Safety Study of Herpes Simplex Vaccine in HSV Seronegative and Seropositive Females Between 10 and 17 Years Old

Herpes Simplex Clinical Trial

Official title:

A Study to Evaluate the Immunogenicity and Safety of GlaxoSmithKline Biologicals' Herpes Simplex Candidate Vaccine (gD2‑AS04) in Healthy HSV Seronegative and Seropositive Female Subjects Aged 10-17 Years.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00224484
• Other study ID #: 208141/040
• Status: Completed
• Phase: Phase 3
• Start date: April 7, 2004
• Est. completion date: July 24, 2007

Study information

• Verified date: January 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Main goal of this study is to compare the occurrence of serious adverse events (SAEs) between the herpes simplex (gD2-AS04) vaccine group and the Saline control group throughout the study period (up to month 12).

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Description:

Three groups of females (3000, 1500 and 1500 subjects, respectively) were injected 3 times (at months 0, 1 and 6) with the herpes simplex vaccine, the HavrixTM vaccine (control) and a Saline solution (placebo), respectively. Subjects were followed over 18 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5960
• Est. completion date: July 24, 2007
• Est. primary completion date: July 24, 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 10 Years to 17 Years

Eligibility

Inclusion Criteria:

• Subjects who the investigator believes that can and will comply with the requirements of the protocol should be enrolled in the study.

• Healthy female between, and including, 10 and 17 years of age at the time of the first vaccination.

• Written informed assent obtained from the subject and written informed consent obtained from a parent or legal guardian of the subject prior to enrolment. If the subject is above the legal age of consent in her country, written informed consent will only be obtained from the subject.

• Subjects must have a negative urine pregnancy test.

• Subjects of childbearing potential at the time of study entry must be abstinent or must be using an effective method of birth control for 30 days prior to vaccination and must agree to continue such precautions for two months after completion of the vaccination series. Subjects who reach menarche during the study and therefore are of childbearing potential must agree to follow the same precautions.

Exclusion Criteria:

• Use of any investigational or non-registered product (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.

• Pregnant or lactating female.

• Female planning to become pregnant or likely to become pregnant during the first eight months of the study (months 0-8).

• Any previous confirmed history of, or current clinical signs or symptoms of, oro labial herpes (cold sores), herpetic whitlow or genital herpes disease, such as swelling, papules, vesicles, pustules, ulcers, crusts, fissures, erythema, discharge, dysuria or pain, burning, itching, tingling in the ano-genital area.

• History of previous or planned vaccination against hepatitis A or a history of hepatitis A infection.

• Previous vaccination against herpes.

• History of herpetic keratitis.

• History of multiform erythema.

• Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after the first dose of study vaccine with the following exceptions: administration of routine meningococcal, hepatitis B, inactivated influenza, diphtheria/tetanus and/or diphtheria/tetanus-containing vaccine up to 8 days before and 30 days after the first dose of study vaccine.

• History of allergic disease or reactions likely to be exacerbated by any component of the study vaccines

• Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination

• History of a current acute or chronic autoimmune disease.

• History of any neurological disorders or seizures, with the exception of a single febrile seizure during childhood.

• Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality

• Acute disease at the time of enrolment

• Oral temperature >= 37.5°C (99.5°F) / axillary temperature >= 37.5°C (99.5°F) at the time of enrolment.

• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.

• 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.

Related Conditions & MeSH terms

• Herpes Simplex

Intervention

Biological:
• GSK208141
3 intramuscular doses
• Havrix (investigational formulation)
3 intramuscular doses
• Placebo
3 intramuscular doses

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Carlton	Victoria
Australia	GSK Investigational Site	Garran	Australian Capital Territory
Australia	GSK Investigational Site	Hobart	Tasmania
Australia	GSK Investigational Site	South Brisbane	Queensland
Australia	GSK Investigational Site	Westmead	New South Wales
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Wilrijk
Canada	GSK Investigational Site	Beauport	Quebec
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Sainte-Foy	Quebec
Canada	GSK Investigational Site	Surrey	British Columbia
Canada	GSK Investigational Site	Vancouver	British Columbia
Denmark	GSK Investigational Site	Aarhus N
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tartu
France	GSK Investigational Site	Château Renault
France	GSK Investigational Site	Derval
France	GSK Investigational Site	Evreux
France	GSK Investigational Site	Haute Goulaine
France	GSK Investigational Site	La Chapelle sur Erdre
France	GSK Investigational Site	Le Temple De Bretagne
France	GSK Investigational Site	Luynes
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Nort sur Erdre
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Pont de L'Arche
France	GSK Investigational Site	Saint Aubin des Chateaux
France	GSK Investigational Site	Saint Avertin
France	GSK Investigational Site	Saint Sebastien sur Loire
France	GSK Investigational Site	Tours
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Komotini
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Bordány
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Gyor
Hungary	GSK Investigational Site	Hódmezovásárhely
Hungary	GSK Investigational Site	Szeged
Hungary	GSK Investigational Site	Szeged
Hungary	GSK Investigational Site	Zsombó
Iceland	GSK Investigational Site	Gardabaer
Iceland	GSK Investigational Site	Kopavogur
Iceland	GSK Investigational Site	Reykjavik
Lithuania	GSK Investigational Site	Kaunas
Lithuania	GSK Investigational Site	Panevezys
Lithuania	GSK Investigational Site	Vilnius
Lithuania	GSK Investigational Site	Vilnius
Lithuania	GSK Investigational Site	Vilnius
Netherlands	GSK Investigational Site	Rotterdam
New Zealand	GSK Investigational Site	Christchurch
Norway	GSK Investigational Site	Bergen
Norway	GSK Investigational Site	Oslo
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucuresti
Spain	GSK Investigational Site	Blanes
Spain	GSK Investigational Site	Castellon
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Montgat/Barcelona
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Karlskrona
Sweden	GSK Investigational Site	Linköping
Sweden	GSK Investigational Site	Malmö
Sweden	GSK Investigational Site	Örebro
Sweden	GSK Investigational Site	Umeå
United Kingdom	GSK Investigational Site	Blackpool	Lancashire
United Kingdom	GSK Investigational Site	Blackpool	Lancashire
United Kingdom	GSK Investigational Site	Blackpool	Lancashire
United Kingdom	GSK Investigational Site	Bolton	Lancashire
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Coventry	Warwickshire
United Kingdom	GSK Investigational Site	Coventry	Warwickshire
United Kingdom	GSK Investigational Site	Coventry	West Midlands
United Kingdom	GSK Investigational Site	Doncaster
United Kingdom	GSK Investigational Site	Leeds
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Sheffield
United Kingdom	GSK Investigational Site	Southampton	Hampshire
United States	GSK Investigational Site	Akron	Ohio
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Arkansas City	Kansas
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Beaumont	Texas
United States	GSK Investigational Site	Beaver	Pennsylvania
United States	GSK Investigational Site	Beverly Hills	California
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Centennial	Colorado
United States	GSK Investigational Site	Chandler	Arizona
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Clearwater	Florida
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Cocoa Beach	Florida
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Fountain Valley	California
United States	GSK Investigational Site	Fridley	Minnesota
United States	GSK Investigational Site	Galveston	Texas
United States	GSK Investigational Site	Gray	Tennessee
United States	GSK Investigational Site	Hilliard	Ohio
United States	GSK Investigational Site	Kingsport	Tennessee
United States	GSK Investigational Site	Lake Jackson	Texas
United States	GSK Investigational Site	Littleton	Colorado
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Magna	Utah
United States	GSK Investigational Site	Marshfield	Wisconsin
United States	GSK Investigational Site	Melbourne	Florida
United States	GSK Investigational Site	Mesa	Arizona
United States	GSK Investigational Site	Mesa	Arizona
United States	GSK Investigational Site	Naples	Florida
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Norwich	Connecticut
United States	GSK Investigational Site	Pickerington	Ohio
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Raleigh	North Carolina
United States	GSK Investigational Site	Rolling Hills Estates	California
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Sandy	Utah
United States	GSK Investigational Site	Stony Brook	New York
United States	GSK Investigational Site	Sylva	North Carolina
United States	GSK Investigational Site	Tempe	Arizona
United States	GSK Investigational Site	Temple	Texas
United States	GSK Investigational Site	Thornton	Colorado
United States	GSK Investigational Site	Towson	Maryland
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	West Jordan	Utah
United States	GSK Investigational Site	West Jordan	Utah
United States	GSK Investigational Site	Westerville	Ohio
United States	GSK Investigational Site	Westminster	Colorado
United States	GSK Investigational Site	Wheat Ridge	Colorado
United States	GSK Investigational Site	Whitehouse Station	New Jersey
United States	GSK Investigational Site	Wichita	Kansas
United States	GSK Investigational Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  Estonia,  France,  Greece,  Hungary,  Iceland,  Lithuania,  Netherlands,  New Zealand,  Norway,  Romania,  Spain,  Sweden,  United Kingdom, 

References & Publications (3)

HSV-040 Study Group, Abu-Elyazeed RR, Heineman T, Dubin G, Fourneau M, Leroux-Roels I, Leroux-Roels G, Richardus JH, Ostergaard L, Diez-Domingo J, Poder A, Van Damme P, Romanowski B, Blatter M, Silfverdal SA, Berglund J, Josefsson A, Cunningham AL, Flodmark CE, Tragiannidis A, Dobson S, Olafsson J, Puig-Barbera J, Mendez M, Barton S, Bernstein D, Mares J, Ratner P. Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: results from a randomised, controlled, double-blind trial. Vaccine. 2013 Dec 9;31(51):6136-43. doi: 10.1016/j.vaccine.2013.06.081. Epub 2013 Jul 9. — View Citation

Tavares F, Cheuvart B, Heineman T, Arellano F, Dubin G. Meta-analysis of pregnancy outcomes in pooled randomized trials on a prophylactic adjuvanted glycoprotein D subunit herpes simplex virus vaccine. Vaccine. 2013 Mar 25;31(13):1759-64. doi: 10.1016/j.vaccine.2013.01.002. Epub 2013 Jan 10. — View Citation

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8. doi: 10.1016/j.vaccine.2008.09.049. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Serious Adverse Events (SAEs)	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.	From Month 0 to Month 12
Secondary	Number of Subjects With Any and Grade 3 Solicited Local Symptoms	Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any local symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activities. Grade 3 redness/swelling = greater than (>) 30mm diameter and persisting more than 24 hours.	Within 7 days (Days 0-6) after each and any vaccination
Secondary	Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms	Assessed solicited general symptoms were arthralgia, fatigue, headache, malaise, rash, temperature [defined as oral temperature equal to or above (=) 37.5 degrees Celsius (°C)] and urticaria. Any = occurrence of any general symptom regardless of intensity grade or relation to vaccination. Grade 3 arthralgia, fatigue, headache, malaise, rash = general symptom that prevented normal activity. Grade 3 temperature = greater than 39 degrees Celsius (°C). Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related = general symptom assessed by the investigator as causally related to the study vaccination.	Within 7 days (Days 0-6) after each and any vaccination
Secondary	Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs)	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 = event which prevented normal, everyday activities. In adults/ adolescents, such an AE would, for example, prevent attendance at work/ school and would necessitate the administration of corrective therapy. Related = event assessed by the investigator as causally related to study vaccination.	Within 30 days (Day 0-29) after any vaccination
Secondary	Number of Subjects With Unsolicited Adverse Events (AEs) With Medically Attended Visits	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. A medically attended visit is an event which prompted the subject to seek medical advice.	Within the 30 Day (Day 0-29) post-vaccination period
Secondary	Number of Subjects With New Onset Chronic Diseases (NOCD)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies.	During the active phase (up to Month 12)
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents ALT results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents CREA results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents Hct results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents PLA results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents RBC results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents UREA results.	At months 7 and 12
Secondary	Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed	Assessed parameters were alanine aminotransferase (ALT), creatinine (CREA), haematocrit (Hct), platelets (PLA), red blood cells (RBC), urea and white blood cells (WBC). A subset of subjects was formed for these analyses. Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range at other timepoints. This outcome presents WBC results.	At months 7 and 12
Secondary	Number of Subjects With Unsolicited Adverse Events (AEs) With Medically Attended Visits	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. A medically attended visit is an event which prompted the subject to seek medical advice.	Starting from Day 30 until the end of study (Month 18)
Secondary	Number of Subjects With Medically Significant Conditions (MSC)	MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. For outcomes covering the ESFU period, the Havrix Group and Saline Group were pooled.	During the Extended Safety Follow Up (ESFU) period (Month 12 to Month 18)
Secondary	Number of Subjects With New Onset Chronic Diseases (NOCD)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. For outcomes covering the ESFU period, the Havrix Group and Saline Group were pooled.	During the Extended Safety Follow Up (ESFU) period (Month 12 to Month 18)
Secondary	Number of Subjects With Serious Adverse Events (SAEs)	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. For outcomes covering the ESFU period, the Havrix Group and Saline Group were pooled.	Up to month 18 (during active phase and ESFU period)
Secondary	Anti-glycoprotein D (Anti-gD) Antibody Concentrations	Concentrations are presented as geometric mean concentrations (GMCs), expressed in ELISA units per millilitre (EU/mL). Analysis was based on an immunogenicity subset, stratified by initial serostatus: HSV seronegative (-)/ seropositive (+), this included gD2-AS04 vaccine recipients, as follows: HSV 1 and HSV 2 seronegative (HSV1-/2-) and HSV 1 seropositive and HSV 2 seronegative (HSV1+/2-)	At months 0, 7 and 12
Secondary	Anti-deacylated Monophosphoryl Lipid A (Anti-MPL) Antibody Concentrations	Concentrations are presented as geometric mean concentrations (GMCs), expressed in ELISA units per millilitre (EU/mL). The subset of subjects used for this analysis was 50% of the pre-defined subset of subjects that underwent assessment of biochemical and hematological parameters.	At months 0, 7 and 12

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