Pilot Study: Randomized, Placebo-controlled Comparator Trial of IV vs Oral Iron Treatment of RLS With IDA. (IVOR-IDA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pilot Study: Randomized, Placebo-controlled Comparator Trial of IV vs Oral Iron Treatment of RLS With IDA. (IVOR-IDA) (NCT02499354), a randomized phase 2 study. The primary outcome is Change From Baseline in the Restless Legs Syndrome Rating Scale.

2. Clinical Question

The registry describes a pilot, randomized, placebo-controlled comparator trial, while the official title describes a double-blind comparison of oral ferrous sulfate with intravenous ferumoxytol. The stated purpose was to determine the relative effect size of standard IV and oral iron treatment for RLS with IDA and to examine the time course of response. The primary endpoint is change from baseline in the International Restless Legs Severity Scale (IRLS) score, measured at baseline and 6 weeks after treatment.

Both groups had negative mean changes, and the scale description says that a more negative change represents a better outcome. The posted mean change was -14.0 in the oral iron group and -9.735 in the IV iron group. The recalculated mean difference is expressed as IV minus oral, so its positive direction corresponds to a less negative mean change in the IV group. That numerical contrast is not, by itself, a conclusion about treatment benefit or clinical importance.

The registry record does not report a minimum clinically important difference or a separate threshold for interpreting a change in IRLS score. The comparison therefore addresses the measured difference in mean score change, not whether that difference is important to participants. The available results also do not establish how the two treatments compare at other follow-up times; the primary outcome timeframe reported is 6 weeks after treatment.

3. Trial Design

This was a randomized, parallel-group Phase 2 trial. The registry lists triple masking and describes the study as a pilot, placebo-controlled comparator trial. The official title specifies a double-blind comparison. The registry record does not explain the difference in masking descriptions, identify which roles were masked, or report how randomization and allocation concealment were carried out.

The two interventions were oral ferrous sulfate and intravenous ferumoxytol. The oral regimen is described as 325mg tablets in the morning and evening. The IV regimen is described as 1020 mg, using two 510 mg vials given by IV push 2-7 days apart. The registry records an enrollment of 100. The primary outcome results are based on 45 participants in the oral iron group and 47 in the IV iron group who had baseline data and data at 6 weeks. Those outcome counts should not be mistaken for a description of all randomized participants or all follow-up data.

The study status is completed. Its recorded start is 2014-08, and its primary completion date is 2021-09-28. The registry record identifies restless legs syndrome and iron deficiency anemia as the conditions under study. The trial’s stated aim was to compare relative effect size and treatment-response timing; however, the posted primary outcome is the mean change in IRLS score at 6 weeks.

The registry record does not report the original sample-size justification, the trial’s planned statistical assumptions, or whether interim analyses were conducted. It also does not describe the randomization sequence, stratification, adherence, treatment discontinuations, or the handling of participants who did not contribute primary outcome data. These omissions limit what can be said about the design beyond the registered parallel, randomized comparison and the reported outcome population.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Those participants with baseline data and at 6 weeks

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 Change From Baseline in the Restless Legs Syndrome Rating Scale, measured over Baseline and at 6 weeks after treatment.

The primary endpoint is change from baseline in the Restless Legs Syndrome Rating Scale, identified in the description as the International Restless Legs Severity Scale (IRLS). The scale ranges from 0-40, with higher scores reflecting greater RLS severity. The registry describes the endpoint as a mean change and states that a higher negative score indicates a better outcome. The outcome timeframe is baseline and 6 weeks after treatment.

A change score expresses how much the measured score moved from its baseline value, rather than describing the follow-up score alone. Comparing mean changes between randomized groups can therefore summarize the difference in average change over the specified interval. In this record, the mean change was -14.0 for oral iron and -9.735 for IV iron. Because more negative changes are described as better, the direction of the group means is important when interpreting the contrast.

IRLS is used as a continuous measure of RLS severity: it retains the scale information rather than reducing each participant’s outcome to a simple event/no-event category. Reporting a mean gives a measure of the group’s average change, while the standard deviation describes variation in individual changes around that mean. Neither statistic alone shows every participant’s response or the clinical importance of the average change.

The registry record does not report a threshold for clinically important change, a separate responder definition, or a rationale for choosing the 6-week endpoint. The stated purpose includes examining response timing, but the registered primary endpoint details describe the comparison at 6 weeks; other timing results are not specified in the posted primary outcome information.

7. Results Posted in the Registry

• IV Iron: mean -9.74 versus -14.00 on control; difference 4.26 (95% CI 0.55 to 7.98), standardized effect d = 0.47; z-test p = 0.024.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant’s outcome is a change in IRLS score, and the registry reports the mean and standard deviation for each group. A mean is the arithmetic average of the observed values. A standard deviation describes the spread of those values around the mean; a larger standard deviation indicates more variability in the observed changes. These summaries help describe the groups, but they do not show the full distribution or the pattern of each participant’s response.

What does the mean difference represent?

The recalculated contrast is the IV group mean minus the oral group mean. With a mean change of -9.735 for IV iron and -14.0 for oral iron, the recalculated difference is 4.265 units. The sign depends on the order used for subtraction. Since the scale description says that a more negative change is better, a positive difference under this ordering means that the IV group’s average change was less negative. It does not mean that each IV participant had a positive change, nor does it quantify the number of participants who improved.

This is an unadjusted comparison of posted group summaries. It does not account for other variables, and it does not reproduce any participant-level model. The posted standard deviations, 8.33 for IV iron and 9.75 for oral iron, describe variability within each group. The recalculation uses the summaries to characterize the difference in means and its uncertainty. The registry record does not report an adjusted primary estimate.

What does a confidence interval tell the reader?

A confidence interval expresses uncertainty around an estimated effect under the method used to calculate it. It gives a range of values that are compatible with the data and the calculation’s assumptions, rather than a guarantee that the true effect lies within a particular realized interval. The recalculated interval for the mean difference has both limits above zero. This indicates that the unadjusted calculation does not include a zero difference, but it should be read alongside the discrepancy with the sponsor’s reported analysis and not as an independent confirmation of clinical importance.

The width of an interval is informative: narrower intervals indicate greater precision, while wider intervals leave more uncertainty about the effect size. The posted summary does not include confidence intervals around each group’s mean change. The primary reported uncertainty measure available for the group contrast is the recalculated interval, not a sponsor-reported interval.

How should the p-values be understood?

A p-value assesses how compatible observed data are with a specified null hypothesis under a statistical method. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The recalculated unadjusted p-value is 0.024. The registry’s sponsor-reported analysis is described as a one-sided t-test for superiority and has a p-value of 0.274. The two results differ. The registry record does not explain the discrepancy, including whether the analyses used different directions, assumptions, populations, or other specifications. Those explanations should not be guessed.

A t-test is a method for comparing means while accounting for variation and the amount of information in the groups. A one-sided test evaluates a prespecified direction of difference rather than departures in either direction. The registry record identifies the sponsor’s test as one-sided, but does not report the detailed analysis plan or the prespecified direction. The recalculation is unadjusted and is not a replacement for that sponsor analysis.

Why do assumptions matter?

Statistical calculations rely on assumptions about the data and the comparison. For a mean-based analysis, the observed means, variability, and group sizes contribute to uncertainty. Approximate methods can be useful for planning or summarizing, but their results may not reproduce an analysis based on participant-level data, particular handling of missing outcomes, or other model choices. The registry record does not report the full analysis specification needed to establish how the sponsor’s analysis was conducted beyond the listed one-sided t-test.

The outcome is a continuous score and the calculation uses group-level summary statistics. No count of participants meeting a response threshold is posted for the primary endpoint. The registry record also does not report whether the analysis checked distributional assumptions, used robust methods, or adjusted for baseline score. No claim about those procedures can be made from the reported information.

What is meant by over-dispersion?

Over-dispersion is a general issue for count-data models: the observed variation can exceed what a model assumes, making uncertainty estimates too small if that extra variation is ignored. It is not the central modeling issue for this reported continuous mean-change outcome, and the registry record does not report a count-model analysis for the primary endpoint. This general concept should not be confused with the standard deviations reported for the continuous score.

Overall, the recalculated statistics provide a transparent summary based on the posted means, standard deviations, and group sizes. The sponsor’s own reported analysis remains the primary reported analysis when the results conflict. Neither the recalculation nor the sponsor’s p-value, by itself, supplies the missing information about clinical importance, missing-data handling, or the full analysis plan.

10. Confidence Intervals and Precision

The recalculated mean difference is 4.265 IRLS units, with the contrast defined as IV minus oral. The recalculated confidence interval lies entirely above zero: its lower limit is positive, and its upper limit is 7.978. This interval describes uncertainty in the unadjusted mean difference under the calculation used. It is not a range of individual participant outcomes and does not indicate how much each person’s score changed.

An interval that excludes zero is consistent with a nonzero mean difference under that calculation, but precision and clinical importance are separate questions. The registry record does not report a threshold for a clinically important difference, so the interval cannot be judged against such a threshold. The interval also does not resolve the disagreement with the sponsor’s one-sided analysis, which reports a p-value of 0.274 and no estimate or confidence interval in the listed analysis.

The group standard deviations were 9.75 for oral iron and 8.33 for IV iron. These values show substantial spread around the average changes, relative to the scale of the group means, but do not provide the observed range or shape of the outcome distributions. The registry record does not provide confidence intervals for the separate group means, participant-level data, or an adjusted interval for the contrast.

Precision is also limited by the outcome population: the primary results include participants with baseline data and data at 6 weeks. The record does not explain the impact of unavailable outcome data or whether it could affect the estimate. The displayed recalculation is therefore best understood as an estimate with stated statistical uncertainty for the reported data, rather than a complete measure of uncertainty about all possible outcomes or populations.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original design assumptions. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The registry record does not report the original sample-size justification or the assumptions used when the trial was designed.

For planning at 100% of the observed effect, the figures are 71 participants per arm for 80% power and 95 participants per arm for 90% power. At 75% of the observed effect, they are 126 participants per arm for 80% power and 169 participants per arm for 90% power. At 50% of the observed effect, they are 283 participants per arm for 80% power and 379 participants per arm for 90% power.

In plain language, 80% power is the chance, under the planning assumptions and if the target effect were the true effect, of detecting an effect at the chosen significance level. The 90% column represents a higher chance of detecting that target effect under those same assumptions. Higher power generally requires more participants. When the effect to detect is smaller, it is harder to distinguish from random variation, so the planning illustration requires more participants per arm.

These figures are planning illustrations, not observed power and not a description of what the completed trial was designed to achieve. Their interpretation depends on the stated assumptions and on using the recalculated observed effect as the starting point. They do not establish that the observed effect is stable, clinically important, or the effect likely to be seen in a future study.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 4.265; pooled standard deviation σ = 9.052.
2. n = 2 × (1.96 + 0.842)² × 9.052² / 4.265² = 70.7, rounded up to 71 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 4.2647                      # observed difference in means
sigma <- 9.05209576715678                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2499354)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 71 (80% power), 95 (90% power)
 75% of observed effect: n per arm = 126 (80% power), 169 (90% power)
 50% of observed effect: n per arm = 283 (80% power), 379 (90% power)
power.t.test: 71.7 
Simulated power at n = 71 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports a sponsor analysis using a one-sided t-test for superiority, with a p-value of 0.274. It does not list an estimate or confidence interval for that analysis. The separate recalculation from posted summary statistics gives an unadjusted mean difference of 4.265, with a confidence interval that excludes zero and an unadjusted p-value of 0.024. These results do not agree.

Because the discrepancy is flagged, the sponsor’s own analysis takes precedence over the recalculation. The recalculation is a simple comparison based on the posted group summaries and does not necessarily reproduce all choices made in the sponsor’s analysis. The registry record does not explain why the p-values differ or provide enough detail to identify the cause. It would therefore be speculative to attribute the discrepancy to a particular test direction, population, variance assumption, or analysis rule.

The sponsor’s reported p-value should not be read as an effect-size estimate, and the recalculated contrast should not be presented as though it were the sponsor’s result. A fuller reconciliation would require details not reported in the registry record, such as the sponsor’s estimated contrast, confidence interval, analysis population, and complete statistical specification. Until those details are available, the two results should be described separately, with the sponsor’s analysis treated as the primary reported analysis.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 2 analyses, and the posted secondary outcome information identifies one secondary outcome: the number of participants with adverse events judged related or possibly related to treatment. The registry record does not report a plan for controlling multiplicity across outcomes, analyses, time points, or treatment comparisons. It is therefore not possible to determine whether the reported p-values were adjusted, whether one outcome was designated as the sole confirmatory test, or how any additional analyses were treated.

Multiplicity matters because making several statistical comparisons can increase the chance of observing at least one result that appears unusual under a null hypothesis. This is a general statistical consideration, not evidence that the trial conducted a particular number or type of unreported comparisons. The registry record does not provide enough detail to reconstruct the full set of planned or performed tests.

The primary outcome population is described as participants with baseline data and data at 6 weeks. The posted outcome counts are 45 for oral iron and 47 for IV iron. The record does not state how many randomized participants lacked the required outcome data, why data were unavailable, or how missing measurements were handled. It does not report imputation, a sensitivity analysis for missing data, or an analysis of all randomized participants.

The registry record also does not state whether the primary analysis followed intention-to-treat principles, used a per-protocol population, or applied another analysis population definition. The result should consequently be interpreted as pertaining to the stated outcome population, without assuming that it represents all randomized participants. The registry record does not report baseline adjustment or other covariate adjustment for the primary comparison.

These reporting gaps do not show that a particular procedure was or was not used; they mean that the procedure is not reported in the registry record. They matter because population definitions, missing-data choices, and multiplicity plans can affect interpretation of uncertainty and the meaning of a p-value. The discrepancy between the sponsor’s result and the recalculation makes the absence of a more complete analysis description especially relevant.

15. 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 non-serious adverse event terms

For serious adverse events, the posted figures show 0 affected participants among 46 at risk in the oral iron group and 0 among 47 at risk in the IV iron group. The registry also reports 0 deaths in each group. No serious adverse event terms are listed. These counts describe what was recorded in the registry; they do not establish that the risk of a serious event is absent.

The record separately lists other adverse events affecting 22 of 46 participants in the oral group and 11 of 47 participants in the IV group. Those are not the serious-adverse-event counts. The registry’s secondary outcome refers to adverse events judged related or possibly related to treatment, but the record does not explain whether the other-event figures correspond exactly to that outcome or provide event-level detail in the registry record. They should not be relabeled as treatment-related without that information.

Zero observed serious events in these groups does not prove that a treatment cannot be associated with serious events. A trial of this size and duration may provide limited information about uncommon harms, and the record does not report a detailed safety analysis, event timing, or severity breakdown for other events. The figures are descriptive and should be read alongside the limited population and follow-up information in the registry record.

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

The posted results describe mean change in RLS severity at 6 weeks among participants with baseline and follow-up data. The oral iron group had a mean change of -14.0, and the IV iron group had a mean change of -9.735. Because the registry states that a more negative score is better, the observed group averages were more negative for oral iron. The recalculated difference, expressed as IV minus oral, is 4.265 units.

The recalculated confidence interval lies above zero, while the sponsor’s own one-sided superiority analysis reports a p-value of 0.274. The discrepancy means the recalculated analysis should not be treated as a substitute for the sponsor’s result; the sponsor’s analysis takes precedence. The registry record does not provide enough detail to explain why these results differ. Neither result alone establishes whether a difference is clinically important, because a clinically important threshold is not reported.

The result concerns a short-term average change on a symptom scale. It does not show the full range of participant outcomes, the proportion who reached a response threshold, or how symptoms changed after the reported 6-week timeframe. It also does not establish comparative effectiveness in populations other than those represented in this trial. The registry record does not report longer-term primary outcome data or a threshold for translating score changes into a judgment about importance.

The safety counts show no recorded serious adverse events and no deaths in either group, alongside other adverse-event counts of 22 of 46 for oral iron and 11 of 47 for IV iron. These observations are not proof that serious harms cannot occur, and the available record does not establish that every other event was related to treatment.

Accordingly, the posted data support a description of the observed group means, variability, and reported safety counts, together with uncertainty and a notable analysis discrepancy. They do not support a definitive claim that either treatment works or does not work, nor do they settle which option is preferable. Clinical importance, missing outcomes, analysis details, and longer-term results are not reported in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically informative because it places two treatment routes in a randomized, parallel-group comparison and reports a continuous symptom outcome. Mean change preserves more information about the measured scale than a simple count of participants classified as improved or not improved. The group means and standard deviations allow readers to see both the average direction of change and the variability around it.

The record also illustrates why a point estimate, its uncertainty, and the analysis method must be considered together. The recalculated unadjusted contrast and p-value differ from the sponsor’s reported one-sided t-test result. The registry does not explain the discrepancy, so the recalculation cannot stand in for the sponsor’s analysis. This is a useful reminder that summary statistics can support a transparent re-analysis, but may not capture every feature of the original analysis.

Precision matters as much as direction. The recalculated interval lies above zero, but there is no reported threshold for judging clinical importance, no sponsor-reported confidence interval, and no detail on missing-data handling or the full analysis population. A statistically nonzero contrast under one calculation is not automatically a clinically meaningful contrast.

The planning illustrations also demonstrate the relationship between target effect and required sample size: planning for a smaller fraction of the observed effect requires more participants per arm under the stated assumptions. Since the trial’s original design assumptions are not reported, those illustrations should be kept distinct from claims about the trial’s design or power.

Finally, the safety results require cautious reading. No serious events or deaths were posted, but the number of observed events does not establish that serious harms are impossible. Taken together, the statistical importance of the record lies in the observed comparison, its uncertainty, and the limits of what can be concluded from incomplete reporting—not in a treatment recommendation.

18. 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 registry record contains a material discrepancy between the recalculated unadjusted comparison and the sponsor’s reported one-sided t-test. It does not report the sponsor’s effect estimate or confidence interval, or explain the difference between the analyses. This limits the ability to reconcile the inferential results.

The primary outcome analysis is described as including participants with baseline data and data at 6 weeks, with outcome counts of 45 in the oral iron group and 47 in the IV iron group. The record does not describe missing data, withdrawals, adherence, treatment discontinuation, or whether the analysis included all randomized participants. The original sample-size justification and statistical assumptions are also not reported.

The primary result is a mean change on a 0-40 severity scale, but a threshold for clinically important change is not reported. Group means and standard deviations do not reveal the distribution of individual outcomes or the proportion of participants with a particular degree of improvement. The record does not provide participant-level data, adjusted estimates, or a sponsor-reported confidence interval for the contrast.

Although the study purpose mentions the time course of response, the primary outcome information reported specifies the 6-week assessment. Other response-time details are not reported in the registry record. The record also does not report a multiplicity plan or explain how the posted outcomes and analyses relate to any prespecified hierarchy.

Safety reporting is limited in the registry entries: serious adverse events and deaths are listed as zero in both groups, but detailed serious-event terms are absent, and the relationship of the other adverse-event counts to the secondary outcome is not clarified. These limitations constrain interpretation of both comparative symptom changes and safety; they do not, on their own, establish that an unreported procedure or outcome was absent.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Pilot Study: Randomized, Placebo-controlled Comparator Trial of IV vs Oral Iron Treatment of RLS With IDA. (IVOR-IDA) — NCT02499354.
• Registry record last updated 2024-01-30; status last verified 2024-01.
• Results first posted 2023-08-15.
• 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.

22. Record Summary

The registry describes NCT02499354, a completed randomized, parallel-group Phase 2 pilot study comparing oral ferrous sulfate with intravenous ferumoxytol in people with restless legs syndrome and iron deficiency anemia. The primary outcome is mean change in IRLS score at 6 weeks, among participants with baseline and 6-week data.

The posted mean changes were -14.0 for oral iron and -9.735 for IV iron. The recalculated IV-minus-oral mean difference is 4.265, but the recalculated result conflicts with the sponsor’s reported one-sided t-test p-value of 0.274; the sponsor’s own analysis takes precedence. The registry record does not explain the discrepancy or report a clinically important difference threshold.

The posted serious adverse-event and death counts were zero in both groups. The record does not report the original sample-size justification, complete missing-data procedures, or a detailed multiplicity plan.