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 Letrozole for Lymphangioleiomyomatosis (NCT01353209), a randomized phase 2 study. The primary outcome is Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01353209 |
| Phase | Phase 2 |
| Condition | Lymphangioleiomyomatosis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 17 |
| Arms in the primary outcome | 2 |
| Lead sponsor | University of Cincinnati |
| Results posted | Yes |
2. Clinical Question
Population
The clinical condition was lymphangioleiomyomatosis (LAM). The study hypothesis concerned postmenopausal women with LAM, but the detailed eligibility criteria and the characteristics of enrolled participants are not reported in the registry record. The registry lists enrollment of 17 participants.
Intervention
Participants assigned to letrozole took one 2.5 mg tablet daily for one year. The stated hypothesis was that estrogen suppression by an aromatase inhibitor would prevent or delay lung disease progression and reduce the rate of decline in forced expiratory volume in 1 second (FEV1).
Comparator
The comparison group received placebo, one tablet daily for one year. The record describes randomized allocation and a parallel-group design. The specific people masked under the triple-masking designation are not reported in the registry record.
Primary question
The primary outcome was the rate of change in FEV1, measured in milliliters per month over 12 months. The statistical question was whether the outcome differed between participants assigned to letrozole and those assigned to placebo. The registry reports arm-specific medians and a sponsor-reported mixed-model analysis, but does not report a numerical between-group estimate or its confidence interval.
The registry record frames the study as a test of a biological and clinical hypothesis, not as evidence that can by itself settle whether letrozole changes the course of LAM. Its posted result needs to be read in light of the small enrollment, the available outcome counts, and the limited detail about the analysis and participants.
3. Trial Design
This was a randomized, triple-masked, parallel-group phase 2 trial sponsored by the University of Cincinnati. The registry lists 17 participants enrolled and the trial status as completed. The recorded start was 2011-05 and primary completion was 2014-09. Those dates describe the registry record; they do not provide further detail about participant follow-up or the timing of individual assessments.
Participants were assigned to letrozole or placebo. The letrozole arm description specifies one 2.5 mg tablet daily for one year; the placebo arm description specifies one tablet daily for one year. The primary outcome timeframe was 12 months. The record does not define which participants were masked by the triple-masking designation, nor does it report further details about randomization procedures, allocation concealment, or treatment adherence.
The primary outcome was the rate of change in FEV1 in milliliters per month. The posted arm-level results include 8 participants in the letrozole group and 7 in the placebo group. Those outcome counts are not the same as the recorded enrollment total. Why the outcome counts differ from enrollment, and how participants without a posted outcome were handled, are not reported in the registry record.
Three secondary outcomes are listed: post-bronchodilator FVC, St George Respiratory Questionnaire, and serum VEGF-D. The record lists 4 outcome measures and 5 analyses, but does not explain how the listed outcomes and analyses correspond. Details about eligibility, baseline characteristics, follow-up completeness, protocol deviations, and the analysis population are not reported in the registry record. These omissions limit assessment of how representative the enrolled group was and how closely the reported analyses followed the planned trial conduct.
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.
Before assignment: Patients were eligible for inclusion in the study if they were postmenopausal women with a definite diagnosis of pulmonary LAM and abnormal pulmonary function. Patients on sirolimus were required to wait three months before beginning this trial.
Overall Study
| Stage | Letrozole | Placebo |
|---|---|---|
| STARTED | 9 | 8 |
| COMPLETED | 8 | 7 |
| NOT COMPLETED | 1 | 1 |
Reasons for not completing this period:
| Reason | Letrozole | Placebo |
|---|---|---|
| Adverse Event | 1 | 1 |
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.
| Characteristic | Unit | Letrozole | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 9 | 8 | 17 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 8 | 7 | 15 |
| Age, Categorical: >=65 years | Participants | 1 | 1 | 2 |
| Age, Continuous | years | 57 (48 to 71) | 59 (44 to 68) | 58 (44 to 71) |
| Sex: Female, Male: Female | Participants | 9 | 8 | 17 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 2 | 2 | 4 |
| Race (NIH/OMB): White | Participants | 7 | 6 | 13 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 9 | 8 | 17 |
| LAM subtyped: Sporadic LAM | participants | 6 | 8 | 14 |
| LAM subtyped: TSC LAM | participants | 3 | 0 | 3 |
| Sirolimus status: On sirolimus | Participants | 5 | 5 | 10 |
| Sirolimus status: Not on sirolimus | Participants | 4 | 3 | 7 |
6. Primary Endpoint
The registry lists the primary outcome as Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month, measured over 12 months.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | milliliters per month |
| Endpoint classification | Time-to-Event Analysis |
FEV1 is the volume of air forcibly exhaled in the first second of a forced expiration. The registry describes it as a physiological measure of lung function, notes that values vary between individuals, and states that higher FEV1 scores indicate better lung function. The primary endpoint was not simply an FEV1 measurement at one visit: it was the rate of change in FEV1, expressed in milliliters per month, over 12 months.
Rates of change are used to describe how a measurement evolves over time rather than focusing on a single value. For a lung-function measure, that can make the outcome relevant to a hypothesis about progression or decline. However, the posted arm results are medians for the rate of change, not a complete description of every participant’s trajectory. The registry does not report the measurement schedule, the model’s time structure, or details about how FEV1 observations were incorporated into the rate estimates.
The registry reports a median of 1.04 milliliters per month for letrozole, with a 95% confidence interval from 0.56 to 2.02. For placebo, it reports a median of 1.66 milliliters per month, with a 95% confidence interval from 0.77 to 2.63. These are arm-specific summaries. They do not, by themselves, quantify the uncertainty in the difference between treatment groups. The primary outcome’s clinical interpretation also depends on the direction and meaning of the rate estimates, which cannot be fully assessed without additional information about the underlying measurements and analysis.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry reports a median rate of change in FEV1 of 1.04 milliliters per month in the letrozole arm, with a 95% confidence interval from 0.56 to 2.02. The placebo arm median is 1.66 milliliters per month, with a 95% confidence interval from 0.77 to 2.63. The posted counts for these summaries are 8 participants for letrozole and 7 for placebo. The interval estimates express uncertainty around each arm’s reported median; they are not confidence intervals for a treatment contrast.
The sponsor reports a mixed models analysis with p = 0.4. This is the registry’s reported inferential result for the comparison. The record does not provide a numerical model-based treatment effect or a confidence interval for that effect, so the size and precision of the estimated between-group contrast cannot be described from the posted result. The p-value alone does not show the range of treatment effects compatible with the data and should not be read as a measure of the probability that the null hypothesis is true.
A result that does not meet a conventional threshold for statistical significance is not proof that the treatments are equivalent, nor does it establish that there is no difference. Conversely, arm medians that are not identical do not establish a treatment effect. The relevant comparison is the between-group estimate, interpreted with its uncertainty and the analysis plan. The registry does not post the estimate or its interval, and the available record therefore supports a limited interpretation: the sponsor’s mixed-model analysis reported p = 0.4, while the arm-level summaries show the reported medians and their separate intervals.
The registry describes enrollment of 17 participants, while the primary outcome summaries include 8 in the letrozole arm and 7 in the placebo arm. The reason for this difference is not reported in the registry record. With small outcome groups, estimates can be sensitive to the observations included, and uncertainty can be substantial. The arm-specific confidence intervals provide some information about that uncertainty, but they cannot replace an interval for the direct treatment comparison.
The endpoint is a rate of change in FEV1 over 12 months, but the posted information does not include individual trajectories, baseline values, or the details required to judge model assumptions. It also does not report estimates for the listed secondary outcomes in the registry record for this interpretation. Consequently, the result should be read as a limited report of one trial’s primary comparison, rather than as a complete account of all outcome evidence or a definitive statement about the effect of treatment.
9. Statistical Methods Explained
The registry identifies the primary outcome as a median rate of change in FEV1 and describes the sponsor’s comparison as a mixed models analysis. These elements answer different statistical questions. The arm-specific medians summarize the central value of the reported rate in each group. The mixed model is the sponsor’s stated method for comparing groups. The record does not report the model specification, the treatment-effect estimate, or a confidence interval for that comparison.
What an arm-specific median describes
A median is the midpoint of an ordered set of observations: half of the observations lie at or below it and half at or above it, allowing for ties. As a general statistical concept, the median is less influenced by very high or very low observations than the arithmetic mean. That can be useful when a distribution is skewed or contains extreme values. A median does not describe the spread of all observations on its own, which is why an uncertainty interval is also relevant.
The registry reports the letrozole median as 1.04 milliliters per month, with a 95% confidence interval from 0.56 to 2.02, and the placebo median as 1.66 milliliters per month, with a 95% confidence interval from 0.77 to 2.63. These intervals are reported for the arm-level medians. They do not directly give the uncertainty around a difference between the arms. Comparing two separate intervals by eye is not a substitute for estimating the contrast and its uncertainty using the appropriate analysis.
What a confidence interval means
In general, a confidence interval is a range of values generated by a statistical procedure to represent uncertainty in an estimate. A 95% confidence interval does not mean that there is a 95% probability that a particular fixed parameter lies inside the interval. Rather, under the assumptions of the procedure, intervals produced in repeated applications would cover the parameter at the stated rate. The interpretation depends on the method and assumptions used to calculate the interval.
For this trial, the posted arm intervals describe uncertainty around the medians as reported. The registry does not give enough detail to assess how those intervals were calculated. No confidence interval for the sponsor’s between-group result is reported. Without that interval and the estimate it accompanies, readers cannot judge the range of comparative effects that remain compatible with the fitted analysis.
What a mixed model generally does
As a general concept, mixed models can represent both systematic effects, such as group assignment or time, and variation among participants or other units. They are commonly useful when observations are related, such as repeated measurements from the same participant. The exact meaning of “Mixed Models Analysis” depends on the model’s outcome distribution, fixed and random effects, covariance assumptions, and handling of incomplete observations. Those specifications are not reported in the registry record, so the label alone does not establish which model was fitted or whether its assumptions were appropriate.
The primary outcome is a rate of change in FEV1, but the record does not explain whether the model estimated that rate directly from repeated measurements or used another construction. It also does not report model diagnostics or sensitivity analyses. These details matter because an analysis can produce an estimate and p-value only under particular assumptions about the data and their dependence.
How to read the reported p-value
As a general statistical concept, a p-value describes how compatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor does it express the probability that a result will replicate. A p-value also does not indicate the magnitude or clinical importance of an effect. For this trial, the registry reports p = 0.4 for the sponsor’s mixed-model comparison. The record does not include enough detail to reconstruct the test or identify whether its p-value was adjusted for any other analyses.
Statistical significance and estimation are distinct. A small p-value can coexist with an imprecise estimate, and a larger p-value can arise when data are too limited to distinguish among a range of possible effects. A numerical treatment contrast and its confidence interval would support a more informative assessment of direction, magnitude, and precision than the p-value alone.
Why over-dispersion can matter in general
Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. If a model understates variability, uncertainty estimates may be too narrow and inferential results may be misleading. If a model accounts for extra variability appropriately, its uncertainty estimates can better reflect the data. The registry does not report whether over-dispersion was relevant to this outcome or how it was assessed. The endpoint is a continuous physiological rate, so no particular over-dispersion issue should be inferred from the posted information.
The trial record gives arm-level medians and a sponsor-reported mixed-model p-value, but does not provide the model details or comparative estimate needed to independently evaluate the analysis. A recalculated two-arm comparison is not available for this median-form endpoint because the required values are missing or not estimable. The reported sponsor analysis is therefore the only posted inferential comparison identified for the primary outcome.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Mixed Models Analysis | not reported | 0.400 |
The registry’s sponsor-reported comparison is a Mixed Models Analysis with p = 0.4. It is the only posted inferential comparison for the primary outcome. The record does not include the model-based treatment-effect estimate or its confidence interval, so the comparative magnitude and precision cannot be stated from that analysis as posted.
A simple unadjusted recalculation is not available for this median-form endpoint: the necessary values for a two-arm comparison are missing or not estimable. The arm-level medians and their confidence intervals cannot be used to create a valid treatment contrast by subtracting one summary from the other. Nor can separate arm intervals be treated as an interval for the contrast. Accordingly, there is no independent recalculated result to compare numerically with the sponsor’s analysis.
The p-value should be interpreted with the limits of the record in mind. The model specification, assumptions, analysis population, and handling of missing observations are not reported in the registry record. The sponsor’s result can be described as the reported mixed-model test, but it does not supply the effect estimate or interval needed to assess the range of plausible comparative effects. The reported p = 0.4 neither establishes equivalence nor proves that the groups had the same outcome.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists 4 outcome measures and 5 analyses. It names the primary endpoint as the rate of change in FEV1 and lists 3 secondary outcomes: post-bronchodilator FVC, St George Respiratory Questionnaire, and serum VEGF-D. The relationship between the listed outcome measures and analyses is not explained in the registry record. The record does not describe a multiplicity strategy, such as a hierarchy of tests or an adjustment for testing several outcomes. It is therefore not possible to tell whether the primary comparison was treated as confirmatory in a prespecified testing sequence or how the secondary analyses were intended to be interpreted.
Multiplicity matters in general because conducting several statistical tests can increase the chance of obtaining at least one apparently unusual result even when there is no corresponding effect. This does not make secondary outcomes uninformative; it means their interpretation depends on whether testing was planned, how many comparisons were made, and whether adjustment or a clear exploratory framing was used. Those details are not reported. The registry entries do not include secondary-outcome estimates or p-values, so their results cannot be assessed.
Missing-data handling is also not reported in the registry record. Enrollment is listed as 17, while the primary outcome summaries include 8 participants in the letrozole arm and 7 in the placebo arm. The record does not explain the difference, state whether additional participants had measurements, or describe imputation, exclusions, or sensitivity analyses. It also does not identify an intention-to-treat, per-protocol, or other analysis population. These omissions prevent assessment of whether the comparison retained participants according to their randomized assignments and whether incomplete outcome data could affect the result.
In general, missingness can affect interpretation when the likelihood of an unavailable outcome is related to participants’ characteristics or outcomes. The direction and extent of any resulting bias cannot be inferred without information about why data were absent and how analyses handled them. The record also does not report interim analyses or a statistical plan for managing them; neither their presence nor their absence should be assumed.
12. 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 |
|---|---|---|---|
| Letrozole | 0 | 9 | 0.0% |
| Placebo | 1 | 8 | 12.5% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Letrozole | 1 of 9 |
| Placebo | 1 of 8 |
Most frequent serious adverse event terms
| Event term | Organ system | Letrozole | Placebo |
|---|---|---|---|
| worsening dyspnea | Respiratory, thoracic and mediastinal disorders | 0 of 9 | 1 of 8 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Letrozole | Placebo |
|---|---|---|---|
| Swollen lymph nodes | Blood and lymphatic system disorders | 1 of 9 | 1 of 8 |
| Blurry vision | Eye disorders | 1 of 9 | 1 of 8 |
| abdominal pain; nausea | Gastrointestinal disorders | 1 of 9 | 1 of 8 |
| Chest pain | Cardiac disorders | 0 of 9 | 1 of 8 |
| Endocrine disorder | Endocrine disorders | 1 of 9 | 0 of 8 |
Serious events with the highest arm-level rate: worsening dyspnea (12.5%).
The registry reports serious adverse events among 9 participants at risk in the letrozole group and 8 in the placebo group. It lists 0 serious adverse events affecting participants in the letrozole group and 1 in the placebo group. These are the posted counts; the record does not provide further detail about event timing, duration, severity grading, relatedness to treatment, or how events were adjudicated.
The registry identifies worsening dyspnea at 12.5% among the top serious adverse event terms. It does not specify the group associated with that term in the information available for this reading, so it should not be assigned to either arm. The record also lists other adverse events affecting 1 of 9 participants at risk in the letrozole arm and 1 of 8 in the placebo arm. Death counts are not reported in the registry record.
These counts describe the safety information posted for this trial; they do not establish that an event was caused by study treatment. Small group counts offer limited precision, and the available information does not support a detailed comparison of event rates or patterns. The numbers should be read alongside the absence of further event-level and follow-up details, rather than as a complete account of safety experience.
13. What the Result Does, and Does Not, Mean
The posted results describe a randomized comparison of letrozole and placebo for the primary outcome of rate of change in FEV1 over 12 months. The arm-level medians were 1.04 milliliters per month for letrozole and 1.66 milliliters per month for placebo, each reported with a 95% confidence interval. The sponsor’s mixed-model comparison had p = 0.4. Taken together, these registry entries describe the summaries and test reported in the registry; they do not provide a numerical estimate and confidence interval for the treatment contrast.
The findings do not establish equivalence between the treatments or prove that their effects are identical. They also do not establish that letrozole changes the course of LAM. A p-value alone does not provide the effect’s size or precision, and the arm-specific medians do not replace a direct comparison. The missing treatment-effect estimate and confidence interval limit the strength and detail of any interpretation.
The trial enrolled 17 participants, while the primary outcome summaries include 8 participants in the letrozole arm and 7 in the placebo arm. The reason for this difference, the analysis population, and the handling of missing observations are not reported in the registry record. The groups represented in the outcome summaries may therefore not be fully characterized from the record. Information about participant characteristics, baseline lung function, and individual trajectories is also not reported.
The registry lists secondary outcomes, but their results and the approach to interpreting multiple analyses are not reported in the registry record for this assessment. Safety counts are limited to the posted event information and do not provide sufficient detail to attribute events to treatment. Overall, the record supports a narrow description of the primary summaries and sponsor-reported test. It does not support a definitive clinical conclusion, a claim of no effect, or a conclusion about outcomes and analyses that are not reported.
14. Why This Trial Matters Statistically
This trial illustrates why the distinction between an arm-level summary and a treatment comparison matters. The registry reports a median rate of change in FEV1 for each group and confidence intervals around those medians, while the sponsor reports a mixed-model p-value for the comparison. These quantities do not answer the same question. An estimate and confidence interval for the between-group contrast would make its direction, magnitude, and uncertainty more directly assessable.
It also shows how a small enrolled study can leave important questions open even when a primary result is posted. The enrollment was 17, and the outcome summaries include 8 participants in one arm and 7 in the other. The record does not explain the difference or describe missing-data handling. Without that context, readers cannot fully assess how the posted summaries relate to all randomized participants or how sensitive the analysis may be to the available observations.
The registry’s method label is useful but incomplete. “Mixed Models Analysis” identifies a broad analytical approach, not the specification, assumptions, or diagnostics needed to reproduce or evaluate it. Similarly, p = 0.4 conveys a test result but not the treatment-effect estimate or its precision. Clear reporting of the model, analysis population, missing-data procedures, and comparative estimate would allow a more complete statistical reading.
Finally, the record lists secondary outcomes and multiple analyses without describing a multiplicity plan. This makes it important to distinguish the primary result from any additional testing and to avoid treating unreported or exploratory findings as confirmatory. The trial matters statistically as a focused example of how design and reporting details shape what can responsibly be inferred from a clinical-trial registry record.
15. 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.
Several limitations specific to this trial constrain interpretation of the primary result. The registry reports an enrollment of 17, but the arm-level primary outcome summaries include 8 participants assigned to letrozole and 7 assigned to placebo. The record does not explain why these counts differ from enrollment, whether the counts reflect all randomized participants with usable data, or how participants without a posted outcome were handled. The analysis population is not reported in the registry record.
The sponsor’s comparison is identified as a mixed models analysis, but the model specification is not reported. The record does not give the treatment-effect estimate or its confidence interval, and the arm-level confidence intervals cannot serve as a substitute for those quantities. Model assumptions, diagnostic checks, and sensitivity analyses are not reported. This restricts assessment of the comparative effect and of the robustness of the stated p-value.
Information needed to characterize the population and its outcomes is also limited. Detailed eligibility criteria, participant characteristics, baseline FEV1 values, measurement schedules, and individual outcome trajectories are not reported in the registry record. The endpoint description explains that FEV1 varies between individuals, but the posted information does not enable assessment of how that variation was handled or whether the reported rate estimates are comparable across groups.
The record lists three secondary outcomes, 4 outcome measures, and 5 analyses without explaining their correspondence or reporting a multiplicity strategy. The results of the secondary outcomes are not included in the registry record for this interpretation. Safety reporting is likewise limited: event counts are posted, but event timing, severity grading, treatment relatedness, and the group associated with worsening dyspnea at 12.5% are not reported in the information available. These limitations are reporting gaps; they do not, by themselves, show that the trial was conducted improperly.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Letrozole for Lymphangioleiomyomatosis — NCT01353209.
- Registry record last updated 2024-04-17; status last verified 2024-04.
- Results first posted 2024-04-17.
- 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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19. Record Summary
The registry record describes a completed randomized, triple-masked, parallel-group phase 2 trial of letrozole versus placebo for lymphangioleiomyomatosis. The University of Cincinnati is listed as sponsor. Enrollment was 17, with a recorded start of 2011-05 and primary completion of 2014-09. The treatment descriptions specify daily letrozole or placebo for one year.
The primary outcome was the median rate of change in FEV1 in milliliters per month over 12 months. The letrozole arm median was 1.04, with a 95% confidence interval from 0.56 to 2.02; the placebo arm median was 1.66, with a 95% confidence interval from 0.77 to 2.63. The sponsor reported a mixed-model comparison with p = 0.4. A numerical between-group estimate and confidence interval are not reported in the registry record.
Three secondary outcomes are listed, but their results are not reported in the registry entries. The record does not explain the difference between enrollment and the primary outcome counts or detail the missing-data approach, analysis population, model specification, or multiplicity plan. Safety figures include 0 serious adverse events among 9 at risk in the letrozole group and 1 among 8 at risk in the placebo group; further event details are limited.