HerpeVac Trial for Young Women

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to see if a herpes vaccine may prevent genital herpes disease in women who are not infected. The study will enroll approximately 7550 healthy women. These women will be randomly assigned to 1 of 2 possible study groups: herpes vaccine (experimental group) or hepatitis A vaccine (control group). Participants will receive their assigned vaccine at 0, 1, and 6 months. Participants will have 9 scheduled study visits and additional unscheduled visits for an evaluation of herpes if it is suspected. Participants will be involved in study related procedures for up to 20 months.

Detailed Description
-----------------
This study is a double-blind, randomized, controlled Phase III trial to assess the prophylactic efficacy and safety of gD-Alum/MPL vaccine in the prevention of genital herpes disease in young women who are herpes simplex virus (HSV)-1 and -2 seronegative. The primary efficacy objective is to evaluate vaccine efficacy in the prevention of genital herpes disease caused by HSV-1 and/or HSV-2 between months 2 and 20 in healthy adult women who were initially HSV-1 and HSV-2 seronegative. The secondary efficacy objectives are to: evaluate vaccine efficacy in the prevention of genital herpes disease caused by HSV-1 and/or HSV-2 occurring between the months 7 and 20; evaluate vaccine efficacy in the prevention of HSV-2 infection between months 2 and 20; and to evaluate vaccine efficacy in the prevention of HSV-2 infection occurring between months 7 and 20. The study will enroll approximately 7,550 women, ages 18-30 years. Participants will be randomized to 1 of 2 possible study groups: candidate vaccine; or control vaccine (hepatitis A vaccine). The study duration for each subject will be approximately 20 months. Study procedures will include 9 scheduled study visits (including the screening visit) and additional unscheduled visits for evaluation of suspected herpes disease episodes. Three doses of vaccine or control will be administered intramuscularly in the non-dominant deltoid on a 0, 1, and 6 month schedule. Subjects will attend clinic visits at screening, months 2, 7, 12, 16, and 20. In subjects who present with suspected herpes disease between months 17 and 20, an additional visit to collect a serum sample will be scheduled 3 months after the evaluation for suspected genital herpes.

Official Title
-----------------
A Double-Blind, Randomized, Controlled Phase III Study to Assess the Prophylactic Efficacy and Safety of gD-Alum/MPL Vaccine in the Prevention of Genital Herpes Disease in Young Women Who Are HSV-1 and -2 Seronegative

Conditions
-----------------
Herpes Simplex Infection

Intervention / Treatment
-----------------
* Biological: HSV vaccine or SB208141, GSK Biologicals' glycoprotein D (gD)-Alum/3-deacylated form of Monophosphoryl Lipid A (MPL) candidate genital herpes vaccine
* Biological: Havrix™, GlaxoSmithKline (GSK) Biologicals' licensed Hepatitis A vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A female between, and including, 18 and 30 years of age at the time of the first vaccination. Written informed consent obtained from the subject. Free of obvious health problems as established by medical history and clinical examination before entering into the study. Seronegative for HSV-1 and HSV-2 by Western blot. Subject must be non-childbearing potential, i.e. either surgically sterilized or, if of child bearing potential, she must be using a highly effective method of birth control (e.g., intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant®; DepoProvera®; contraceptive skin patch or cervical ring) for 30 days prior to vaccination, have a negative urine pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series. A subject for whom the investigator believes can and will comply with the requirements of the protocol (e.g. completion of the memory aid/diary cards, return for follow-up visits, accessible by phone or pager, able to self-sample and not planning on moving from study area). Exclusion Criteria: Pregnant or nursing female. Clinical signs or symptoms of current oro-labial, genital or non-genital HSV disease, such as swelling, papules, vesicles, pustules, ulcers, crusts, fissures, erythema, discharge, pain, burning, itching, tingling or dysuria. Previous vaccination against herpes. Previous administration of monophosphoryl lipid A (MPL) adjuvant (no vaccines currently licensed in the USA contain this). History of any confirmed oro-labial, genital or non-genital HSV disease or infection. Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. Planned administration/ administration of a non-study vaccine within 30 days of the first dose of the study vaccine with the following exceptions: Administration of routine Meningococcal, Hepatitis B, inactivated Influenza, and Diphtheria/Tetanus vaccine up to 8 days before the first dose of study vaccine is allowed. History of allergic disease or reactions likely to be exacerbated by any component of the study vaccines, e.g. aluminum, MPL, alum-MPL, 2-phenoxyethanol or neomycin. Any confirmed or suspected immunosuppressive or immunodeficient condition including, human immunodeficiency virus (HIV) infection. Acute or chronic, clinically significant (unresolved, requiring on-going medical management or medication, etc.) pulmonary, cardiovascular, hepatic or renal function abnormality, as determined by medical history or physical examination. Acute disease at the time of enrollment (defer vaccination until subject recovers). Acute disease is defined as the presence of a moderate or severe illness with or without fever. Study vaccine can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness. Oral temperature greater than or equal to 99.5º F (greater than or equal to 37.5º C) / axillary temperature greater than or equal to 99.5º (greater than or equal to 37.5º C) / tympanic temperature on oral setting greater than or equal to 99.5º F (greater than or equal to 37.5º C). Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. (For corticosteroids, this will mean prednisone or, equivalent, greater than or equal to 0.5 mg/kg/day. Inhaled or topical steroids are allowed.) Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Recent history of chronic alcohol consumption (defined as more than 5 oz of ethanol [absolute alcohol] per day) and/or drug abuse. History of sexually transmitted infection within 30 days preceding the first dose of study vaccine.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Herpes Simplex Virus Group<br>Females between, and including, 18 and 30 years of age at the time of first vaccination who received 3 doses of herpes simplex virus (HSV) vaccine intramuscularly in the non-dominant deltoid on a 0, 1, 6 month schedule. | Biological: HSV vaccine or SB208141, GSK Biologicals' glycoprotein D (gD)-Alum/3-deacylated form of Monophosphoryl Lipid A (MPL) candidate genital herpes vaccine<br>* the vaccine was administered intramuscularly in the non-dominant deltoid<br>|
| Experimental: Havrix Group<br>Females between, and including, 18 and 30 years of age at the time of first vaccination who received 3 doses of the investigational formulation of Havrix vaccine intramuscularly in the non-dominant deltoid on a 0, 1, 6 month schedule. | Biological: Havrix™, GlaxoSmithKline (GSK) Biologicals' licensed Hepatitis A vaccine<br>* the vaccine was administered intramuscularly in the non-dominant deltoid<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Newly Acquired Genital Herpes Disease, Caused by Either Herpes Simplex Virus (HSV)-1 or HSV-2 | Genital herpes disease was defined as signs (swelling, papules, vesicles, ulcers, crusts, fissures, erythema, or vaginal discharge) and/or symptoms (pain, burning, itching, tingling, dysuria) which developed on the skin or mucosa of the anogenital region and/or buttocks and laboratory confirmation of Herpes Simplex Virus (HSV)-1 or 2 infection (either concomitant positive HSV culture or HSV seroconversion within 6 months after onset of signs and/or symptoms). Seroconversion to HSV-1 and/or HSV-2 was defined as a positive HSV-1 and/or HSV-2 Western blot in a subject with a previously negative Western blot result for the corresponding HSV type. | Between Months 2 and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Newly Acquired Genital Herpes Disease, Caused by Either Herpes Simplex Virus (HSV)-1 or HSV-2 | Genital herpes disease was defined as signs (swelling, papules, vesicles, ulcers, crusts, fissures, erythema, or vaginal discharge) and/or symptoms (pain, burning, itching, tingling, dysuria) which developed on the skin or mucosa of the anogenital region and/or buttocks and laboratory confirmation of Herpes Simplex Virus (HSV)-1 or 2 infection (either concomitant positive HSV culture or HSV seroconversion within 6 months after onset of signs and/or symptoms). Seroconversion to HSV-1 and/or HSV-2 was defined as a positive HSV-1 and/or HSV-2 Western blot in a subject with a previously negative Western blot result for the corresponding HSV type. | Between Months 7 and 20 | 
| Number of Subjects With Newly Acquired Herpes Simplex Virus (HSV)-2 Infection Confirmed by Either Virus Culture or HSV-2 Seroconversion. | The number of subjects with newly acquired HSV-2 infection confirmed by either virus culture or HSV-2 seroconversion was tabulated. Seroconversion to HSV-1 and/or HSV-2 was defined as a positive HSV-1 and/or HSV-2 Western blot in a subject with a previously negative Western blot result for the corresponding HSV type. | Between Months 2 and 20 | 
| Number of Subjects With Newly Acquired Herpes Simplex Virus (HSV)-2 Infection Confirmed by Either Virus Culture or HSV-2 Seroconversion | The number of subjects with newly acquired HSV-2 infection confirmed by either virus culture or HSV-2 seroconversion was tabulated. Seroconversion to HSV-1 and/or HSV-2 was defined as a positive HSV-1 and/or HSV-2 Western blot in a subject with a previously negative Western blot result for the corresponding HSV type. | Between Months 7 and 20 | 
| Concentrations for Anti-glycoprotein D (Anti-gD) Antibodies. | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in ELISA units per milliliter (EU/mL). The seroprotection cut-off of the assay was 40 EU/mL | At Months 0, 2, 6, 7, 12, 16 and 20 | 
| Titers for Anti-herpes Simplex Virus (Anti-HSV) Neutralizing Antibodies. | Titers for Anti-HSV neutralizing antibodies are presented as Geometric Mean Titers (GMTs), and are expressed in Estimated Doses (ED), that is, the reciprocal of the dilution necessary to achieve neutralization. Antibody titers below the lowest level of quantification were not calculated . | At Months 0, 2, 6, 7, 12, 16 and 20 | 
| Number of Subjects Reporting Solicited Local and General Symptoms | Solicited local symptoms assessed were pain, redness and swelling. Solicited general symptoms assessed were fatigue, headache, malaise and fever (defined as oral/axillary/tympanic temperature equal to or above 37.5 degrees Celsius). | Within 7 days (Days 0-6) after vaccination | 
| Number of Subjects Reporting Grade 3 Solicited Local Symptoms | Solicited local symptoms assessed were pain, redness and swelling. Grade 3 pain = pain that prevented normal activities. Grade 3 redness/swelling = redness/swelling above 30 mm and persisting for more than 24 hours | Within 7 days (Days 0-6) after vaccination | 
| Number of Subjects Reporting Grade 3 and Related Solicited General Symptoms | Solicited general symptoms assessed were fatigue, headache, malaise and fever (oral/axillary/tympanic). Grade 3 headache, fatigue, malaise = symptom that prevented normal activities. Grade 3 fever = temperature above 39.0 degrees Celsius. Related = symptom assessed by the investigator as causally related to the vaccination | Within 7 days (Days 0-6) after vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AEs have been tabulated for a 31-day period. An unsolicited AE was any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Within 31 days after vaccination | 
| Number of Subjects With New Onset Chronic Diseases (NOCDs), Medically Significant Conditions (MSCs) and Serious Adverse Events (SAEs) | NOCDs included adverse events (AEs) as autoimmune disorders, asthma, type I diabetes, allergies. MSCs included AEs prompting emergency room or physician visits unrelated to common diseases or routine visits for physical examination or vaccination, or SAEs unrelated to common diseases. SAEs included medical occurrences either life-threatening, requiring hospitalization, or resulting in death, disability/incapacity or congenital anomaly/birth defect in a subject's offspring. Common diseases included upper respiratory infections (URIs), sinusitis, pharyngitis, gastroenteritis, urinary tract infection, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. The following were not reported if not considered as SAEs and occurring more than 30 days post vaccination: URIs, sinusitis, pharyngitis, gastroenteritis, injury, or visits for routine physical examination or vaccination. AEs are described, using Medical Dictionary for Regulatory Activities' preferred terms. | Throughout the study (From Month 0 up to Month 20) | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or were a congenital anomaly/birth defect in a subject's offspring. | Throughout the study (From Month 0 up to Month 20) |