CIN2 or CIN3 on biopsies or excisional treatment) on histology (i.e. biopsies or excisional treatment) and no evidence of HPV-16 and/or HPV-18 by type specific HPV testing at Week 36 visit
    6. Proportion of subjects with no progression of cervical HSIL to cervical carcinoma from baseline on histology (i.e. biopsies or excisional treatment) at Week 36 visit
    7. Proportion of subjects 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
    8a. Levels of serum anti-HPV-16 and anti-HPV-18 antibody concentrations at Weeks 15 and 36 visits
    8b. Interferon-γ ELISpot response magnitudes at baseline, Weeks 15 and 36 visits
    8c. Flow Cytometry response magnitudes at baseline and Week 15 visits
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Brazil
    Canada
    Estonia
    Finland
    Germany
    Italy
    Lithuania
    Mexico
    Peru
    Philippines
    Poland
    Portugal
    Puerto Rico
    Slovakia
    South Africa
    Spain
    Thailand
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 188
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 198
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no plans for provision of this treatment following the end of the trial. The product is a therapeutic drug and therefore once administered per protocol, there is no additional benefit of further administration. Patients will resume typical standard of care and follow-up according to their country healthcare system.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-05
    P. End of Trial
    P.End of Trial StatusOngoing
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