Herpes Labialis
Conditions
Keywords
Recurrent Genital Herpes
Brief summary
Eligible subjects will be randomized to receive VALTREX 1g or placebo once daily for 60 days in a two-way crossover study with a washout period of 7 days in between.
Interventions
DRUGvalacyclovir
valacyclovir
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is in overall general good health. * If female, subject must be of: 1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial or post-menopausal or surgically sterile); or 2. Childbearing potential, but must have a negative pregnancy test at randomization, and must be compliant with one of the following: Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period of 1 week after study completion or premature discontinuation from the study (to account for elimination of the drug); Have a male partner who is confirmed to be sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; Use of contraceptive(s) with a documented failure rate of less than 1% per year, including but not limited to: implants of levonorgestrel, use of injectable progestogen, oral contraceptives (either combined or progestogen only), an intrauterine device (IUD) or spermicide plus a mechanical barrier (condom/diaphragm). * Subjects must be newly diagnosed with a first recognized episode of genital herpes as described in (a) or (b) below (See Appendix 3): a.HSV-2 seropositive at screen, with documented clinical signs and symptoms consistent with genital herpes at screen or within 4 months prior to randomization or b.HSV-2 seronegative at screen, AND HSV-2 culture positive or HSV-2 PCR positive with documented clinical signs and symptoms consistent with genital herpes at screen or within 4 months prior to randomization. * Subject must be willing and able to provide written informed consent and comply with the protocol.
Exclusion criteria
* Subject is known or suspected to be immunocompromised (e.g., subjects receiving immunosuppressive therapy or chemotherapy for malignancy, or are seropositive for HIV). * Subject received an investigational drug in the 30 days prior to the randomization visit. * Subject is receiving systemic antiviral or immunomodulatory treatments. * Subjects who have received systemic antiherpetic treatments (e.g., valacyclovir, acyclovir, ganciclovir, famciclovir) within 3 days of starting study drug, or immunomodulatory treatments in the 30 days before starting study drug. * Subject has clinically significantly impaired renal function as defined by creatinine clearance less than 50ml/min (calculated using the Cockcroft-Gault formula). * Subjects with a history or evidence of decompensated liver disease, or clinically significantly impaired hepatic function defined as an ALT (alanine transaminase) level \>3 times the normal upper limit. * Subject is known to be hypersensitive to valacyclovir, acyclovir, ganciclovir or famciclovir. * Subject has malabsorption or vomiting syndrome or other gastrointestinal dysfunction that may impair drug pharmacokinetics. * Female subject who is contemplating pregnancy within the duration of the study drug dosing period. * Female subject who is pregnant and/or nursing. * Subject with current alcohol or drug abuse. * Subjects who have received suppressive (daily) therapy for genital herpes prior to randomization. Suppressive therapy is defined as daily antiherpetic therapy of at least 4 weeks duration. * Subjects with a history of ocular HSV (herpes simplex virus) infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Days of Total Shedding (Clinical and Subclinical) as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for Herpes Simplex Virus Type 2 (HSV-2) | Up to 60 days in each treatment period (Up to 148 days) | Each participant's study day were classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab are positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Percent of days with HSV-2 shedding was defined for each participant as the percent of days with PCR data for which HSV-2 shedding was detected by a positive PCR result, i.e., the number of days with HSV-2 PCR shedding divided by total number of days with PCR data, multiplied by 100. Sum of the percent clinical and nonclinical shedding days was reported as total shedding. Mean percent of days with HSV-2 shedding was reported for each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Days Clinical Shedding (Presence of Genital Lesions) | Up to 60 days in each treatment period (Up to 148 days) | The percent of days with clinical HSV-2 shedding was defined as the percent of all days with PCR data for which clinical HSV-2 shedding was detected (shedding in the presence of a genital lesion). Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Mean percent of days with clinical HSV-2 shedding was reported for each treatment group. |
| Percentage of Participants With no Shedding | Up to 60 days in each treatment period (Up to 148 days) | The proportion of participants with no shedding was defined as the number of participants with no HSV-2 shedding detected by PCR divided by the total number of participants with PCR data in the Treatment Period. Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Mean percent of days with no shedding was reported for each treatment group. |
| Mean Percent Days Subclinical Shedding (no Genital Lesions Present) | Up to 60 days in each treatment period (Up to 148 days) | The percent of days with subclinical HSV-2 shedding was defined as the percent of all days with PCR data for which subclinical HSV-2 shedding was detected (shedding in the absence of a genital lesion). Mean percent of days with subclinical HSV-2 shedding was reported for each treatment group. Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. |
| Median Time to First Genital Herpes Recurrence (Days) | Up to Day 68 | Time to first genital herpes recurrence was evaluated using Kaplan-Meier estimates of investigator-confirmed genital herpes recurrences censoring the data from participants who prematurely discontinue the study at the time of discontinuation. |
| Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE) | Up to 148 days | 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. SAE include adverse events that result in death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. No SAEs were reported in this study. |
| Percentage of Participants With at Least One Genital Herpes Recurrence | Up to 60 days in each treatment period (Up to 148 days) | The proportion of participants with at least one genital herpes recurrence was defined as the number of participants with at least one investigator-confirmed genital herpes recurrence divided by the total number of participants with at least one clinic visit in the treatment period. |
Countries
United States
Participant flow
Recruitment details
Seventy participants were enrolled at 14 centers in the United States. The study was conducted between 20 February 2006 and 28 November 2006.
Pre-assignment details
Out of the 70 participants 35 participants were randomized to the VALTREX 1 g First then Placebo treatment sequence (VAL-PBO) and 35 participants were randomized to the Placebo first then VALTREX 1 g treatment sequence (PBO-VAL).
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Participants received VALTREX 1 g (2 x500 mg caplets) and matching placebo 2 caplets, orally, OD, for 60 days in a two-way crossover design either in sequence VAL-PBO or PBO-VAL. The two treatment periods were separated by washout period of seven days. | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (Day 1 to Day 60) | Adverse Event | 1 | 0 |
| Period 1 (Day 1 to Day 60) | Lost to Follow-up | 3 | 4 |
| Period 1 (Day 1 to Day 60) | Positive pregnancy Test | 2 | 2 |
| Period 1 (Day 1 to Day 60) | Withdrawal by Subject | 2 | 2 |
| Period 2 (Day 67 to Day 126 ) | Adverse Event | 1 | 0 |
| Period 2 (Day 67 to Day 126 ) | Lost to Follow-up | 1 | 0 |
| Period 2 (Day 67 to Day 126 ) | Participant determined HSV-2 negative | 0 | 1 |
| Period 2 (Day 67 to Day 126 ) | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 30.9 Year STANDARD_DEVIATION 9.64 |
| Race/Ethnicity, Customized African American/African Heritage | 28 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 2 Participants |
| Race/Ethnicity, Customized Mixed Race | 1 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 36 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 62 |
| other Total, other adverse events | 19 / 62 | 26 / 62 |
| serious Total, serious adverse events | 0 / 62 | 0 / 62 |
Outcome results
Primary
Mean Percent Days of Total Shedding (Clinical and Subclinical) as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for Herpes Simplex Virus Type 2 (HSV-2)
Each participant's study day were classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab are positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Percent of days with HSV-2 shedding was defined for each participant as the percent of days with PCR data for which HSV-2 shedding was detected by a positive PCR result, i.e., the number of days with HSV-2 PCR shedding divided by total number of days with PCR data, multiplied by 100. Sum of the percent clinical and nonclinical shedding days was reported as total shedding. Mean percent of days with HSV-2 shedding was reported for each treatment group.
Time frame: Up to 60 days in each treatment period (Up to 148 days)
Population: Intent to Treat Crossover population comprised of all participants in the Intent to Treat population who had at least one PCR swabbing result in each Treatment Period. Intent to Treat population comprised of all participants who received at least one dose of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g, OD | Mean Percent Days of Total Shedding (Clinical and Subclinical) as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for Herpes Simplex Virus Type 2 (HSV-2) | 2.9 Percent of days | Standard Deviation 5.6 |
| Placebo | Mean Percent Days of Total Shedding (Clinical and Subclinical) as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for Herpes Simplex Virus Type 2 (HSV-2) | 13.5 Percent of days | Standard Deviation 16.9 |
Secondary
Mean Percent Days Clinical Shedding (Presence of Genital Lesions)
The percent of days with clinical HSV-2 shedding was defined as the percent of all days with PCR data for which clinical HSV-2 shedding was detected (shedding in the presence of a genital lesion). Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Mean percent of days with clinical HSV-2 shedding was reported for each treatment group.
Time frame: Up to 60 days in each treatment period (Up to 148 days)
Population: Intent-to-Treat Crossover
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g, OD | Mean Percent Days Clinical Shedding (Presence of Genital Lesions) | 0.6 Percentage of Days | Standard Deviation 1.7 |
| Placebo | Mean Percent Days Clinical Shedding (Presence of Genital Lesions) | 2.4 Percentage of Days | Standard Deviation 4.4 |
p-value: 0.014Wilcoxon Rank Sum
Secondary
Mean Percent Days Subclinical Shedding (no Genital Lesions Present)
The percent of days with subclinical HSV-2 shedding was defined as the percent of all days with PCR data for which subclinical HSV-2 shedding was detected (shedding in the absence of a genital lesion). Mean percent of days with subclinical HSV-2 shedding was reported for each treatment group. Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits.
Time frame: Up to 60 days in each treatment period (Up to 148 days)
Population: Intent-to-Treat Crossover
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g, OD | Mean Percent Days Subclinical Shedding (no Genital Lesions Present) | 2.4 Percentage of days | Standard Deviation 4.8 |
| Placebo | Mean Percent Days Subclinical Shedding (no Genital Lesions Present) | 11 Percentage of days | Standard Deviation 15.1 |
p-value: <0.001Wilcoxon Rank Sum Test
Secondary
Median Time to First Genital Herpes Recurrence (Days)
Time to first genital herpes recurrence was evaluated using Kaplan-Meier estimates of investigator-confirmed genital herpes recurrences censoring the data from participants who prematurely discontinue the study at the time of discontinuation.
Time frame: Up to Day 68
Population: First Period Efficacy Population included participants in the Intent to Treat Exposed Population and was used for efficacy analyses restricted to the First Treatment Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VALTREX 1 g, OD | Median Time to First Genital Herpes Recurrence (Days) | NA Days |
| Placebo | Median Time to First Genital Herpes Recurrence (Days) | 61 Days |
Secondary
Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE)
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. SAE include adverse events that result in death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. No SAEs were reported in this study.
Time frame: Up to 148 days
Population: Intent to treat exposed population comprised of all participants who received at least one dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VALTREX 1 g, OD | Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE) | Any AE | 19 Participants |
| VALTREX 1 g, OD | Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE) | Any SAE | 0 Participants |
| Placebo | Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE) | Any AE | 26 Participants |
| Placebo | Number of Participants With Any Adverse Event (AE) and Serious Adverse Event (SAE) | Any SAE | 0 Participants |
Secondary
Percentage of Participants With at Least One Genital Herpes Recurrence
The proportion of participants with at least one genital herpes recurrence was defined as the number of participants with at least one investigator-confirmed genital herpes recurrence divided by the total number of participants with at least one clinic visit in the treatment period.
Time frame: Up to 60 days in each treatment period (Up to 148 days)
Population: Intent-to-Treat Crossover
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VALTREX 1 g, OD | Percentage of Participants With at Least One Genital Herpes Recurrence | 21 Percetage of participants |
| Placebo | Percentage of Participants With at Least One Genital Herpes Recurrence | 48 Percetage of participants |
Secondary
Percentage of Participants With no Shedding
The proportion of participants with no shedding was defined as the number of participants with no HSV-2 shedding detected by PCR divided by the total number of participants with PCR data in the Treatment Period. Each participant's study day was classified as either 'shedding' (positive HSV-2 result), 'no shedding' (negative HSV-2 result), or 'unknown' (swabbing not done or assay result not available) confirmed by PCR. If either the daily genital swab or a lesion swab was positive, the day was classified as 'shedding'. Study shedding day was classified as either 'clinical' (investigator-confirmed presence of genital lesions) or 'subclinical' (no genital lesions) by the investigator during recurrence visits. Mean percent of days with no shedding was reported for each treatment group.
Time frame: Up to 60 days in each treatment period (Up to 148 days)
Population: Intent-to-Treat Crossover
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VALTREX 1 g, OD | Percentage of Participants With no Shedding | 60 Percentage of participants |
| Placebo | Percentage of Participants With no Shedding | 29 Percentage of participants |