Herpes Genitalis
Conditions
Keywords
VALTREX®, valaciclovir, genital herpes, HSV-2, suppression
Brief summary
Genital herpes (GH) is a commonly occurring sexually transmitted disease caused by herpes simplex virus (HSV). There are two types of HSV, type 1 (HSV-1) and type 2 (HSV-2); both can cause GH, although the latter is much more likely to produce frequent recurrences of GH lesions. Evidence suggests that there are advantages to using suppressive vs. episodic treatment, which include increased intervals between the pain and discomfort of genital herpes recurrences. Therefore, this study will collect safety and efficacy data on suppressive therapy with valaciclovir in subjects newly diagnosed with HSV-2 genital herpes.
Interventions
DRUGValaciclovir
1g once daily
DRUGPlacebo
placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In overall general good health. * Females can enter and participate in this study if they are of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or if of childbearing potential, has a negative pregnancy test (urine) at screening and agrees to use GSK stipulated contraceptive methods. * Must be newly diagnosed with a first recognized episode of GH at the time of the Screening Visit or within 3 months prior to the Screening Visit.
Exclusion criteria
* Known or suspected to be immunocompromised (e.g., subjects receiving immunosuppressive therapy or chemotherapy for malignancy, or are seropositive for HIV). * Received an investigational drug in the 30 days prior to the study. * Receiving systemic antiviral or immunomodulatory treatments. * Must not have received systemic antiviral treatments (e.g., valaciclovir, Famvir (famciclovir), acyclovir, lysine) within 3 days of starting study drug or immunomodulatory treatments in the 30 days before starting study drug. * Clinically significant impaired renal function as defined by a creatinine clearance \<30 ml/min, calculated using the Cockcroft-Gault formula. * Clinically significant impaired hepatic function defined as an ALT (alanine transaminase) level \> 5 times the normal upper limit. * Subjects with active liver disease. * Known to be hypersensitive to acyclovir, famciclovir, ganciclovir or any component of valaciclovir formulations. * Known resistance to acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir or valganciclovir. * Subjects with malabsorption or vomiting syndrome or other gastrointestinal dysfunction that might impair drug pharmacokinetics. * Women contemplating pregnancy within the duration of the study drug dosing period. * Women who are pregnant and/or nursing mothers * Current history of alcohol or drug abuse. * Received suppressive (daily) therapy for genital herpes prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Time to First GH Recurrence | Day 168 | Diary cards were issued to the participants during randomization visit for recording GH recurrences. HSV recurrences since the last visit was assessed after review of the diary card and discussion with the participant. The percentage of participants with time to first GH recurrence was based on Kaplan-Meier estimates. Confidence intervals for differences in proportions was calculated using the standard error for the Kaplan-Meier estimate derived using Greenwood's formula. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of GH Recurrences Per Month Within the 6-month Study Period | Up to Day 168 | Mean number of GH recurrence reaching macular/papular stage per month was reported. Diary cards were issued to the participants during randomization visit for the recording GH recurrences. HSV recurrences since the last visit was assessed after review of the diary card and discussion with the participant. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Upto Day 168 | An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE was defined as any untoward medical occurrence that, at any dose results in death, was life-threatening, required hospitalization or prolongation of hospitalization, results in disability/incapacity, was a congenital anomaly/birth defect or medically significant. |
| Percentage of Participants With Time to First Oral Herpes Simplex Virus (HSV) Outbreak Within 6-months | Day 168 | Diary cards were issued to the participants during randomization visit for recording HSV outbreak within 6-momths. HSV outbreak was assessed after review of the diary card and discussion with the participant. The percentage of participants who had first oral HSV outbreak at 6-months was reported. |
| Number of Isolates With Resistance to Acyclovir (ACV) | Day 168 | Culture samples were tested for AVC-susceptibility by the analytical laboratory. Re-testing of the ACV resistant isolates was carried out to check if the half maximal inhibitory concentration (IC-50s) for all the ACV resistant isolates were within the expected errors of 2.0 microgram per milliliters (mcg/ml) cut-off for the plaque reduction assay. Those isolates that confirm to be resistant in repeat assays were considered as resistant to ACV. |
Countries
Argentina, Brazil, Canada, Chile, United States
Participant flow
Recruitment details
The study was conducted in 74 centers in the Unites States, Canada, Argentina, Brazil, and Chile.
Pre-assignment details
A total of 384 participants with first recognized episode of genital herpes (GH) were randomized in this study, out of which one participant did not take the study medication, hence, the Intent-to-treat (ITT) population consisted of 383 participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to this treatment arm received matching placebo to valacyclovir 1 g given as 2 x 500 mg caplets QD for 6 months (24 weeks). Participants with GH recurrences during the study temporarily discontinued their blinded treatment assignment and received open label valaciclovir 500 mg BID for 3 days after which the double-blind therapy was resumed. | 128 |
| Valaciclovir 1g QD Participants received double blinded treatment of oral dose of valacyclovir 1 g given as 2 x 500 mg caplets QD for 6 months (24 weeks). Participants with GH recurrences during the study temporarily discontinued their blinded treatment assignment and received open label valaciclovir 500mg BID for 3 days after which the double-blind therapy was resumed. | 255 |
| Total | 383 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Closed per sponsor | 0 | 1 |
| Overall Study | Lost to Follow-up | 11 | 17 |
| Overall Study | Lost to Follow up but returned per GSK | 0 | 1 |
| Overall Study | MOVING OUT OF STATE | 1 | 0 |
| Overall Study | Pregnancy | 3 | 3 |
| Overall Study | Protocol Violation | 8 | 23 |
| Overall Study | SPONSOR REQUEST | 0 | 1 |
| Overall Study | SPONSOR STOPPED STUDY | 2 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 17 |
Baseline characteristics
| Characteristic | Valaciclovir 1g QD | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 30.9 Years STANDARD_DEVIATION 10.48 | 31.3 Years STANDARD_DEVIATION 10.84 | 32.2 Years STANDARD_DEVIATION 11.52 |
| Race/Ethnicity, Customized Race American Hispanic | 34 Participants | 51 Participants | 17 Participants |
| Race/Ethnicity, Customized Race Arabic/North African | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black | 84 Participants | 123 Participants | 39 Participants |
| Race/Ethnicity, Customized Race East & South East Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Unknown | 8 Participants | 12 Participants | 4 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 125 Participants | 193 Participants | 68 Participants |
| Sex: Female, Male Female | 176 Participants | 268 Participants | 92 Participants |
| Sex: Female, Male Male | 79 Participants | 115 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 128 | 1 / 255 |
| other Total, other adverse events | 75 / 128 | 138 / 255 |
| serious Total, serious adverse events | 4 / 128 | 3 / 255 |
Outcome results
Primary
Percentage of Participants With Time to First GH Recurrence
Diary cards were issued to the participants during randomization visit for recording GH recurrences. HSV recurrences since the last visit was assessed after review of the diary card and discussion with the participant. The percentage of participants with time to first GH recurrence was based on Kaplan-Meier estimates. Confidence intervals for differences in proportions was calculated using the standard error for the Kaplan-Meier estimate derived using Greenwood's formula.
Time frame: Day 168
Population: ITT population was defined as all participants randomized to treatment who were administered at least one dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Time to First GH Recurrence | 43 Percentage of participants |
| Valaciclovir 1g QD | Percentage of Participants With Time to First GH Recurrence | 71 Percentage of participants |
p-value: <0.00195% CI: [16, 38.6]Log Rank
p-value: <0.00195% CI: [0.282, 0.57]Log Rank
Secondary
Mean Number of GH Recurrences Per Month Within the 6-month Study Period
Mean number of GH recurrence reaching macular/papular stage per month was reported. Diary cards were issued to the participants during randomization visit for the recording GH recurrences. HSV recurrences since the last visit was assessed after review of the diary card and discussion with the participant.
Time frame: Up to Day 168
Population: ITT population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of GH Recurrences Per Month Within the 6-month Study Period | 0.48 Number of recurrences | Standard Deviation 1.86 |
| Valaciclovir 1g QD | Mean Number of GH Recurrences Per Month Within the 6-month Study Period | 0.11 Number of recurrences | Standard Deviation 0.254 |
p-value: <0.001Wilcoxon rank sum test
Secondary
Number of Isolates With Resistance to Acyclovir (ACV)
Culture samples were tested for AVC-susceptibility by the analytical laboratory. Re-testing of the ACV resistant isolates was carried out to check if the half maximal inhibitory concentration (IC-50s) for all the ACV resistant isolates were within the expected errors of 2.0 microgram per milliliters (mcg/ml) cut-off for the plaque reduction assay. Those isolates that confirm to be resistant in repeat assays were considered as resistant to ACV.
Time frame: Day 168
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Isolates With Resistance to Acyclovir (ACV) | 0 Number of isolates |
| Valaciclovir 1g QD | Number of Isolates With Resistance to Acyclovir (ACV) | 0 Number of isolates |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE was defined as any untoward medical occurrence that, at any dose results in death, was life-threatening, required hospitalization or prolongation of hospitalization, results in disability/incapacity, was a congenital anomaly/birth defect or medically significant.
Time frame: Upto Day 168
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 98 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAEs | 4 Participants |
| Valaciclovir 1g QD | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 185 Participants |
| Valaciclovir 1g QD | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAEs | 3 Participants |
Secondary
Percentage of Participants With Time to First Oral Herpes Simplex Virus (HSV) Outbreak Within 6-months
Diary cards were issued to the participants during randomization visit for recording HSV outbreak within 6-momths. HSV outbreak was assessed after review of the diary card and discussion with the participant. The percentage of participants who had first oral HSV outbreak at 6-months was reported.
Time frame: Day 168
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Time to First Oral Herpes Simplex Virus (HSV) Outbreak Within 6-months | 11 Percentage of participants |
| Valaciclovir 1g QD | Percentage of Participants With Time to First Oral Herpes Simplex Virus (HSV) Outbreak Within 6-months | 14 Percentage of participants |