| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018150 |
| E.1.2 | Term | Genital herpes |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 | 10073931 |
| E.1.2 | Term | Genital herpes simplex |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084891 |
| E.1.2 | Term | Anal herpes |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054225 |
| E.1.2 | Term | Anogenital herpes |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018151 |
| E.1.2 | Term | Genital herpes, unspecified |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019937 |
| E.1.2 | Term | Herpes genital |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019938 |
| E.1.2 | Term | Herpes genitalis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019997 |
| E.1.2 | Term | Herpetic infection of penis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020003 |
| E.1.2 | Term | Herpetic ulceration of vulva |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020004 |
| E.1.2 | Term | Herpetic vulvovaginitis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 | 10065050 |
| E.1.2 | Term | Perianal herpes simplex |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
• To evaluate the reactogenicity and safety of the HSVTI.
• Only for PART II: To demonstrate the efficacy of the HSVTI in reducing the risk of having confirmed Recurrent Genital Herpes (RGH) episodes.
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the humoral immune response induced by the HSVTI
•To evaluate the cellular immune response induced by the HSVTI
•PART II: To compare the HSVTI to placebo in terms of incidence rate of RGH episodes
•PART II: To compare the HSVTI to placebo in terms of percentage of RGH-free participants at 6, 12, 18 and 24 months after the last dose of study intervention
•PART II: To compare the HSVTI to placebo in terms of severity of RGH episode associated symptoms during each RGH episode
•PART II: To compare the HSVTI to placebo in terms of duration of RGH episode-associated symptoms, as assessed by the participant
•PART II: To evaluate the lesion rate after administration of the last dose of the HSVTI
•PART II (shedding sub-cohort): To evaluate the effect of the HSVTI, about 6 weeks, 6, 12 and 24 months after the last dose of the HSVTI on HSV-2 shedding rate
•PART II (shedding sub-cohort): To evaluate the HSV shedding
•PART II: To evaluate the long-term safety of the HSVTI |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the Protocol.
• Written informed consent obtained from the participant prior to performance of any study-specific procedure.
• Women of non-childbearing potential can be enrolled in the study.
• Women of childbearing potential can be enrolled in the study, if the participant:
- Has practiced highly effective contraception for one month prior to study intervention administration, and,
- Has a negative pregnancy test result at the Screening visit and on the day of each study intervention administration, and,
- For PART I: Has agreed to continue highly effective contraception until the end of the study.
- For PART II: Has agreed to continue highly effective contraception until 3 months after last study intervention administration.
• Seronegative for human immunodeficiency virus (HIV), as determined by laboratory screening tests. Participants documented to be seropositive to HIV will not be eligible for study participation.
• Only for PART I: Healthy participants as established by medical history and physical examination, at the discretion of the investigator, before entering into the study.
• Only for PART I: Man or woman aged 18 to 40 years, included, at the time of the first study intervention administration.
• Only for PART I: Seronegative for HSV-2 as determined by Western blot performed at the Screening visit.
• Only for PART II: Participants with recurrent genital herpes and with no significant health problems as established by medical history and physical examination, at the discretion of the investigator, before entering the study.
- Diagnosis of genital herpes for at least one year before the Screening visit.
- History of self-reported or documented recurrent genital herpes frequency of at least 3 and no more than 9 reported clinical recurrences in the 12 months preceding the screening visit, or, if currently on suppressive therapy, prior to initiation of suppressive therapy.
• Only for PART II: Man or woman aged 18 to 60 years, included, at the time of the first study intervention administration.
• Only for PART II: Seropositive for HSV-2 as determined by Western blot performed at the Screening visit, or having experienced a genital herpes recurrence during the screening period tested positive for HSV-1 DNA or HSV-2 DNA by polymerase chain reaction (PCR).
• Only for PART II (shedding sub-cohort): Participants agreeing to collect 2 swabs per day from anogenital area for the full duration of the 5 swabbing periods planned in the study.
• Only for PART II (shedding sub-cohort) after baseline completion: Participants having collected at least 45 out of 56 anogenital swabs during the baseline period. |
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| E.4 | Principal exclusion criteria |
Medical Conditions
• Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, endocrine, or renal functional abnormality, as determined by physical examination or laboratory screening tests.
• Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study or that would interfere with the efficacy and immunogenicity assessments planned in this study.
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
• Hypersensitivity to latex.
• Recurrent history or uncontrolled neurological disorders or seizures.
• Haematological and/or biochemical parameters outside the normal laboratory ranges at the Screening visit, unless the laboratory abnormalities are considered not clinically significant by the investigator.
• Body mass index =<18 kg/m^2 or >=35 kg/m^2.
• Past or current Guillain-Barré syndrome.
• History of any form of ocular HSV infection, HSV-related erythema multiforme, or HSV-related neurological complications.
Prior/Concomitant Therapy
• Use of any investigational or non-registered product other than the study intervention during the period beginning as of the Screening visit, or planned use during the study period.
• Planned administration/administration of a vaccine not foreseen by the Protocol in the period starting 15 days before each dose and ending 15 days after each dose of study intervention administration.
• Administration or planned administration of long-acting immune-modifying drugs at any time during the study period.
• Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the first dose of study intervention or planned administration during the study period.
• Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first study intervention dose. For corticosteroids, this will mean prednisone equivalent >= 20 mg/day, or equivalent. Inhaled, intra articular and topical steroids are allowed.
• Prior receipt of another vaccine containing HSV antigens.
• Only for PART II: Planned use of suppressive anti-HSV therapy from the Screening visit until the end of the study.
• Only for PART II: Planned use of tenofovir therapy, or other medication known to affect HSV shedding or genital lesions from the Screening visit until the end of the study. Only for PART II: Planned use of topical antiviral medication in the anogenital region from the Screening visit until the end of the study.
• Only for PART II: Planned use of any episodic antiviral medications during the 5 swabbing periods (including the baseline period) (only for the shedding sub-cohort).
Prior/Concurrent Clinical Study Experience
• Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational intervention.
Other Exclusions
• Pregnant or lactating women.
• Woman planning to become pregnant or planning to discontinue contraceptive precautions in the period starting from the Screening visit up to 3 months post-last dose of study intervention. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1, 2. Percentage of participants reporting each solicited administration site event
3, 4. Percentage of participants reporting each solicited systemic event
5, 6. Percentage of participants reporting unsolicited adverse events (AEs)
7. Percentage of participants reporting medically attended events (MAEs)
8. Percentage of participants reporting any serious adverse events (SAEs)
9. Percentage of participants reporting any potential immune-mediated disease (pIMDs) (classified as newly diagnosed or exacerbation of pre-existing events)
10. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at pre-study intervantion administration (Day 1) in Part I of the study
11. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 8 in Part I of the study
12. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 29 in Part I of the study
13. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 36 in Part I of the study
14. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 64 in Part I of the study
15. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at pre-study intervantion administration (Day 1) in Part II of the study
16. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 8 in Part II of the study
17. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 29 in part II of the study
18. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 36 in Part II of the study
19. Percentage of participants reporting any haematological and biochemical laboratory abnormalities at Day 57 in Part II of the study
20. Time-to-first confirmed HSV-2 RGH episode in Part II of the study
21. Time-to-first confirmed RGH episodes of any HSV type in Part II of the study |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1, 3. Within 7 days after the first study intervention dose (administered at Day 1)
2, 4. Within 7 days after the second study intervention dose (administered at Day 29)
5. Within 28 days after the first study intervention dose (administered at Day 1)
6. Within 28 days after the second study intervention dose (administered at Day 29)
7, 8, 9. From Dose 1 (Day 1) up to 12 months after last study intervention administration (Day 394)
10, 15. At pre-study intervention administration (Day 1)
11, 16. At Day 8
12, 17. At Day 29
13, 18. At Day 36
14. At Day 64
19. At Day 57
20, 21. 14 days post-Dose 2 (Day 43) to Day 759 |
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| E.5.2 | Secondary end point(s) |
1. Number of confirmed RGH episodes of any HSV type in Part II of the study
2. Percentage of participants free from confirmed RGH episode of any HSV type in Part II of the study
3. Herpes Symptoms Checklist (HSC) total score during each confirmed RGH episode of any HSV type in Part II of the study
4. Number of days with RGH-associated symptoms during each confirmed RGH episode of any HSV type in Part II of the study
5. Number of days with confirmed genital herpes lesions of any HSV type in Part II of the study
6. HSV-2 shedding rate reduction from baseline to 6 weeks post-Dose 2 (Day 71) in Part II of the study
7. HSV-2 shedding rate reduction from baseline to 6 months post-Dose 2 (Day 209) in Part II of the study
8. HSV-2 shedding rate reduction from baseline to 12 months post-Dose 2 (Day 394) in Part II of the study
9. HSV-2 shedding rate reduction from baseline to 24 months post-Dose 2 (Day 759) in Part II of the study
10,11,12,13,14. Number of HSV DNA shedding episodes in Part II of the study
15,16,17,18,19. Duration of HSV DNA shedding episodes in Part II of the study
20. Anti-HSVTI antibody geometric mean concentrations (GMCs) in Part I of the study
21. Anti-HSVTI antibody geometric mean concentrations (GMCs) in Part II of the study
22. Percentage of seropositive participants for anti-HSVTI antibodies in Part I of the study
23. Percentage of seropositive participants for anti-HSVTI antibodies in Part II of the study
24. Geometric mean of HSVTI -specific Cluster of Differentiation (CD)4+ T-cells frequency expressing at least 2 activation markers and including at least 1 cytokine in Part I of the study
25. Geometric mean of HSVTI-specific CD8+ T-cells frequency expressing at least 2 activation markers and including at least 1 cytokine in Part I of the study
26. Geometric mean of HSVTI-specific CD4+ T-cells frequency expressing at least 2 activation markers and including at least 1 cytokine in Part II of the study
27. Geometric mean of HSVTI-specific CD8+ T-cells frequency expressing at least 2 activation markers and including at least 1 cytokine in Part II of the study
28. Percentage of participants with a fatal SAE, SAE related to study intervention and potential immune-mediated disease (pIMDs) related to study intervention in Part II of the study |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 3, 4, 5. 14 days post-Dose 2 (D 43) to D 759
2. At 6, 12, 18 and 24 months after the last dose of study intervention (D 29)
6. At 6 weeks post-Dose 2 (D 71) compared to baseline (D -28 to D -1)
7. At 6 months post-Dose 2 (D 209) compared to baseline (D -28 to D -1)
8. At 12 months post-Dose 2 (D 394) compared to baseline (D -28 to Day -1)
9. At 24 months post-Dose 2 (D 759) compared to baseline (D -28 to D -1)
10, 15. D -28 to D -1
11, 16. D 43 to D 70
12, 17. D 181 to D 208
13, 18. D 366 to D 393
14, 19. D 731 to D 758
20, 22, 24, 25, 27. At pre-study intervention administration (D 1), D 29, D 64, D 209 and D 394
21, 23, 26. At pre-study intervention administration (D 1), D 29, D 57, D 209,D 394, D 574 and D 759
28. From Dose 1 (D 1) up to study end(D 759) |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Reactogenicity
Immune response |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Data will be collected in an observer-blind manner. |
|
| 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 | 13 |
| 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 | 12 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Estonia |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The End of Study (EoS) is defined as the date of the last testing released of the human biological samples, related to primary and secondary endpoints for PART I and PART II. The EoS must be achieved no later than 8 months after Last Subject Last Visit (LSLV). |
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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 | 8 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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