Iron Sucrose In The Treatment of Restless Legs Syndrome: Safety of Three Dose Regimens as Evaluated by Clinical Assessments: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Iron Sucrose In The Treatment of Restless Legs Syndrome: Safety of Three Dose Regimens as Evaluated by Clinical Assessments (NCT00895232), a non-randomized phase 2 study. The primary outcome is Mean Change From Baseline to Day 84 for International Restless Leg Syndrome Study Group (IRLSSG) Scale.

2. Clinical Question

3. Trial Design

This was a completed, open-label Phase II trial with a parallel-cohort design. The registry identifies the allocation as non-randomized, and states that cohorts were enrolled and treated subsequently. That sequence is important: the cohorts were not concurrent randomized groups, so differences between them cannot be attributed to dose schedule alone. Participant characteristics, clinical care, or other circumstances may have varied over time; whether they did is not reported in the registry record.

The registry lists 21 participants. Cohort I received one 500 mg Venofer infusion over four hours. Cohort II received two 500 mg infusions, described as being administered over four to six hours on Day 0 and repeated on Day 2 to 7. Cohort III received two 500 mg infusions, each described in the arm details as lasting six hours, with the second infusion within 24 hours after the first. The brief summary describes the timing for Cohort III as within 30 hours of the start of the first infusion. Those descriptions differ, and the registry record does not clarify the discrepancy.

Masking was none, so participants and study personnel were not blinded to the assigned regimen. The study began in 2003-11, reached primary completion in 2005-08, and is listed as completed. The record identifies American Regent, Inc. as sponsor. It does not report a randomized comparison, a control treatment, or a statistical analysis plan. The sequential, non-randomized design is primarily descriptive and does not support a like-for-like causal comparison among regimens.

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: A Baseline score \> or = to 15 was required on the International RLS Study Group (IRLSSG) Rating Scale. At least 1 leg was required to have an average baseline Periodic Leg Movement (PLM) while asleep \> or = to 15 movements per hour by actigraphy.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Only subjects who completed the IRLSSG Rating Scale at baseline AND on Day 84.

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.

6. Primary Endpoint

The registry lists the primary outcome as Mean Change From Baseline to Day 84 for International Restless Leg Syndrome Study Group (IRLSSG) Scale, measured over Baseline to Day 84.

The primary endpoint was mean change from baseline to Day 84 on the International Restless Leg Syndrome Study Group (IRLSSG) Scale. The record describes this as a validated rating scale of RLS symptoms, with scores ranging from 1 for mild symptoms to 40 for severe symptoms. A change score expresses how a participant’s rating differs at follow-up from the baseline rating; the mean summarizes those changes for the analyzed participants.

Symptom rating scales are used to turn a clinical experience into a defined measure that can be recorded consistently over time. A baseline-to-follow-up measure can describe whether the recorded symptom ratings changed during the observation period. It does not, by itself, identify the cause of a change. In this study, the absence of randomization and a control group limits attribution of any observed change to the infusion regimen rather than to other influences.

The primary-outcome population was restricted to participants who completed the scale at both baseline and Day 84. The registry record does not report the mean change, its standard deviation, the number included in this outcome, or a confidence interval. As a result, the magnitude and precision of the primary endpoint cannot be assessed from the reported information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with the outcome definition and the population included in its analysis. The primary endpoint is a continuous measure: change in the IRLSSG Scale from baseline to Day 84. The registry identifies the summary measure as a mean and the dispersion measure as a standard deviation. The mean describes the average change among analyzed participants. The standard deviation describes how spread out individual values are around that mean; it is not the precision of the estimated mean.

What would a confidence interval add?

In general, a confidence interval gives a range of values compatible with the data and the statistical procedure used. It helps readers judge the precision of an estimate, rather than focusing only on whether a result crosses a significance threshold. A narrow interval indicates greater precision than a wide interval, assuming the same method and interpretation. No confidence interval for the primary outcome is reported in the registry record, so its precision cannot be evaluated.

Why does the allocation matter?

In general, random allocation helps balance measured and unmeasured characteristics across treatment groups, on average. This supports causal comparisons when the study is otherwise conducted appropriately. Here, allocation was non-randomized, and cohorts were enrolled and treated subsequently. That means a difference between cohorts, if estimates were available, could reflect differences in participants or circumstances as well as the regimens. Open-label conduct also means treatment assignment was known, which can affect subjective ratings or reporting. The registry record does not report methods intended to adjust for these potential sources of bias.

How should the change score be understood?

In general, a change score compares a follow-up measurement with a baseline measurement for the same participant, then summarizes those individual changes. It can be useful when the question concerns movement from a starting value. The interpretation depends on the scale’s direction, the size of the change, and the uncertainty around the estimate. The record describes the scale’s range and symptom severity anchors, but does not state the observed mean change. Therefore, it is not possible to describe the direction or size of the study’s primary result.

The endpoint population requires a baseline and Day 84 assessment. In general, analyzing only participants with both assessments can yield a biased summary if missingness is related to the outcome or treatment experience. This is a potential concern, not proof that bias occurred in this study. The number with complete assessments, the amount of missingness, and the reasons for missing data are not reported in the registry record.

What do safety counts describe?

In general, an adverse-event count records how many participants experienced an event under the study’s definitions and observation procedures. Serious and other adverse events are distinct categories in the record. Counts are descriptive: they do not, on their own, establish that treatment caused an event or permit a reliable comparison between non-randomized cohorts. The registry lists participants at risk and affected for each category, but does not report a comparative statistical analysis.

The registry’s sample-size assumptions describe planning illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These illustrations are not observed power. The record does not report the sample-size justification used to design this trial, and the primary numerical effect needed to evaluate such illustrations is not reported in the registry record. No sample-size illustration should be read as an observed result or as evidence about the adequacy of the enrolled cohort sizes.

Finally, the registry states that there were 3 outcome measures and 0 analyses. Statistical tests, model specifications, handling of multiple outcomes, and any interim analyses are not reported in the registry record. General statistical principles can clarify what such methods would mean, but cannot substitute for an analysis that is not recorded.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort I (Venofer 500mg x 1 Dose)", "Cohort II (Venofer 500mg X 2 Doses)", "Cohort III (Venofer 500mg x 2 Doses)")
n   <- c(5, 3, 2)
m   <- c(-2.4, -14.3, -16)
sp  <- c(5.41, 5.03, 8.49)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort I (Venofer 500mg x 1 Dose)  5  -2.400  5.410  -9.117  4.317
CARM  Cohort II (Venofer 500mg X 2 Doses)  3  -14.300  5.030  -26.795  -1.805
CARM  Cohort III (Venofer 500mg x 2 Doses)  2  -16.000  8.490  -92.280  60.280

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures, including the primary mean change in IRLSSG Scale score and a secondary mean change in total periodic limb movements from baseline to Day 84. It reports 0 analyses. The statistical plan, any adjustment for testing multiple outcomes, and the relationship between outcomes and any planned hypotheses are not reported in the registry record.

In general, multiplicity arises when several outcomes, comparisons, or analyses are evaluated. Looking across multiple results can increase the chance of finding an apparently notable result by chance. A prespecified approach to multiplicity can help readers understand how much weight to place on each finding. No such approach is reported, and no outcome-specific statistical results are available in the registry record. The multiplicity implications therefore cannot be evaluated from the posted information.

The primary endpoint was defined for participants who completed the IRLSSG Scale at both baseline and Day 84. This is a completer-based population, but the number with both measurements, the number missing either assessment, and the reasons for missingness are not reported in the registry record. The record does not describe imputation, sensitivity analyses, or other missing-data methods. In general, incomplete follow-up can affect both the estimate and its precision, particularly when missingness is associated with participant outcomes or treatment experience.

The registry does not report an intention-to-treat population or any other analysis population beyond the stated primary-outcome completion requirement. It also does not report interim analyses or a statistical analysis plan. Those omissions make it impossible to determine whether the posted outcome population and analysis methods followed a prespecified plan.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: heart rate irregular (12.5%).

The registry reports serious adverse events by cohort as participants at risk and participants affected. Cohort I lists 7 at risk and 0 affected; Cohort II lists 6 at risk and 0 affected; Cohort III lists 8 at risk and 1 affected. The record identifies “Heart rate irregular” as the top serious-event term and gives 12.5% for that term.

For other, non-serious adverse events, the record lists 7 at risk and 5 affected in Cohort I, 6 at risk and 4 affected in Cohort II, and 8 at risk and 5 affected in Cohort III. These are descriptive counts recorded within each cohort. They do not establish that the infusion caused an event, and they do not constitute a reliable comparison of risk across regimens because the cohorts were not randomized and were enrolled and treated sequentially.

Deaths are not reported in the registry record. The record does not provide event-level timing, duration, outcome, or further detail on the serious event beyond the listed term. The counts should therefore be read as a limited account of events captured under the study’s reporting, not as a complete estimate of safety or as evidence that one regimen is safer than another.

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

The registry record establishes that this completed Phase II study evaluated three iron sucrose dosing schedules in people with RLS and defined a Day 84 symptom-scale outcome. It also records serious and other adverse-event counts by cohort. These are useful descriptive elements for understanding what was studied and what safety information was reported.

The record does not report the mean change on the primary IRLSSG Scale endpoint, its standard deviation, a confidence interval, or a statistical test. It therefore does not show the direction, magnitude, or precision of the symptom results. Missing numerical results should not be interpreted as no change or as evidence of no effect.

The design also does not establish a causal comparison among schedules. Treatment allocation was non-randomized, cohorts were enrolled and treated subsequently, and the study was open-label. Even if cohort-specific outcome estimates were available, the results could not be interpreted as a like-for-like randomized comparison. Differences might reflect the regimen, differences between participants, or changes in study circumstances over time.

The safety figures describe participants affected within each cohort, but the small cohort counts and lack of randomization limit comparative interpretation. They do not establish whether an event was caused by treatment. In general, a study’s observed event counts can inform description of what occurred during observation, but should not be treated as a definitive estimate of risk.

Overall, the posted information is insufficient to determine whether symptom ratings changed or how precisely any change was estimated. It supports a cautious description of study design and recorded adverse events, rather than a conclusion about efficacy or comparative safety.

14. Why This Trial Matters Statistically

This trial is statistically notable because its three dosing cohorts were not randomized and were enrolled and treated subsequently. That structure makes the distinction between describing groups and comparing treatments especially important. A numerical difference between cohorts would not, by itself, identify a treatment effect. The same interpretive caution applies to safety counts.

The primary outcome is a repeated symptom rating, defined as change from baseline to Day 84. This endpoint raises familiar issues in clinical research: how to summarize change, how to describe uncertainty, and how to handle participants without both measurements. The registry defines the complete-measurement population but does not report the resulting estimate or the extent and handling of missing data. This makes clear definitions only part of the information needed for statistical interpretation.

The registry also lists multiple outcome measures but no analyses. Without estimates, uncertainty measures, or details of the analysis plan, readers cannot assess how the results were evaluated or how multiple outcomes were handled. The absence of these details is distinct from a finding of no effect; it is a limit on what can be concluded from the record.

For researchers and readers, the study illustrates why design, outcome reporting, and analysis details must be interpreted together. Sequential cohorts can describe the use of different regimens, while causal comparisons generally require stronger protection against systematic differences. Complete outcome reporting is also necessary to judge both the size and precision of a clinical result. The record’s safety counts remain descriptive, with no basis for a definitive ranking of regimens.

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.

The most consequential limitation for interpreting clinical outcomes is that the numerical primary endpoint result is not reported in the registry record. The mean change, standard deviation, confidence interval, and statistical test are absent. The secondary outcome for total periodic limb movements is named, but its numerical result is also not reported.

The study was non-randomized, open-label, and conducted in sequential cohorts. Those features limit causal interpretation and direct comparison of the regimens. The record does not report baseline characteristics by cohort or methods for adjusting for differences, so the extent of any group imbalance cannot be assessed.

The primary endpoint included only participants with both baseline and Day 84 IRLSSG Scale assessments. The number meeting that requirement and the extent, reasons, and handling of missing outcome data are not reported in the registry record. The record also does not report a detailed statistical analysis plan, multiplicity procedure, interim analyses, or the sample-size justification used for the trial.

Descriptions of Cohort III timing differ: the brief summary says the second infusion occurred within 30 hours of the start of the first, while the arm description says it occurred within 24 hours after the first infusion. The record does not resolve that difference. The available safety information is also limited to cohort-level counts and a listed serious-event term; deaths are not reported in the registry record. These limitations restrict interpretation of both treatment comparisons and safety patterns.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Iron Sucrose In The Treatment of Restless Legs Syndrome: Safety of Three Dose Regimens as Evaluated by Clinical Assessments — NCT00895232.
• Registry record last updated 2024-11-07; status last verified 2024-11.
• Results first posted 2015-06-10.
• 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.

19. Record Summary

NCT00895232 is a completed, open-label Phase II study of iron sucrose in people meeting criteria for restless legs syndrome. It enrolled 21 participants in three non-randomized, sequential cohorts with different infusion schedules. The primary outcome was mean change from baseline to Day 84 on the IRLSSG Scale, analyzed among participants with assessments at both time points.

The registry record lists 3 outcome measures and 0 analyses. It does not report numerical primary or secondary outcome results, estimates of precision, or details of the statistical analysis plan. Safety information includes serious and other adverse-event counts by cohort; deaths are not reported in the registry record. The design and reporting support a limited descriptive account, not a randomized comparison of the dosing regimens.