This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effect of Tenofovir on Genital Herpes Simplex Virus (HSV) Shedding (NCT01448616), a randomized phase 4 study. The primary outcome is HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01448616 |
| Phase | Phase 4 |
| Condition | Herpes Simplex Type II |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Triple |
| Enrollment | 73 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Washington |
| Results posted | Yes |
2. Clinical Question
Population
Women who were HSV-2 seropositive and HIV seronegative. The primary analysis population is described as all randomized participants who returned at least one swab in each study phase.
Intervention
Two tenofovir strategies are described: oral tenofovir disoproxil fumarate (TDF) tablets with placebo vaginal gel, and oral placebo tablets with tenofovir 1% vaginal gel. Study drugs were administered once daily.
Comparator
Double placebo: oral placebo tablets plus placebo vaginal gel. The trial also included a run-in phase with twice-daily genital swabbing.
Primary question
Within each treatment arm, how did the rate of genital HSV shedding during treatment compare with the rate during the same participants’ lead-in observation phase? The primary endpoint was analyzed separately by arm, rather than as a comparison between treatment arms.
The registry describes the study as randomized, triple-masked, and crossover. Its brief summary says the investigators hypothesized that tenofovir would reduce genital HSV shedding relative to placebo. That stated hypothesis is not itself a result. The primary outcome description specifies within-person changes in the percentage of swabs positive for HSV, comparing a treatment phase with a lead-in phase. It does not report the estimates needed to determine the direction or precision of those changes.
3. Trial Design
The registry record identifies this as a randomized, phase 4, triple-masked crossover trial, with an enrollment of 73. The listed condition is herpes simplex type II, and the intended participants are described as HSV-2 seropositive and HIV seronegative women. The study status is completed. The record lists a start date of 2012-02 and a primary completion date of 2015-06.
Participants first entered a run-in phase involving twice-daily swabbing. The intervention descriptions include oral TDF with placebo vaginal gel, oral placebo with vaginal tenofovir 1% gel, and double placebo. In each described study-drug phase, participants took or applied study drugs once daily and swabbed the genital region twice daily for 5 more weeks. The primary outcome description uses weeks 2-5 of treatment and compares them with 4 weeks of lead-in observation. It says the first week of treatment samples was excluded to allow for physiologic run-in of the treatment.
The crossover label indicates that the study is organized around participants receiving treatment conditions across phases, but the registry record does not report the treatment sequence, period-specific allocation details, or whether a washout was used. Those details should not be inferred from the design label. The record also does not state the masking roles, or explain whether participants, investigators, and outcome assessors were all masked, despite listing triple masking. The registry identifies the sponsor as the University of Washington.
The record describes an intent-to-treat population for the primary outcome, defined as randomized participants who returned at least one swab in each phase. The number included in that analysis is not reported in the registry record. Nor does the record report the number completing each treatment phase or the handling of participants who did not meet this swab-return condition.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Lead-In (Observational Phase)
| Stage | Observational Group | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal Tenofovir 1% Gel | Placebo Oral + Placebo Vaginal Gel |
|---|---|---|---|---|
| STARTED | 73 | 0 | 0 | 0 |
| COMPLETED | 64 | 0 | 0 | 0 |
| NOT COMPLETED | 9 | 0 | 0 | 0 |
Reasons for not completing this period:
| Reason | Observational Group | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal Tenofovir 1% Gel | Placebo Oral + Placebo Vaginal Gel |
|---|---|---|---|---|
| Collected no genital swabs | 3 | 0 | 0 | 0 |
| Collected <90% of required swabs | 6 | 0 | 0 | 0 |
Study Drug (Treatment Phase)
| Stage | Observational Group | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal Tenofovir 1% Gel | Placebo Oral + Placebo Vaginal Gel |
|---|---|---|---|---|
| STARTED | 0 | 24 | 27 | 13 |
| COMPLETED | 0 | 22 | 23 | 9 |
| NOT COMPLETED | 0 | 2 | 4 | 4 |
Reasons for not completing this period:
| Reason | Observational Group | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal Tenofovir 1% Gel | Placebo Oral + Placebo Vaginal Gel |
|---|---|---|---|---|
| Adverse Event | 0 | 1 | 1 | 0 |
| Never initiated study drug | 0 | 0 | 1 | 2 |
| Withdrawal by Subject | 0 | 1 | 2 | 2 |
Analysis population for the primary outcome, as defined in the registry: This is the intent-to-treat population (all randomized participants returning at least 1 swab in each phase of study)
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: Participants were randomized 2:2:1 to one of the 3 treatment arms after completing the lead-in phase
| Characteristic | Unit | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal TFV Gel | Oral Placebo + Vaginal Placebo Gel | Total |
|---|---|---|---|---|---|
| Participants analysed | 24 | 27 | 13 | 64 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 24 | 27 | 13 | 64 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 |
| Age, Continuous | years | 39.1 (20.8 to 50.8) | 36.7 (21.1 to 50.7) | 41.0 (19.2 to 48.7) | 37.3 (20.8 to 50.7) |
| Sex: Female, Male: Female | Participants | 24 | 27 | 13 | 64 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 24 | 27 | 13 | 64 |
6. Primary Endpoint
The registry lists the primary outcome as HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo, measured over Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | 95% Confidence Interval |
| Unit | percentage of swabs positive (%) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the HSV shedding rate, expressed as the percentage of swabs positive for HSV. Repeated swabs provide observations of genital shedding over time, while the percentage positive gives a summary of how frequently HSV was detected in the sampled periods. The stated primary comparison is within person: the rate during study-drug treatment is compared with the rate during the same participant’s lead-in observation phase.
The description specifies that weeks 2-5 of treatment are used and that the first week of treatment samples is excluded. The comparison period is 4 weeks of lead-in observation. The registry says this analysis is conducted separately for each treatment arm and not compared between arms. Thus, the endpoint as described does not directly estimate a randomized between-arm contrast of oral TDF, vaginal tenofovir gel, and double placebo.
The registry lists the endpoint as a number with a 95% confidence interval. A confidence interval communicates the uncertainty around an estimated quantity; its width reflects how precisely the data estimate that quantity under the analysis used. The actual primary estimates and their confidence intervals are not reported in the registry record. As a result, the direction, size, and precision of the observed within-person changes cannot be described from this record.
HSV shedding is the direct biological measure named in the primary question. The registry also lists secondary outcomes concerning within-person changes in log-copy numbers of HSV, genital lesion rate, and asymptomatic shedding. Those outcomes address different aspects of viral detection and symptoms; their results are not reported in the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record gives the primary endpoint definition and analysis approach, but it does not report the primary endpoint results. No arm-specific shedding-rate estimates, within-person changes, confidence intervals, or p-values are included in the record. Consequently, the posted information does not establish whether the measured shedding rate rose or fell during any treatment phase, nor how precisely any change was estimated.
This absence matters because the endpoint is not a single pooled comparison across the randomized arms. The registry says the treatment-versus-lead-in analysis was performed separately for each arm and not compared between arms. Even if arm-specific changes were available, they would answer within-arm questions. They would not, on their own, quantify the randomized contrast between active treatment and double placebo. A between-arm comparison is generally the more direct basis for separating a treatment-related change from changes that might also occur over time or during observation.
The crossover structure and within-person comparison can be useful because each participant contributes observations in more than one phase. In general, paired observations can account for stable differences between individuals. However, this design also makes treatment sequence, period effects, and possible carryover important to interpretation. The registry record does not report how these issues were handled or whether a washout was used. The primary outcome description does not provide enough detail to establish the analysis model or how repeated swabs within a participant were represented.
The registry reports an enrollment of 73, but the primary analysis population is defined by returning at least one swab in each phase. The number meeting that definition is not reported in the registry record. Enrollment therefore should not be treated as the analyzed sample size for the primary endpoint.
The record contains adverse-event counts, including zero affected participants in the serious-event field for each listed group. It also reports affected counts for other adverse events. These figures provide descriptive safety information, but they do not replace the missing efficacy estimates, and the registry does not provide event terms for serious events. Death counts are not reported in the registry record. Overall, the available record supports a description of the planned endpoint and design, not a conclusion about the magnitude or precision of the primary outcome.
9. Statistical Methods Explained
The primary outcome is a count-based summary of repeated swab results: the percentage of swabs that tested positive for HSV. In general, a proportion such as this can be analyzed with methods that account for the number of positive swabs relative to the number collected. The registry identifies the outcome parameter as a number and its dispersion as a 95% confidence interval, but does not report the statistical model, test, or estimation procedure used.
Why repeated swabs require care
Swabs collected from the same participant are not necessarily independent observations. In general, measurements from one person can be more alike than measurements from different people, because they share individual characteristics and study conditions. Treating every swab as fully independent can make uncertainty appear smaller than it is. Statistical methods for repeated measures account for the relationship among observations from the same participant. The registry record does not identify which, if any, such method was used.
In general, count data can show over-dispersion when observed variability is greater than a simple model expects. If a count-based outcome is over-dispersed, a model that assumes less variability may understate uncertainty and produce confidence intervals that are too narrow. This is a general statistical consideration, not a statement that over-dispersion was present or that a particular correction was used in this trial. The registry record does not report an over-dispersion assessment or a method for addressing it.
What the within-person comparison estimates
The stated primary analysis compares each participant’s treatment-phase shedding rate with that participant’s lead-in rate, separately for each arm. In general, a within-person comparison can reduce the influence of characteristics that remain stable over time. It does not automatically remove changes associated with time, study participation, or differences between periods. In a crossover study, treatment sequence and period effects may matter, and exposure in one period may affect observations in another. The record does not report the sequence structure, a washout, or the statistical handling of period or carryover effects.
The endpoint description specifies weeks 2-5 of treatment, excludes the first treatment week, and uses 4 weeks of lead-in observation. It says the first treatment week was excluded to allow for physiologic run-in. This defines the intended observation windows, but does not explain how missing or unusable swabs were handled within those windows, or how the percentage positive was estimated when the number of returned swabs differed across periods.
Reading the confidence interval
A confidence interval gives a range of values compatible with an estimate under the method used and its assumptions. A narrower interval indicates greater precision, while a wider interval indicates more uncertainty. It is not a guarantee that the true value lies within the interval, and its interpretation depends on the analysis being appropriate. The record specifies a 95% confidence interval as the dispersion measure, but does not include the actual interval limits or the calculation method. No assessment of statistical significance can be made from the endpoint definition alone.
The registry lists 12 analyses and 4 outcome measures. Multiple analyses raise a general multiplicity concern: when many hypotheses are examined, the chance of at least one apparently notable result can increase if each is interpreted without adjustment. The record does not report whether a multiplicity adjustment was planned or applied, nor does it identify a hierarchy of confirmatory and exploratory analyses. The number of listed analyses alone does not show that any particular adjustment was or was not appropriate.
What can be inferred from the record
The analysis population is described as all randomized participants who returned at least one swab in each phase. This is the registry’s stated intent-to-treat definition for the primary outcome. In general, an analysis that depends on observations from both phases can exclude randomized participants who lack observations in either phase. The record does not state how many participants met the definition, whether missing swabs were imputed, or how deviations from the intended analysis population were handled.
The sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such calculations are planning illustrations, not observed power, and the registry says this illustration is not the trial’s own design. It is not a substitute for a trial-specific sample-size justification. The trial’s own sample-size rationale is not reported in the registry record. No interim analyses or full statistical analysis plan are reported either.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 4 outcome measures and 12 analyses. The primary outcome is analyzed separately for each treatment arm, and three secondary outcomes are named: within-person changes in log-copy numbers of HSV, genital lesion rate, and asymptomatic shedding. Multiple outcomes and analyses can create multiplicity: when many statistical questions are assessed, some results may appear notable by chance even if no corresponding effect exists. This is a general issue, not evidence that the trial’s findings are false. Whether adjustment is needed depends on the planned questions and interpretation.
A multiplicity strategy, testing hierarchy, or adjustment procedure is not reported in the registry record. The record also does not report whether analyses were prespecified in a statistical analysis plan, or distinguish confirmatory from exploratory analyses. Without those details and without outcome estimates, the amount of evidence represented by any reported statistical tests cannot be assessed.
The primary analysis population is described as all randomized participants who returned at least one swab in each phase. That definition makes availability of swabs from both phases relevant to inclusion. The number meeting the definition is not reported in the registry record. Missing-swab rates, reasons for missingness, imputation, and sensitivity analyses for missing data are also not reported. The record does not specify how unequal numbers of swabs within a phase were handled.
These limitations do not establish that data were missing or that any analysis was biased. They mean only that the registry record does not describe those details. The stated analysis population and outcome windows should therefore be distinguished from an assumption that every randomized participant contributed complete data to every analysis.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Observational Group | 0 | 73 | 0.0% |
| Oral TDF + Vaginal Placebo Gel | 0 | 24 | 0.0% |
| Oral Placebo + Vaginal Tenofovir 1% Gel | 0 | 27 | 0.0% |
| Placebo Oral + Placebo Vaginal Gel | 0 | 13 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Observational Group | 11 of 73 |
| Oral TDF + Vaginal Placebo Gel | 12 of 24 |
| Oral Placebo + Vaginal Tenofovir 1% Gel | 11 of 27 |
| Placebo Oral + Placebo Vaginal Gel | 3 of 13 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Observational Group | Oral TDF + Vaginal Placebo Gel | Oral Placebo + Vaginal Tenofovir 1% Gel | Placebo Oral + Placebo Vaginal Gel |
|---|---|---|---|---|---|
| Upper Respiratory Viral Illness | Respiratory, thoracic and mediastinal disorders | 8 of 73 | 4 of 24 | 2 of 27 | 0 of 13 |
| Headache | Nervous system disorders | 0 of 73 | 3 of 24 | 4 of 27 | 0 of 13 |
| Vulvovaginitis | Reproductive system and breast disorders | 2 of 73 | 1 of 24 | 2 of 27 | 1 of 13 |
| Diarrhea | Gastrointestinal disorders | 0 of 73 | 5 of 24 | 0 of 27 | 0 of 13 |
| Vulvovaginal pruritis | Reproductive system and breast disorders | 1 of 73 | 1 of 24 | 1 of 27 | 2 of 13 |
| Nausea | Gastrointestinal disorders | 0 of 73 | 3 of 24 | 0 of 27 | 0 of 13 |
| Abdominal Pain | Gastrointestinal disorders | 0 of 73 | 3 of 24 | 0 of 27 | 0 of 13 |
| Vulvovaginal burning | Reproductive system and breast disorders | 0 of 73 | 0 of 24 | 2 of 27 | 0 of 13 |
| Candida Intertrigo | Infections and infestations | 0 of 73 | 0 of 24 | 0 of 27 | 1 of 13 |
| Skin Irritation | Skin and subcutaneous tissue disorders | 0 of 73 | 0 of 24 | 0 of 27 | 1 of 13 |
The registry reports serious adverse events as affected counts of 0 in each listed group. The corresponding numbers at risk are 73 for the observational group, 24 for oral TDF plus vaginal placebo gel, 27 for oral placebo plus vaginal tenofovir 1% gel, and 13 for double placebo. These counts are reported by group and should be read as registry entries, not as a comparison establishing that serious events cannot occur.
The record also lists affected counts for other adverse events: 11 in the observational group, 12 in the oral TDF plus vaginal placebo gel group, 11 in the oral placebo plus vaginal tenofovir 1% gel group, and 3 in the double-placebo group. The record does not provide event terms for serious events, and the serious-event term list is empty. It does not provide enough detail to characterize the nature, timing, severity, or relatedness of the other events.
Death counts are not reported in the registry record. The group counts should not be treated as a direct risk comparison between treatments without further information about exposure, observation time, and the study’s crossover structure. These descriptive safety figures do not answer the primary shedding question.
12. What the Result Does, and Does Not, Mean
The registry record establishes that the trial asked whether genital HSV shedding changed within participants during treatment relative to a lead-in observation phase. It describes three treatment conditions: oral TDF with vaginal placebo gel, oral placebo with vaginal tenofovir gel, and double placebo. The primary outcome is the percentage of swabs positive for HSV, measured in specified treatment and lead-in windows.
However, the primary estimates are not reported in the registry record. There is no reported arm-specific change, confidence interval, or p-value from which to judge the direction, magnitude, or precision of the observed shedding rates. The record therefore cannot support a claim that any regimen reduced or increased shedding, or that one regimen differed from another.
Even with arm-specific results, the registry’s stated primary analysis is within arm rather than between arms. A change from lead-in to treatment in one arm would not by itself isolate a treatment effect, because changes over time or study conditions may also contribute. A direct comparison between randomized treatment conditions would address a different question, and that comparison is not the stated primary analysis.
The record’s enrollment of 73 does not tell how many participants contributed to the primary analysis, which requires at least one swab in each phase. The analysis population size and missing-data handling are not reported. The crossover structure also raises general questions about treatment order and period effects that the record does not resolve.
These limits concern what can be concluded from the registry record, not what the full study may have found. No medical conclusion follows from an endpoint description or from the absence of results in this record. The available information is most useful for understanding the study question, measurement windows, and the need for outcome estimates and analysis details to assess the findings.
13. Why This Trial Matters Statistically
This trial illustrates a statistical distinction between measuring change within participants and estimating a contrast between randomized treatment groups. Repeated swabbing makes it possible to describe shedding over time, and a within-person analysis can use each participant’s own lead-in observations as a reference. But an observed change during treatment is not automatically the effect attributable to treatment. Time trends, period effects, and the crossover sequence can also matter.
The endpoint also demonstrates why repeated observations need an analysis that reflects their structure. Multiple swabs from one participant share a person and study period; they do not necessarily contribute independent information. Accounting for within-person dependence is important for estimating uncertainty. The registry describes the outcome and confidence-interval type, but does not report the model used to handle repeated measurements.
Defining the analysis population is equally important. The stated primary population requires participants to return at least one swab in each phase, so the enrollment figure alone does not establish the number analyzed. Missing-data rules and the number meeting the criterion would help readers assess how representative the analyzed participants were of everyone randomized.
Finally, the primary outcome is not reported in the registry record. This prevents interpretation of the observed effect and its precision, regardless of the trial’s design labels or stated hypothesis. Statistical transparency requires both a clearly described question and results detailed enough to connect the estimate to its uncertainty, population, and analysis.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The most direct limitation of the registry record is that it does not report the primary outcome estimates or their confidence intervals. The direction and precision of the arm-specific within-person changes are therefore unknown from this record. Results for the listed secondary outcomes are also not reported.
The design is identified as crossover, but the record does not state the treatment sequences, period structure, or whether a washout was used. It does not describe how period effects, sequence effects, or possible carryover were assessed. Those details are relevant when interpreting observations collected across treatment phases.
The primary analysis population requires at least one swab in each phase, but its size is not reported. The record also does not describe missing swabs, reasons for non-return, handling of incomplete sampling, or sensitivity analyses. It is therefore not possible to determine from the registry whether the analyzed participants differed from the full randomized group.
The primary endpoint is described as a percentage of positive swabs, but the statistical model and method for estimating uncertainty are not reported. The record does not specify how dependence among repeated swabs was handled, or how differing numbers of samples across participants or phases were accommodated. The multiplicity approach for the 12 listed analyses is also not reported.
Finally, the adverse-event record provides group-level counts without event terms for serious events, and death counts are not reported. The registry record does not contain enough detail to characterize event timing, duration, severity beyond the serious-event classification, or attribution. These are limitations of the information available in the record and do not establish that the full study lacked such analyses or documentation.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effect of Tenofovir on Genital Herpes Simplex Virus (HSV) Shedding — NCT01448616.
- Registry record last updated 2023-02-16; status last verified 2023-02.
- Results first posted 2016-01-12.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry record describes a completed, randomized, phase 4, triple-masked crossover trial sponsored by the University of Washington, with an enrollment of 73. Its stated population is HSV-2 seropositive, HIV seronegative women. The treatment conditions were oral TDF with placebo vaginal gel, oral placebo with vaginal tenofovir 1% gel, and double placebo.
The primary endpoint was the percentage of swabs positive for HSV. The analysis compared treatment-phase observations with lead-in observations within participants, using weeks 2-5 of treatment and 4 weeks of lead-in, and was conducted separately by treatment arm. The registry defines the primary analysis population as randomized participants returning at least one swab in each phase.
The record does not report primary outcome estimates, confidence intervals, or p-values. It also does not report the number in the primary analysis population, detailed missing-data procedures, the statistical model, or the multiplicity strategy. It lists serious adverse-event affected counts of 0 in each group; death counts are not reported in the registry record.