Safety and Efficacy of 4 Investigational HSV 2 Vaccines in Adults With Recurrent Genital Herpes Caused by HSV 2

Study Overview
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Brief Summary
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The primary objectives of the study are: To describe the safety profile of different investigational vaccine regimens against herpes simplex virus type 2 (HSV-2). To evaluate the efficacy of the investigational vaccine regimens with respect to: the frequency of herpes simplex virus (HSV) deoxyribonucleic acid (DNA) detection in the genital area (shedding rate) following a 2 dose vaccine schedule the proportion of participants free of HSV genital recurrence at 6 months after the 2-dose vaccine schedule The secondary objectives of the study are: To describe the impact of each of the investigational vaccine regimens in terms of total number of days with genital lesion up to 6 months after vaccination 2 and number of recurrences 60 days after the second vaccination compared with the placebo group To describe the efficacy of each of the investigational vaccine regimens with respect to the frequency of HSV DNA detection in the genital area (shedding rate) 60 days following the first vaccination visit plus 60 days following the second vaccination visit compared with the placebo group To describe the efficacy of each of the investigational vaccine regimens with respect to the frequency of HSV DNA detection in the genital area (shedding rate) 60 days following the first vaccination visit compared with the placebo group

Detailed Description
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Study duration per participant is approximately 16 months

Official Title
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Safety and Efficacy of 4 Investigational HSV 2 Vaccines Administered by Intramuscular Route in Adults With Recurrent Genital Herpes Caused by HSV 2

Conditions
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Genital Herpes

Intervention / Treatment
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* Biological: HSV 2 Formulation 1
* Biological: HSV 2 Formulation 2
* Biological: HSV 2 Formulation 3
* Biological: HSV 2 Formulation 4
* Biological: HSV 2 Formulation 5
* Biological: HSV 2 Formulation 6
* Biological: Sodium Chloride 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Aged 18 to 55 years on the day of inclusion Informed consent form has been signed and dated Able to attend all scheduled visits and to comply with all trial procedures In good general health with absence of significant health problems as determined by medical history, physical examination, and laboratory screening performed during screening visits HSV-2 seropositive confirmed by Western blot A history of established HSV-2 infection ≥ 1 year A history of at least 2 and no more than 9 reported HSV clinical recurrences in the prior 12 months, or, if currently on suppressive therapy, history of at least 2 and no more than 9 reported clinical recurrences in the 12 months prior to initiation suppressive therapy For Part A and Part B, the participant is willing to refrain from using suppressive antiviral therapy starting 5 days before the first vaccination visit and up to 6 months after the second vaccination visit; and for Part B, throughout the 3, 60-day swabbing periods, and up to 6 months after the second vaccination visit For Part A and Part B, the participant is willing to refrain from using antiviral therapy to treat recurrences starting 5 days before V01 and up to 6 months after the second vaccination visit; and for Part B, throughout the 3, 60-day swabbing periods (i.e., up to 60 days after the second vaccination visit) Exclusion criteria: For Part A, the participant is pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 6 months after the last vaccination. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, or surgically sterile. For Part B, the participant is pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence with her/his partner from at least 4 weeks before the enrollment visit until at least 6 months after the last vaccination. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, or surgically sterile. Participants whose female partners are pregnant at the time of enrollment or plan to become pregnant between study entry through 12 weeks (for Part A) and 6 months (for Part B) after the second vaccination visit. Participation at the time of study enrollment (or in the 4 weeks preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily Receipt of any vaccine in the 4 weeks preceding the first study vaccination or planned receipt of any vaccine in the 4 weeks before and/or following any trial vaccination except for influenza vaccination, which may be received at a gap of at least 2 weeks before or 2 weeks after any study vaccination Current alcohol abuse or drug addiction Positive serologic test or polymerase chain reaction for human immunodeficiency virus type 1 infection Positive hepatitis B surface antigen Positive antibody for hepatitis C virusribonucleic acid and positive hepatitis C test Severe active infection or serious HSV-2 related medical conditions on the day of enrollment that, in the opinion of the Investigator, would prevent study completion Active genital herpes determined by the presence of outbreaks (genital lesions) at the time of enrollment. A prospective subject should not be included in the trial until 24 hours after the outbreak has resolved (the lesions have completely disappeared) Hemoglobin, white blood cell count with differential, platelet count, renal function tests (serum creatinine, blood urea nitrogen), liver function tests, creatine phosphokinase and C-reactive protein screening laboratory results that fall into the range of values that are Grade 2 or greater as per the study toxicity grading scale for this study. Also the range of values that are Grade 1 and are deemed clinically significant in the opinion of the Investigator (Grade 1 values deemed not clinically significant may be enrolled at the Investigator's discretion) Previous vaccination against HSV infection with either the trial vaccine or another vaccine against HSV History of HSV infection of the eye (e.g., herpes simplex interstitial keratitis or uveitis) History of eczema herpeticum History of herpes-associated erythema multiforme History of lesions caused by HSV on either arm History of any autoimmune disorder Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months) Receipt of immune globulins, blood or blood-derived products in the past 3 months Thrombocytopenia or bleeding disorder, contraindicating IM vaccination based on Investigator's judgment Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances Known allergy or intolerance to nickel Known allergy or intolerance to acyclovir or valacyclovir Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study Chronic illness or other conditions that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion Moderate or severe acute illness/infection (according to the Investigator's judgment) on the day of vaccination or febrile illness (temperature ≥ 100.4 °F ([≥ 38 °C]). The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Group 1<br>HSV 2 formulation 1 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 1<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part A - Group 2<br>HSV 2 formulation 2 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 2<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part A - Group 3<br>HSV 2 Formulation 3 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part A - Group 4<br>HSV 2 Formulation 4 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0, then HSV 2 Formulation 3 administered with concomitantly with 0.9% sodium chloride in the opposite arm at Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 4<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part A - Group 5<br>HSV 2 Formulation 5 administered in one arm and Formulation 3 in the opposite arm, at Month 0 and Month 2. | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 5<br>* Route of administration: Intramuscular<br>|
| Placebo Comparator: Part A - Group 6<br>Sodium chloride 0.9% (in both arms) at Month 0 and Month 2 | Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 1<br>HSV 2 Formulation 1 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 1<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 2<br>HSV 2 Formulation 2 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 2<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 3<br>HSV 2 Formulation 3 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 4<br>HSV 2 Formulation 4 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0, then HSV 2 Formulation 3 administered with concomitantly with 0.9% sodium chloride in the opposite arm at Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 4<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 5<br>HSV 2 Formulation 5 administered in one arm and Formulation 3 in the opposite arm, at Month 0 and Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 5<br>* Route of administration: Intramuscular<br>|
| Placebo Comparator: Part B (Stage 1) - Group 6<br>Sodium Chloride 0.9% (in both arms) at Month 0 and Month 2 | Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 1) - Group 7<br>HSV 2 Formulation 6 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 6<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 1<br>HSV 2 Formulation 1 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 1<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 2<br>HSV 2 Formulation 2 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 2<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 3<br>HSV 2 Formulation 3 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 4<br>HSV 2 Formulation 4 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0, then HSV 2 Formulation 3 administered with concomitantly with 0.9% sodium chloride in the opposite arm at Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 4<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 5<br>HSV 2 Formulation 5 administered in one arm and Formulation 3 in the opposite arm, at Month 0 and Month 2 | Biological: HSV 2 Formulation 3<br>* Route of administration: Intramuscular<br>Biological: HSV 2 Formulation 5<br>* Route of administration: Intramuscular<br>|
| Placebo Comparator: Part B (Stage 2) - Group 6<br>Sodium Chloride 0.9% (in both arms) at Month 0 and Month 2 | Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|
| Experimental: Part B (Stage 2) - Group 7<br>HSV 2 Formulation 6 administered concomitantly with 0.9% sodium chloride in the opposite arm at Month 0 and Month 2 | Biological: HSV 2 Formulation 6<br>* Route of administration: Intramuscular<br>Biological: Sodium Chloride 0.9%<br>* Route of administration: Intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with immediate adverse events | Unsolicited systemic adverse events occurring immediately after vaccination | Within 4 hours (participants in Part A) or 30 minutes (participants in Part B) after vaccination | 
| Number of participants with solicited injection site and systemic reactions | Injection site reactions: injection site pain, erythema, and swelling. Systemic reactions: fever, headache, malaise, myalgia, arthralgia and chills | Within 7 days after vaccination | 
| Number of participants with unsolicited adverse events | An unsolicited adverse event is an event that does not fulfill the conditions prelisted in the Case Report Book in terms of diagnosis and/or onset post-vaccination | Within 30 days after vaccination | 
| Number of participants with medically-attended adverse events (MAAEs) | An MAAE is a new onset or a worsening of a condition that prompts the participant to seek unplanned medical advice at a physician's office or Emergency Department | From Day 0 to Month 14 | 
| Number of participants with adverse events of special interest (AESIs) | AESIs are collected throughout the study | From Day 0 to Month 14 | 
| Number of participants with serious adverse events (SAEs) | SAEs are collected throughout the study | From Screening to Month 14 | 
| Number of participants with out-of-range biological test results | Out-of-range biological test results area assessed at Days 8 and 30 after each vaccination and 15 days prior to second vaccination in Part A and Days 8 and 30 after each vaccination in Part B | From Day 8 to Day 30 | 
| Viral genital shedding rate | Relative change in HSV DNA detection frequency between swabs collected before the first vaccination and those collected after the second vaccination visit | 60 days before first vaccination and 60 days after the second vaccination | 
| Genital HSV recurrence | Proportion of participants free of genital HSV recurrence following the second vaccination | 6 months following the second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genital lesion rate | Total number of days that the participants who receive investigational product or placebo report genital herpes lesions following the second vaccination | 6 months after the second vaccination | 
| Genital HSV recurrence | Number of recurrences of genital HSV following the second vaccination in participants who receive investigational product or placebo. Recurrence is defined as the appearance of genital and perineal lesions (i.e., shingles, blisters, ulcers) in a previously asymptomatic participant. Regarding 2 separate episodes of recurrences, recurrence is defined as the presentation of a new lesion (or lesions) after a 1-day-minimum (≥ 24 hours) lesion-free period | 60 days following the second vaccination | 
| Viral genital shedding rate after the first and second vaccination | Relative change in HSV DNA detection frequency between swabs collected before the first vaccination visit and those collected 60 days after the first vaccination visit plus after the second vaccination visit in participants who receive investigational product or placebo | 60 days before first vaccination, and 60 days after the first vaccination, plus 60 days after the second vaccination | 
| Viral genital shedding rate after the first vaccination | Relative change in HSV DNA detection frequency between swabs collected before the first vaccination visit and those collected 60 days after the first vaccination visit in participants who receive investigational product or placebo | 60 days before and 60 days after the first vaccination | 
| Change in serum HSV 2-antibody levels | Change between pre-vaccination and post-first and second vaccinations | Before and 30 days after the first and second vaccinations and 6 months after the second vaccination | 
| Change in level of HSV 2-specific cellular immune responses | Change between pre-vaccination and post-first and second vaccinations | Before and 8 days after the first and second vaccination and 6 months after the second vaccination |