Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis (NCT01687179), a registered phase 1 study. The primary outcome is Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients.

2. Clinical Question

The trial asked whether sirolimus combined with hydroxychloroquine was safe and well tolerated in women with lymphangioleiomyomatosis (LAM). The registry also describes aims concerning indicators of disease, whether changes persisted after therapy stopped, and whether a LAM-specific peripheral blood signature could predict progression or treatment responsiveness. The primary endpoint, however, was safety.

The central question is therefore whether adverse events were observed during exposure to the combination, and how the reported safety experience differed across the dose groups. These data describe events among participants who received the regimen; without a randomized control group, they do not isolate the contribution of hydroxychloroquine, sirolimus, the combination, or other causes.

3. Trial Design

This was a phase I, open-label study with a sequential model. The registry lists masking as none and reports enrollment of 14. The study began in 2012-09, reached primary completion in 2015-08, and is recorded as completed. Its title and description identify women with lymphangioleiomyomatosis as the intended population.

The intervention combined sirolimus and hydroxychloroquine. Sirolimus began at 2 mg, with adjustment intended to keep trough levels between 5-15 ng/ml. The listed hydroxychloroquine regimens were 200 mg and 400 mg. The arm description specifies hydroxychloroquine 200 mg daily for 6 months, but its text is incomplete in the registry record. Additional details about how participants moved through the sequential dose groups are not reported in the registry record.

The design is not a randomized comparison. Allocation is not stated, and the registry explicitly cautions that the arms are not a like-for-like control comparison. The groups can be described separately, but their results should not be read as establishing that dose alone caused any difference in observed events. Sequential enrollment can also mean that participants in different groups were treated at different points in the study; whether that occurred in a way that affected these results is not reported in the registry record.

The planned enrollment described in the study summary was up to 18 adult women, whereas recorded enrollment was 14. Reasons for the difference, the number completing treatment, and the number completing follow-up are not reported in the registry record. The primary safety timeframe is 48 weeks. The registry describes other aims relating to disease indicators and a blood signature, but does not provide posted analyses for those aims.

As a phase I safety study, the design is suited to describing tolerability and identifying events that merit attention during exposure. The registry does not report a protocol-defined hypothesis test, a sample-size justification, or a statistical analysis plan. No conclusion about formal comparative efficacy can be drawn from the design or the posted safety counts.

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.

Overall 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: 1 subject failed to qualify for the study at the screening visit. Since the subject had signed consent, we considered the participant to be enrolled on the study.

6. Primary Endpoint

The registry lists the primary outcome as Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients, measured over 48 weeks.

The primary endpoint is titled as safety of combination therapy and has a timeframe of 48 weeks. The registry describes safety assessment as based on adverse events and serious adverse events occurring while participants were receiving sirolimus with hydroxychloroquine. Events were classified and graded according to CTCAE Version 4.0. The stated endpoint unit is percentage of adverse events, and the description says percentages in each system at a dose were calculated from the total adverse events at that dose.

Safety is a relevant primary endpoint for an early-phase dose-escalation study because it characterizes the kinds of events observed during exposure and can inform whether further investigation is warranted. Event severity and seriousness matter alongside event frequency: a serious event can be important even if it is uncommon, while a count of participants affected does not by itself describe severity or duration.

The registry also posts participant counts for those at risk and affected by serious and other adverse events. Those counts are not the same measure as a percentage of all events by organ system. The registry does not provide a complete system-by-system percentage result in the record, nor does it report a formal inferential analysis of the primary endpoint. The count summaries should therefore be interpreted as descriptive safety information, not as a complete numerical estimate of the endpoint as titled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a phase I study with a sequential model and no masking. These design labels describe how the study was organized; they do not, by themselves, establish how participants were assigned to dose groups. The allocation process is not stated. General statistical interpretation therefore begins with the distinction between describing each group and estimating a causal treatment contrast. A causal contrast typically requires a defensible comparison that makes the groups sufficiently comparable; the registry cautions that these arms are not a like-for-like control comparison.

What do the adverse-event counts represent?

The safety summary reports how many participants were at risk and how many were affected for serious and other adverse events. These are participant-level counts. They are useful for conveying whether any participants experienced reported events, but they do not necessarily equal the number of events: one participant may experience more than one event. The registry’s endpoint description separately refers to the percentage of events in each system at a dose, calculated using the total adverse events at that dose. The two summaries should not be treated as interchangeable.

General statistical principle: event counts and participant counts answer different questions. Counting participants affected describes the proportion of the group with at least one event of the relevant type, while counting events describes event burden. Recurrent events in the same participant can make the event total larger than the number of affected participants. The registry record does not give the full event-level data needed to examine recurrence, timing, or exposure-adjusted rates.

Why does the small group size matter?

The recorded groups include 3 participants at risk in the 200 mg group and 10 in the 400 mg group for the reported safety categories. With few participants, observed counts can change substantially when an additional participant has or does not have an event. A zero count is compatible with the absence of observed events in that group, but it does not prove that an event could never occur. General statistical principle: estimates from small samples tend to be imprecise, and uncertainty is best conveyed with confidence intervals when they are available. Confidence intervals and formal precision estimates are not reported in the registry record.

Group size also affects how much can be learned about uncommon harms. A study with limited enrollment may describe events that occurred but may not reliably characterize rare outcomes. The registry does not report a sample-size justification or an intended precision target. The planning illustrations associated with the posted analysis are not the trial’s own design justification and are not observed power; they are based on an observed effect and stated planning assumptions. No planning values are reported in this registry record.

What does sequential allocation imply?

A sequential model and the absence of masking are relevant context when interpreting observed safety counts. If dose groups were entered at different times, experience in one group could differ from another for reasons apart from dose. However, the registry does not describe the sequence, escalation rules, stopping rules, or how assignment was determined. Those details cannot be inferred from the model label. The record also does not state whether safety reviews occurred during the study or whether any interim analyses were planned.

General statistical principle: in an uncontrolled or nonrandomized comparison, differences between groups may be confounded by baseline characteristics, time, or other treatment and follow-up conditions. Adjustment can sometimes address measured differences, but it cannot guarantee removal of unmeasured confounding. No adjusted analysis is reported. The small counts and missing assignment details make a causal interpretation especially uncertain.

How should uncertainty and significance be read?

The registry reports no analyses, confidence intervals, or p-values for the primary endpoint. There is consequently no posted inferential estimate of the difference between dose groups. General statistical principle: a confidence interval describes the range of values compatible with the data and a specified statistical procedure; it reflects sampling uncertainty, not all possible sources of bias. A p-value, when used appropriately, addresses compatibility with a specified null model and is not a measure of clinical importance or proof of causation. Neither measure can be reconstructed from the participant counts alone without making additional assumptions, and no new analysis is warranted from the information in the record.

The sample-size assumptions describe an illustrative calculation using a two-sided significance level of 0.05, equal allocation, and a normal approximation, with an effect defined as a stated fraction of an observed effect. Such planning calculations ask what sample size might be needed under those assumptions. They do not change the fact that this study enrolled 14 participants, and they do not establish that the study had adequate power for its safety endpoint. Sample-size illustrations are planning aids, not observed power or evidence that an effect is present.

What can be concluded from the endpoint definition?

The endpoint description refers to adverse events grouped by system, while the posted safety summary gives participant counts and a serious-event term. A complete interpretation of a system-specific percentage would require the event totals and corresponding system counts, together with clear denominators. Those details are not reported in the registry record. CTCAE Version 4.0 supplies a classification and grading framework, but citing that framework does not reveal the actual severity distribution unless the grades are posted. The registry does not report the full grade-level distribution or a statistical model for the endpoint.

Overall, the appropriate statistical reading is descriptive and cautious: the counts document the reported experience in the observed groups, while uncertainty, group comparability, event recurrence, and causal attribution remain unresolved in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The study description includes several aims: safety, indicators of disease during combination therapy and after stopping therapy, and the potential role of a LAM-specific peripheral blood signature. The registry identifies safety as the primary endpoint, but does not report a complete analysis plan for these aims, a hierarchy of secondary outcomes, or how multiple outcomes would be handled. It is therefore not possible to determine whether any multiplicity adjustment was planned or applied. Multiplicity matters in general because examining many outcomes can increase the chance of finding an apparently notable result by chance, particularly when results are interpreted selectively.

The registry reports no analyses. It does not provide outcome results for disease indicators, persistence of gains after treatment, or the blood signature aims. The number and definitions of any secondary endpoints are not established in the posted summary beyond its description of the study aims and the one listed outcome measure. The timing, analytical methods, and criteria for interpreting those exploratory aims are not reported in the registry record.

Missing-data handling is also not reported in the registry record. The enrolled number is 14, while adverse-event denominators are 3 in the 200 mg group and 10 in the 400 mg group. The record does not explain the difference between enrollment and the reported group denominators, nor does it state whether participants withdrew, had incomplete follow-up, or were excluded from particular summaries. It does not describe imputation, censoring, or any other method for handling incomplete observations.

Analysis populations are not defined. The registry does not state whether summaries use all enrolled participants, participants who began treatment, participants who completed treatment, or another set. Without population definitions and participant flow, the reported counts should be interpreted only with their stated denominators, not assumed to represent a particular analysis population. These omissions limit assessment of outcome completeness and the possibility of selection bias.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: radiculitis (10.0%).

For serious adverse events, the registry reports 0 affected among 3 at risk in the sirolimus and hydroxychloroquine 200 mg group, and 1 affected among 10 at risk in the 400 mg group. For other adverse events, it reports 3 affected among 3 at risk in the 200 mg group, and 9 affected among 10 at risk in the 400 mg group. The reported number of deaths is 0 in both groups.

These figures count participants affected, not necessarily the total number of events. They also do not indicate when an event occurred, how long it lasted, whether it recurred, or whether investigators attributed it to treatment. The registry says adverse events were classified and graded using CTCAE Version 4.0, but the posted summary does not provide the full grade distribution.

Radiculitis is listed as a top serious-event term at 10.0%. The registry does not provide enough detail in the summary to determine the denominator or interpret this as a comparative rate. The small group sizes, sequential design, and absence of a like-for-like control mean that these counts describe observed safety experience; they do not establish that one dose caused more or fewer events.

12. What the Result Does, and Does Not, Mean

The results establish that adverse events were reported among participants receiving the sirolimus and hydroxychloroquine combination, with counts presented separately for the 200 mg and 400 mg hydroxychloroquine groups. Serious adverse events were reported for 0 of 3 at risk in the 200 mg group and 1 of 10 at risk in the 400 mg group. Other adverse events affected 3 of 3 and 9 of 10 participants, respectively. The registry reports 0 deaths in each group and lists radiculitis at 10.0% among the top serious-event terms.

These observations do not establish that the combination is safe or unsafe in a broader population. They describe a small group of participants in a phase I study, with no randomized control group and no stated allocation process. They also do not establish that the hydroxychloroquine dose explains any difference in the counts. The groups may differ in ways not described in the registry, and the counts are too limited to characterize uncommon events precisely.

The results do not establish treatment benefit. Although the study summary lists aims concerning disease indicators, sustained changes after stopping therapy, and a peripheral blood signature, the registry record does not report analyses of those outcomes. The safety endpoint’s stated unit concerns percentages of adverse events by system, while the posted summary gives participant counts; the complete system-specific event results are not reported.

In general, a descriptive safety signal can identify observations for further investigation, but it is not a causal estimate. A more definitive comparison would require an appropriate comparator, clear allocation and analysis methods, complete outcome reporting, and enough information to quantify uncertainty. These results should therefore be read as limited safety observations from the participants represented in the registry, not as a conclusion about treatment effects or individual care.

13. Why This Trial Matters Statistically

This study illustrates a recurring statistical challenge in early-phase clinical research: the value of a safety study often lies in carefully describing events, while the available sample may be too small and the design too limited for precise comparative conclusions. Reporting participant counts alongside the group denominators helps readers understand the scale of observed experience. At the same time, small denominators mean that the counts should not be mistaken for stable estimates of risk.

The registry also highlights why endpoint definitions and reported results need to align. The primary endpoint is described as percentages of adverse events by system, but the summary emphasizes numbers of participants affected. Both can be useful, yet they answer different questions. Clear reporting of event counts, participant counts, severity, timing, attribution, and denominators would make the safety profile easier to interpret.

Sequential, nonrandomized dose groups create a further interpretive issue. Separate group summaries can document what happened during the study, but without a like-for-like control they cannot isolate a dose effect. Explicit allocation and escalation procedures, participant flow, and analysis-population definitions would help readers judge whether group comparisons are meaningful.

Finally, the study summary names biological and disease-related aims beyond safety, while the registry record does not report analyses for those aims. This distinction matters: a stated objective is not a result. For biostatisticians and clinical researchers, the record is a useful reminder to distinguish trial rationale, endpoint definition, observed counts, and inferential evidence. Each contributes different information, and none should be substituted for another.

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 important limitation for interpretation is the small enrollment and the small group denominators in the safety summary. With only 3 participants at risk in the 200 mg group and 10 in the 400 mg group, the counts offer limited precision and cannot characterize uncommon events reliably. Confidence intervals and other measures of uncertainty are not reported.

The study is sequential, masking is absent, and allocation is not stated. The registry cautions that the arms are not a like-for-like control comparison. Consequently, the observed counts cannot support a causal conclusion about the relative safety of the doses or the effect of the combination compared with another regimen. Baseline characteristics and other details needed to assess group comparability are not reported in the registry record.

The outcome reporting is incomplete for a full evaluation of the stated primary endpoint. The endpoint description refers to percentages of adverse events by system, but the posted summary does not include the complete system-specific event totals or percentage results. The full adverse-event severity distribution, timing, recurrence, duration, and treatment attribution are also not reported in the registry record.

The registry does not explain why enrollment of 14 differs from the adverse-event denominators, define the analysis populations, or describe missing-data handling. It also does not report a statistical analysis plan, a sample-size justification, or whether interim safety analyses occurred. The study summary names additional aims, but corresponding analyses are not reported. These limitations leave uncertainty about completeness, precision, and the scope of conclusions that can be drawn from the posted record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis — NCT01687179.
• Registry record last updated 2018-10-11; status last verified 2018-09.
• Results first posted 2018-10-11.
• 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.

18. Record Summary

NCT01687179 is a completed phase I, sequential, unmasked study sponsored by Brigham and Women's Hospital. It enrolled 14 women with lymphangioleiomyomatosis and evaluated sirolimus combined with hydroxychloroquine. The registry lists hydroxychloroquine 200 mg and 400 mg groups; sirolimus began at 2 mg with adjustment to keep trough levels between 5-15 ng/ml.

The primary endpoint was safety over 48 weeks, assessed through adverse events and serious adverse events classified and graded using CTCAE Version 4.0. The registry reports participant counts affected by serious and other adverse events, 0 deaths in each group, and radiculitis at 10.0% among the top serious-event terms. The posted record reports no analyses and does not provide a complete statistical evaluation of the primary endpoint or results for the other stated aims.