Infections, Herpesviridae
Conditions
Keywords
viral shedding, Recurrent, herpes, genital herpes
Brief summary
Eligible subjects will be randomized to receive VALTREX® tablet 1g or placebo once daily for 60 days in a two-way crossover study with a washout period of 7 days between treatment periods.
Interventions
DRUGValaciclovir
Valtrex 1g once daily
DRUGPlacebo
placebo
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
Yes
Inclusion criteria
* In overall general good health. * HSV-2 (Herpes Simplex Virus-2) seropositive at screening.
Exclusion criteria
* have active lesions consistent with genital herpes. * previous history of symptomatic genital herpes. * history of recurrent, undiagnosed symptoms consistent with genital herpes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Days of Subclinical Shedding as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for HSV-2 | Up to Day 60 of each treatment period (up to 160 days) | Percent of subclinical days with HSV-2 shedding was defined for each participant as the percent of subclinical days with PCR data for which HSV-2 shedding was detected by a positive PCR result, that is, the number of subclinical days with HSV-2 PCR shedding divided by total number of subclinical days with PCR data, multiplied by 100. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or subclinical (no genital lesions). Genital/anal-rectal swabs was collected daily during each entire 60-day treatment period of each period and the washout period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Days of Total HSV-2 Shedding | Up to Day 60 of each treatment period (up to 160 days) | The percent of days with total (clinical and subclinical) HSV-2 shedding was defined as the percent of all days with PCR data for which HSV-2 shedding was detected. Mean percent of days with total HSV-2 shedding was the statistic used to summarize this endpoint for each treatment group. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions). The total shedding rate was defined for each participant as the percentage of all days (clinical and subclinical) on treatment during which shedding was detected by PCR. Genital/anal-rectal swabs was collected daily during each entire 60-day treatment period of each period and the washout period. |
| Number of Participants With no Shedding | Up to Day 60 of each treatment period (up to 160 days) | The number 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. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions). |
| Mean Log HSV-2 DNA Copy Number Per Day on Days With Subclinical Shedding | Up to Day 60 of each treatment period (up to 160 days) | The subclinical shedding rate was defined for each participant as the total number of subclinical days on treatment during which shedding was detected by PCR. Average log HSV-2 DNA copy number per day on days with subclinical shedding was defined as the daily maximum HSV-2 DNA copy number was log transformed and averaged over all subclinical shedding days. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions). |
| Mean Log HSV-2 DNA Copy Number Per Day on Days With Total Shedding | Up to Day 60 of each treatment period (up to 160 days) | The total shedding rate was defined for each participant as the total number of all days (clinical and subclinical) on treatment during which shedding was detected by PCR. Average log HSV-2 DNA copy number per day on days with total shedding (clinical and subclinical) was defined as the daily maximum HSV-2 DNA copy number was log transformed and averaged over all shedding days. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions). |
| Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study | Up to Day 60 of each treatment period (up to 160 days) | Participants who have recognized clinical signs/symptoms of genital herpes infection during the study. Participants were educated on recognizing signs and symptoms of genital herpes infection at the screening/randomization visit. Genital examinations was conducted at the randomization and genital herpes outbreak visits. |
Countries
United States
Participant flow
Recruitment details
From March-2005 to January-2006, 73 participants from 13 centers in the United States were randomized into the study (36 in VALTREX™-Placebo, and 37 in Placebo-VALTEX treatment sequence). One participant in each treatment sequence did not receive study medication and intent-to-treat exposed (ITTE) population was comprised of 71 participants.
Pre-assignment details
Eligible male or female immunocompetent participants in general good health were enrolled. Additionally, participants must be Herpes Simplex Virus Type 2 (HSV-2) seropositive at screening. VALTREX (valacyclovir hydrochloride) is registered trademark of GlaxoSmithKline.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1: VALTREX 1 g Once Daily, Placebo Participants randomized to this sequence received VALTREX 1 g once daily for 60 days, to be taken as two 500 mg caplets in Period 1 followed by matching placebo for 60 days in Period 2 with 7 days of washout period between 2 periods. Participants were instructed to take caplets at approximately the same time of day each day, without regard to meals. If a dose was missed, the participants take the dose later that day provided they take it at least 2 hours before their next scheduled dose; otherwise the dose was omitted. | 35 |
| Sequence 2: Placebo, VALTREX 1 g Once Daily Participants randomized to this sequence received matching placebo for 60 days, to be taken as two 500 mg caplets in Period 1 followed by VALTREX 1 g once daily for 60 days in Period 2 with 7 days of washout period between 2 periods. Participants were instructed to take caplets at approximately the same time of day each day, without regard to meals. If a dose was missed, the participants take the dose later that day provided they take it at least 2 hours before their next scheduled dose; otherwise the dose was omitted. | 36 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1: Treatment Period 1 (60 Days) | Lost to Follow-up | 1 | 1 |
| Period 1: Treatment Period 1 (60 Days) | Other | 1 | 1 |
| Period 1: Treatment Period 1 (60 Days) | Protocol Violation | 0 | 1 |
| Period 1: Treatment Period 1 (60 Days) | Withdrawal by Subject | 5 | 0 |
| Period 1: Treatment Period 2 (60 Days) | Adverse Event | 1 | 0 |
| Period 1: Treatment Period 2 (60 Days) | Lost to Follow-up | 2 | 1 |
| Period 1: Treatment Period 2 (60 Days) | Other | 0 | 2 |
| Period 1: Treatment Period 2 (60 Days) | Protocol Violation | 0 | 1 |
| Period 1: Treatment Period 2 (60 Days) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Sequence 2: Placebo, VALTREX 1 g Once Daily | Total | Sequence 1: VALTREX 1 g Once Daily, Placebo |
|---|---|---|---|
| Age, Continuous | 35.8 Years STANDARD_DEVIATION 11.69 | 37.4 Years STANDARD_DEVIATION 12.35 | 39.1 Years STANDARD_DEVIATION 12.96 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 19 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 19 Participants | 47 Participants | 28 Participants |
| Sex: Female, Male Female | 29 Participants | 53 Participants | 24 Participants |
| Sex: Female, Male Male | 7 Participants | 18 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 63 |
| other Total, other adverse events | 29 / 65 | 42 / 63 |
| serious Total, serious adverse events | 0 / 65 | 1 / 63 |
Outcome results
Primary
Mean Percent Days of Subclinical Shedding as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for HSV-2
Percent of subclinical days with HSV-2 shedding was defined for each participant as the percent of subclinical days with PCR data for which HSV-2 shedding was detected by a positive PCR result, that is, the number of subclinical days with HSV-2 PCR shedding divided by total number of subclinical days with PCR data, multiplied by 100. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or subclinical (no genital lesions). Genital/anal-rectal swabs was collected daily during each entire 60-day treatment period of each period and the washout period.
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: The intent-to-treat crossover (ITTC) population was defined as consisting of all participants who received at least one dose of investigational product and had at least one PCR swabbing result in each treatment period. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g Once Daily | Mean Percent Days of Subclinical Shedding as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for HSV-2 | 1.5 Percentage of days | Standard Deviation 5.3 |
| Placebo | Mean Percent Days of Subclinical Shedding as Determined by Type-specific Polymerase Chain Reaction (PCR) Assay for HSV-2 | 5.1 Percentage of days | Standard Deviation 9 |
p-value: <0.001Nonparametric tests-Wilcoxon Rank Sum
Secondary
Mean Log HSV-2 DNA Copy Number Per Day on Days With Subclinical Shedding
The subclinical shedding rate was defined for each participant as the total number of subclinical days on treatment during which shedding was detected by PCR. Average log HSV-2 DNA copy number per day on days with subclinical shedding was defined as the daily maximum HSV-2 DNA copy number was log transformed and averaged over all subclinical shedding days. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions).
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: ITTC population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g Once Daily | Mean Log HSV-2 DNA Copy Number Per Day on Days With Subclinical Shedding | 4.5 DNA copies per day | Standard Deviation 0.9 |
| Placebo | Mean Log HSV-2 DNA Copy Number Per Day on Days With Subclinical Shedding | 4.6 DNA copies per day | Standard Deviation 0.4 |
p-value: 0.8Nonparametric tests-Wilcoxon Rank Sum
Secondary
Mean Log HSV-2 DNA Copy Number Per Day on Days With Total Shedding
The total shedding rate was defined for each participant as the total number of all days (clinical and subclinical) on treatment during which shedding was detected by PCR. Average log HSV-2 DNA copy number per day on days with total shedding (clinical and subclinical) was defined as the daily maximum HSV-2 DNA copy number was log transformed and averaged over all shedding days. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions).
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: ITTC population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g Once Daily | Mean Log HSV-2 DNA Copy Number Per Day on Days With Total Shedding | 4.5 DNA copies per day | Standard Deviation 0.9 |
| Placebo | Mean Log HSV-2 DNA Copy Number Per Day on Days With Total Shedding | 5.2 DNA copies per day | Standard Deviation 1.2 |
p-value: 0.229Nonparametric tests-Wilcoxon Rank Sum
Secondary
Mean Percent Days of Total HSV-2 Shedding
The percent of days with total (clinical and subclinical) HSV-2 shedding was defined as the percent of all days with PCR data for which HSV-2 shedding was detected. Mean percent of days with total HSV-2 shedding was the statistic used to summarize this endpoint for each treatment group. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions). The total shedding rate was defined for each participant as the percentage of all days (clinical and subclinical) on treatment during which shedding was detected by PCR. Genital/anal-rectal swabs was collected daily during each entire 60-day treatment period of each period and the washout period.
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: ITTC population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VALTREX 1 g Once Daily | Mean Percent Days of Total HSV-2 Shedding | 1.5 Percentage of days | Standard Deviation 5.2 |
| Placebo | Mean Percent Days of Total HSV-2 Shedding | 5.5 Percentage of days | Standard Deviation 9.2 |
p-value: <0.001Nonparametric tests-Wilcoxon Rank Sum
Secondary
Number of Participants With no Shedding
The number 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. During each 60-day treatment period and during washout, swabs were collected daily from the genital/anal-rectal area for HSV-2 detection by PCR. During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR. For each participant, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (presence of genital lesions) or 'subclinical (no genital lesions).
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: ITTC population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VALTREX 1 g Once Daily | Number of Participants With no Shedding | No Shedding | 47 Participants |
| VALTREX 1 g Once Daily | Number of Participants With no Shedding | Shedding | 9 Participants |
| Placebo | Number of Participants With no Shedding | No Shedding | 30 Participants |
| Placebo | Number of Participants With no Shedding | Shedding | 26 Participants |
p-value: <0.001Prescott's method
Secondary
Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study
Participants who have recognized clinical signs/symptoms of genital herpes infection during the study. Participants were educated on recognizing signs and symptoms of genital herpes infection at the screening/randomization visit. Genital examinations was conducted at the randomization and genital herpes outbreak visits.
Time frame: Up to Day 60 of each treatment period (up to 160 days)
Population: ITTC population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VALTREX 1 g Once Daily | Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study | No Signs/Symptoms | 88 Percentage of participants |
| VALTREX 1 g Once Daily | Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study | Signs/symptoms Present | 13 Percentage of participants |
| Placebo | Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study | No Signs/Symptoms | 77 Percentage of participants |
| Placebo | Percent Overall Study Population Who Have Recognized Clinical Signs/Symptoms of Genital Herpes Infection During the Study | Signs/symptoms Present | 23 Percentage of participants |
p-value: 0.0331Prescott's method