Protocol version 1.1: The inclusion and exclusion criteria were clarified to include a satisfactory colposcopy and no evidence of invasive cancer in any specimen and exclude an unsatisfactory colposcopy and an endocervical curettage (ECC) specimen that identified endocervical CIN, that was not directly visualized. The cervical immunology and virologic samples to be collected in the study were clarified. The collection of pre-dose blood immunology samples for the exploratory endpoints was amended to include whole blood and serum samples at screening. A process for the supplementation of study subjects to include additional subjects to be randomized if more than 10 subjects received less than three vaccinations or underwent definitive therapy prior to Week 24 to maintain a per protocol sample size of at least 138 subjects was added. Further clarification was provided regarding the discontinuation and withdrawal of study subjects. Additional information regarding the assessment of injection site reactions to include the use of the “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (Sept 2007) for grading injection site reactions was added. The reporting period for unsolicited adverse events (AEs) was clarified to include the period following signing of the informed consent to study discharge and for solicited AEs to include the period following administration of study treatment through 4 weeks following each injection of VGX-3100 + EP.

Protocol version 1.2: Clarified inclusion criteria to include voluntary signing of the informed consent form. Changed the inclusion criteria from “18-50” to “18-55” years of age. Removed the exclusion criterion about receiving any HPV vaccine at any time in the past. Updated temperature storage condition and label for VGX-3100. Added pregnancy testing prior to any colposcopy and surgical excision. Clarified instructions for subjects who became pregnant during the study. Clarified qualifications for site staff who were to dispense and administer vaccinations during the study. Clarified wording regarding subjects eligible for screening in the study. Updated investigational product information to include storage, handling and accounting of Placebo.

Protocol version 1.3: Updated list of regions where the trial was being conducted. Eliminated optional collection of endocervical brush specimens. Eliminated collection of blood samples at Weeks 6, 36, 62 and collection of cervical samples at Week 6. Specified instructions to permit subjects with a cytological diagnosis of high grade squamous intraepithelial lesion (HGSIL) to undergo biopsy to determine CIN status after approval from the Sponsor’s medical monitor on a case by case basis. Added optional collection of unstained slides or tissue at entry and Week 36 for immunohistochemical analysis. Extended screening period between entry biopsy and first treatment with vaccine/placebo to 10 weeks to allow adequate time to process pathology samples. Added the option to perform Week 2 and 6 study procedures via telephone contact to reduce visit burden on participants. A follow-up clinic visit was at the discretion of the study staff based on the need for further evaluation of any reported events. Added an Exploratory Objective to measure durability of immune responses. Added detail regarding the Data and Safety Monitoring Board (DSMB) reporting of primary aggregate treatment-specific results to Sponsor. Clarified rules for subject inclusion or exclusion from the primary per-protocol analysis. Corrected the Supplementation of Study Subjects section for subjects, who underwent definitive therapy prior to Week 36 and not Week 24.

Protocol version 1.4: The protocol was amended to unblind when all subjects, who had not discontinued, completed their Week 40 Visit. This allowed the Sponsor to have a complete unblinded dataset with respect to the primary Week 36 Visit endpoint on which to make decisions regarding the VGX-3100 program, while awaiting outstanding secondary data through the final Week 88 Visit. Long-term follow up data continued to be collected on all subjects with remaining visits through the final Week 88 Visit post-unblinding, and all data were analysed accordingly in the final full Clinical Study Report. Subjects and study site personnel remained blinded to individual treatment assignment until after all subjects, who had not discontinued, completed their Week 88 visit. Access to this unblinded dataset replaced the DSMB's communication of unblinded primary results at Week 36 to the Sponsor.