This page separates trial registry information from statistical interpretation. The numerical trial data on this page are restricted to the ClinicalTrials.gov record for NCT01617096. ClinicalTrials.gov provides the official trial registry record; the registry record contains posted outcome measures but does not provide formal statistical analyses for the primary endpoints in the ClinicalTrials.gov record.
1. Trial at a Glance
ASPIRE was a randomized, double-blind, parallel phase 3 prevention trial evaluating a 25 mg dapivirine vaginal ring against a placebo ring in women with HIV infections as the registered condition. The trial enrolled 2629 participants and had prevention as its primary purpose.
| Feature | ASPIRE |
|---|---|
| Trial name | ASPIRE |
| Phase | Phase 3 |
| Condition | HIV Infections |
| Purpose | Prevention |
| Design | Randomized, double-blind, parallel |
| Enrollment | 2629 |
| Arms | 2 |
| Interventions | Dapivirine Vaginal Ring; Placebo Ring |
| Status | Completed |
| Start | 2012-07-24 |
| Primary completion | 2015-07-03 |
| Lead sponsor | International Partnership for Microbicides, Inc. |
| Sponsor type | Industry |
| ClinicalTrials.gov | NCT01617096 |
2. Clinical Question
The registered trial evaluates whether a dapivirine vaginal ring can provide HIV-1 prevention compared with a placebo ring. Statistically, the primary efficacy question is expressed through the proportion of women in each randomized arm who experience HIV-1 seroconversion after the prespecified number of endpoints has been observed.
Population
Women enrolled in a phase 3 prevention trial for which the registered condition is HIV Infections.
Intervention
A 25 mg dapivirine administered in a silicone elastomer vaginal matrix ring, inserted once every 4 weeks.
Comparator
Placebo Ring.
Primary question
What proportion of women in each randomized arm experience HIV-1 seroconversion, and how does safety compare between the arms?
3. Trial Design
Dapivirine Vaginal Ring
- Combination product
- 25 mg dapivirine
- Silicone elastomer vaginal matrix ring
- Inserted once every 4 weeks
Placebo Ring
- Combination product
- Placebo ring comparator
The parallel design is statistically important because each participant is assigned to one randomized intervention strategy rather than contributing observations under multiple randomized treatment conditions. Randomization provides the framework for comparing the two groups, while double masking is intended to reduce the potential for knowledge of assignment to influence trial conduct or assessment.
4. Trial Timeline
Trial start
The ASPIRE trial began on July 24, 2012.
Primary completion
The registered primary completion date was July 3, 2015.
Trial status
The ClinicalTrials.gov record identifies the trial as completed.
5. Primary Endpoints
| Endpoint | Registered definition | Time frame | Type |
|---|---|---|---|
| Efficacy | Efficacy as determined by the proportion of women in each arm with HIV-1 seroconversion after 120 endpoints are observed in the trial. | Minimum of 12 months and a maximum of 14 months per participant | Binary |
| Safety | The number of participants that experienced Grade 2, 3, 4 and serious adverse events over the investigational product used period. | Minimum of 12 months and a maximum of 14 months per participant | Binary |
HIV-1 seroconversion endpoint
The registered efficacy endpoint is defined by HIV-1 seroconversion. The registry states that seroconversion is measured using rapid and specialised laboratory testing according to a comprehensive HIV testing algorithm, with confirmation of HIV infection by Western Blot.
Safety endpoint
The registered safety endpoint counts participants experiencing Grade 2, Grade 3, Grade 4, and serious adverse events over the investigational product used period. The registry defines the DAIDS severity grades as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = potentially life-threatening, and Grade 5 = death.
6. Planned Analysis
The registry reports five outcome measures, including both registered primary endpoints, but no formal statistical comparison is reported in the ClinicalTrials.gov record. The appropriate interpretation is therefore different from a conventional results page: the registry establishes what was measured, but the ClinicalTrials.gov record does not establish a numerical comparative treatment effect for the primary efficacy endpoint.
How a binary efficacy endpoint would typically be analysed
The HIV-1 seroconversion endpoint is binary: each participant can be classified according to whether seroconversion occurred during the prespecified assessment period. A standard comparative analysis would summarize the proportion with seroconversion in each randomized arm and quantify the between-arm difference using an appropriate effect measure, such as a risk ratio or risk difference, together with a confidence interval and a hypothesis test.
The appropriate choice among binary-outcome methods depends on the prespecified statistical analysis plan, the number of observed events, the handling of follow-up and censoring, and the trial's error-control strategy. Those details are not provided in the ClinicalTrials.gov record and therefore are not assigned to ASPIRE here.
How the safety endpoint would typically be analysed
The safety endpoint is also binary at the participant level: whether a participant experienced an event meeting the registered Grade 2, 3, 4, or serious-adverse-event definition during the specified period. A typical analysis would display event counts and percentages by randomized arm and compare the arms using an appropriate binary-outcome method.
For a randomized two-arm trial, treatment-group risks can be compared using absolute and relative measures. The ClinicalTrials.gov record does not provide the event counts needed to calculate a primary efficacy effect estimate.
7. Statistical Methods Explained
Why is randomization important?
Randomization assigns participants to intervention groups according to a trial-generated allocation process rather than allowing treatment selection to determine assignment. In a parallel randomized trial, this creates the basis for comparing outcome rates between groups while reducing systematic differences attributable to treatment-selection decisions.
Why does double blinding matter statistically?
Double blinding is a design feature intended to limit the influence of treatment knowledge on trial behavior, assessment, reporting, or other aspects of study conduct. Its importance is particularly clear when outcomes or trial procedures could otherwise be influenced by expectations about which intervention a participant received.
Why is HIV-1 seroconversion a binary endpoint?
The registered efficacy endpoint is based on whether a woman experienced HIV-1 seroconversion during the specified follow-up period. That produces an event/no-event classification, making the endpoint fundamentally different from a continuous measurement such as a laboratory concentration or a change-from-baseline score.
Why does the registry specify 120 endpoints?
The efficacy endpoint is defined after 120 endpoints are observed in the trial. This makes the amount of observed information, rather than simply calendar time, central to the endpoint definition. In event-driven designs, the number of observed events can determine when a primary analysis becomes sufficiently informative for the prespecified evaluation.
What does a proportion of women with seroconversion tell us?
A proportion describes the fraction of participants in a defined analysis population who experience the binary event during the relevant observation period. Comparing proportions between randomized arms can quantify the absolute difference in event frequency. A relative measure such as a risk ratio answers a different question by expressing one risk relative to the other.
Why should safety and efficacy be analysed separately?
Efficacy and safety measure different dimensions of a randomized trial. The efficacy endpoint concerns HIV-1 seroconversion, whereas the registered safety endpoint concerns Grade 2, 3, 4, and serious adverse events. Combining them into a single numerical measure would obscure the distinct statistical questions each endpoint addresses.
8. Safety Results
The ClinicalTrials.gov record provides serious adverse-event counts by arm. They do not provide formal statistical analyses, confidence intervals, or p-values for the serious-adverse-event comparison.
| Safety measure | Dapivirine Vaginal Ring | Placebo Ring |
|---|---|---|
| Participants with serious adverse events | 116/1313 | 130/1316 |
The denominators posted on ClinicalTrials.gov for this safety measure are 1313 and 1316. The data therefore permit a direct display of the reported serious-adverse-event counts and denominators, but the registry-reported statistical-analysis field does not provide a formal between-arm estimate or hypothesis test.
9. Adherence and Measurement Limitations
The registry identifies important limitations concerning adherence measurement. Dapivirine residual levels in used rings and dapivirine plasma concentrations are described as two objective measures of adherence to dapivirine vaginal ring use. However, the registry states that these measures were imperfect because they could not distinguish different patterns of use during the month.
Self-reported adherence based on adherence questionnaires was also considered to have limitations. These issues matter statistically because adherence measurements are not simply descriptive variables: their measurement properties can affect how observed treatment exposure is understood and how efficacy findings are interpreted.
Objective measures
Residual levels in used rings and plasma concentrations provide objective adherence-related measurements but cannot distinguish different patterns of use during the month.
Self-report
Adherence questionnaires provide participant-reported information but were also identified by the registry as having limitations.
10. Statistical Interpretation of the Primary Efficacy Question
The trial was randomized, double-blind, parallel, and phase 3, with 2629 participants enrolled. The primary efficacy endpoint was the proportion of women in each arm with HIV-1 seroconversion after 120 endpoints were observed.
The ClinicalTrials.gov record contains no formal comparison for the primary efficacy endpoint. Therefore, no hazard ratio, risk ratio, risk difference, confidence interval, or p-value is reported here for HIV-1 seroconversion.
An endpoint definition establishes what was measured; it does not establish the magnitude or statistical uncertainty of the difference between treatment groups. A rigorous results interpretation requires both the observed event frequencies and the prespecified inferential analysis.
11. What a Complete Binary-Outcome Analysis Would Show
For a two-arm randomized prevention trial, a complete statistical presentation of the HIV-1 seroconversion endpoint would normally make several quantities visible rather than relying on a single p-value.
| Quantity | Statistical meaning |
|---|---|
| Number of seroconversions | The observed number of participants experiencing the primary event in each arm. |
| Number at risk / analysed | The denominator defining the population from which the event proportion is calculated. |
| Event proportion | The observed frequency of HIV-1 seroconversion in each arm. |
| Absolute risk difference | The arithmetic difference between the event proportions. |
| Relative effect | A ratio-based comparison of event probabilities, if that measure was prespecified. |
| Confidence interval | Quantifies uncertainty around the estimated treatment effect under the selected statistical framework. |
| Hypothesis test | Assesses compatibility of the observed data with a prespecified null hypothesis. |
12. How to Interpret a Future Effect Estimate
If a formal binary-outcome analysis were available, the effect estimate would need to be interpreted in conjunction with its confidence interval and the analysis population. For example, a risk ratio below 1 would indicate a lower observed event probability in the dapivirine-ring group relative to the placebo-ring group, whereas a risk difference below 0 would indicate a lower absolute event probability in that group.
This is a general definition, not an ASPIRE result. No numerical risk ratio is reported in the ClinicalTrials.gov record used for this page.
A confidence interval should be read together with the point estimate. A narrow interval indicates greater statistical precision under the specified model and sampling framework; a wider interval indicates greater uncertainty. The interval does not describe the range of individual treatment responses.
A p-value, if reported, would address the compatibility of the observed data with a prespecified null hypothesis. It would not measure the size of the treatment effect, clinical importance, or the probability that the treatment hypothesis is true.
13. Analysis Population and Follow-Up
The registered primary endpoints specify a minimum of 12 months and a maximum of 14 months per participant. This time frame should remain attached to the endpoint rather than being silently generalized to longer or shorter follow-up.
The ClinicalTrials.gov record does not define a separate intention-to-treat population, per-protocol population, modified intention-to-treat population, or safety analysis population beyond the denominators reported for serious adverse events. Consequently, this page does not assign an analysis population label that is not present in the ClinicalTrials.gov record.
14. Crossover, Factorial Design, and Other Design Features
| Design topic | What the ClinicalTrials.gov record shows |
|---|---|
| Crossover | Not reported in the ClinicalTrials.gov record. |
| Factorial design | Not reported; the design model is parallel. |
| Non-inferiority margin | Not reported in the ClinicalTrials.gov record. |
| Interim analysis | Not reported in the ClinicalTrials.gov record. |
| Missing-data / imputation method | Not reported in the ClinicalTrials.gov record. |
| Bayesian methods | Not reported in the ClinicalTrials.gov record. |
| Stratification factors | Not reported in the ClinicalTrials.gov record. |
| Multiplicity procedure | Not reported in the ClinicalTrials.gov record. |
These omissions are important because each feature can materially affect how a clinical-trial analysis should be interpreted. For example, a non-inferiority trial requires a prespecified margin and a corresponding inferential framework; an interim analysis requires consideration of repeated looks at the data; and missing-data procedures can influence binary endpoint estimates. None of those specific ASPIRE methods are reported here.
15. Why This Trial Matters Statistically
ASPIRE is a useful teaching case because it illustrates how the statistical questions in a prevention trial differ from those in a time-to-event oncology trial. The registered primary efficacy endpoint is a binary event proportion, while the safety endpoint is also participant-level and binary. The randomized and double-blind design provides the framework for a direct comparison between two intervention groups.
| Concept | How it appears in ASPIRE |
|---|---|
| Randomization | The allocation is randomized. |
| Blinding | The trial is double-blind. |
| Parallel design | The design model is parallel with 2 arms. |
| Binary efficacy endpoint | HIV-1 seroconversion is measured as an event/no-event outcome. |
| Binary safety endpoint | Grade 2, 3, 4, and serious adverse events are defined at the participant level. |
| Event-driven endpoint definition | The efficacy endpoint is evaluated after 120 endpoints are observed. |
| Fixed participant follow-up window | The registered primary endpoints specify a minimum of 12 months and maximum of 14 months per participant. |
| Adherence measurement | Objective and self-reported adherence measures are identified, along with their limitations. |
16. Important Limitations and Interpretation Issues
- No formal efficacy analysis in the ClinicalTrials.gov record: no formal statistical analyses were posted, so the magnitude and statistical uncertainty of the primary efficacy comparison cannot be reported from the ClinicalTrials.gov record.
- Posted outcomes are not the same as posted inferential statistics: the registry indicates that results are posted and that the primary endpoints have posted results, but the registry-reported analysis field contains no formal comparison.
- Adherence measurement limitations: dapivirine residual levels, plasma concentrations, and self-reported adherence each have stated limitations. The objective measures cannot distinguish different patterns of use during the month.
- Endpoint timing: the registered primary endpoints use a minimum of 12 months and maximum of 14 months per participant. Results should not be interpreted as if they necessarily represent a different follow-up period.
- Unknown analysis details: the ClinicalTrials.gov record does not identify the statistical method, analysis population, stratification, multiplicity procedure, missing-data method, or interim-analysis strategy.
- Safety scope: serious-adverse-event counts are available by arm, but the complete registered safety endpoint also includes Grade 2, 3, and 4 adverse events.
- Do not infer treatment effect from raw counts alone: the reported serious-adverse-event counts should be interpreted using their denominators and the prespecified analysis framework rather than as a standalone statistical test.
17. Serious Adverse Events: Statistical Perspective
The registry-reported serious-adverse-event data contain both a numerator and denominator for each arm. That permits the construction of an event proportion, but the ClinicalTrials.gov record does not provide the formal inferential comparison.
Dapivirine Vaginal Ring
116 participants with serious adverse events among 1313 participants at risk, as reported in the ClinicalTrials.gov record.
Placebo Ring
130 participants with serious adverse events among 1316 participants at risk, as reported in the ClinicalTrials.gov record.
The denominators are close in size, which is consistent with a two-arm randomized design with broadly comparable numbers represented in the reported safety measure. However, similarity of denominators does not itself establish comparability of safety outcomes, nor does it replace the prespecified statistical analysis.
18. Statistical Methods: A Practical Framework
Binary proportions
For an event such as HIV-1 seroconversion, the basic descriptive quantity is the observed event proportion. This is calculated by dividing the number of participants with the event by the relevant number of participants in the analysis population.
Here, x denotes the number of participants with the event and n denotes the relevant number of participants included in the denominator. This formula is presented as a general statistical definition, not as a calculated ASPIRE efficacy result.
Absolute versus relative effects
An absolute effect compares the event probabilities by subtraction, while a relative effect compares them by division. Both can be useful because a relative measure can emphasize proportional differences whereas an absolute measure describes the actual change in event probability.
Confidence intervals
Confidence intervals quantify uncertainty around an estimated effect under the selected statistical framework. For binary outcomes, the appropriate interval depends on the effect measure and method used. The registry-reported ASPIRE data do not specify such an analysis.
Randomization as the inferential foundation
Randomization supports causal comparison because treatment assignment is determined independently of participants' subsequent outcomes. The statistical analysis should preserve that randomized comparison through a prespecified analysis population and method.
19. Related Tutorials
Learn more about the methods used in this trial:
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: ASPIRE, NCT01617096.
- Linked publication: PubMed record: PMID 38099506.
- Linked publication: PubMed record: PMID 35344520.
- Linked publication: PubMed record: PMID 33892693.
- Linked publication: PubMed record: PMID 33713213.
- Linked publication: PubMed record: PMID 31306167.
Continue through the Clinical Biostats statistical library
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22. Record Summary
ASPIRE is a randomized, double-blind, parallel phase 3 prevention trial with 2629 enrolled participants and two intervention arms: a dapivirine vaginal ring and a placebo ring. Its two registered primary endpoints are binary outcomes: the proportion of women in each arm with HIV-1 seroconversion after 120 endpoints are observed, and the number of participants experiencing Grade 2, 3, 4, and serious adverse events over the investigational product used period.
The ClinicalTrials.gov record establishes the trial design, endpoint definitions, follow-up window, and serious-adverse-event counts. They do not provide formal statistical analyses for the primary endpoints. That distinction is central to a statistically responsible interpretation: an endpoint can be registered and have posted outcome data without the ClinicalTrials.gov record containing the effect estimate, confidence interval, or p-value needed for formal comparative inference.