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 A Randomised, Comparing Fixed Doses of Pramipexole to Investigate the Efficacy and Safety in Patients With RLS. (NCT00390689), a randomized phase 3 study. The primary outcome is Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 6 Weeks.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00390689 |
| Phase | Phase 3 |
| Condition | Idiopathic Restless Legs Syndrome |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 154 |
| Arms in the primary outcome | 3 |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
Population
Participants with idiopathic restless legs syndrome were enrolled. The primary endpoint results are reported for the Full Analysis Set. The registry record lists enrollment of 154 participants.
Intervention
Pramipexole was given once daily at fixed doses of 0.25 mg, 0.5 mg or 0.75 mg during the double-blind period. The official title describes a six-week double-blind study followed by a 46-week open-label long-term study.
Comparator
The reported primary comparisons are between the 0.25 mg group and each of the other pramipexole dose groups. The registry record does not describe a placebo or untreated comparison group for these results.
Primary question
How much did the mean IRLS total score change from baseline to week 6 in each dose group, and how do those changes compare across the fixed doses? The registry describes a decrease of 10 or more points in mean change as clinically important, while the posted endpoint is the change in IRLS score.
This is a dose-comparison question within a randomized, parallel-group phase 3 study, rather than a comparison of pramipexole with no active treatment. The posted primary results describe reductions in mean IRLS score in all three groups. The estimated differences between the 0.25 mg group and the higher-dose groups are small relative to the uncertainty expressed by their confidence intervals. Those intervals include no difference, so the posted summaries do not precisely distinguish the dose groups on this endpoint.
The registry lists additional outcomes concerning IRLS response, sleep quality, sleepiness, global impressions, safety measures and longer-term IRLS results. These provide context about other measured domains, but the registry record does not report a complete statistical analysis plan or multiplicity adjustment. The primary comparison should therefore be read as a description of the posted six-week score changes, not as a stand-alone conclusion about treatment benefit or dose selection.
3. Trial Design
NCT00390689 is a completed, randomized, quadruple-masked, parallel-group phase 3 trial sponsored by Boehringer Ingelheim. The registry record lists idiopathic restless legs syndrome as the condition and enrollment of 154. The recorded start was 2006-10, and primary completion was 2008-03.
The official title describes a double-blind fixed-dose study of pramipexole at 0.25 mg, 0.5 mg and 0.75 mg, followed by an open-label long-term study. The blinded period lasted 6 weeks, and the open-label period lasted 46 weeks. Arm descriptions state that each of the three fixed doses was given once daily. The brief summary distinguishes the objectives: comparing efficacy and safety across the fixed doses during the double-blind phase, and investigating long-term safety and efficacy during the open-label phase.
The primary endpoint is reported at week 6 for the Full Analysis Set. The primary outcome values are listed for 48 participants in the 0.25 mg group, 53 in the 0.5 mg group and 53 in the 0.75 mg group. These are the reported group sizes for that endpoint; the registry record does not explain the relationship between the outcome populations and enrollment in detail.
The registry also lists open-label safety groups at different doses, with different numbers of participants at risk. Those groups belong to the long-term period and should not be treated as if they were randomized blinded dose groups with identical follow-up. The registry record does not report the original sample-size justification, detailed allocation procedures, concealment procedures, or the specific methods used to analyze the primary outcome. The term quadruple masking is recorded, but the registry record does not explain which roles were masked.
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
| Stage | Pramipexole 0.25mg Group | Pramipexole 0.5mg Group | Pramipexole 0.75mg Group |
|---|---|---|---|
| STARTED | 48 | 53 | 53 |
| COMPLETED | 43 | 48 | 50 |
| NOT COMPLETED | 5 | 5 | 3 |
Reasons for not completing this period:
| Reason | Pramipexole 0.25mg Group | Pramipexole 0.5mg Group | Pramipexole 0.75mg Group |
|---|---|---|---|
| Adverse Event | 2 | 5 | 2 |
| Lack of Efficacy | 0 | 0 | 1 |
| Protocol Violation | 1 | 0 | 0 |
| Investigator's judgement | 2 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS).
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 | Pramipexole 0.25mg Group | Pramipexole 0.5mg Group | Pramipexole 0.75mg Group | Total |
|---|---|---|---|---|---|
| Participants analysed | 48 | 53 | 53 | 154 | |
| Age, Continuous | years | 52.5 (SD 13.9) | 52.4 (SD 12.9) | 54.3 (SD 14.4) | 53.1 (SD 13.7) |
| Sex: Female, Male: Female | Participants | 30 | 27 | 32 | 89 |
| Sex: Female, Male: Male | Participants | 18 | 26 | 21 | 65 |
6. Primary Endpoint
The registry lists the primary outcome as Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 6 Weeks, measured over Week 6 - change from baseline.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | Points on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change from baseline in the International Restless Legs Syndrome Study Group (IRLS) total score at 6 weeks. It is a continuous score, with the posted results expressed as least-squares means and standard errors. A negative change represents a reduction in score from baseline. The registry describes IRLS severity categories as 0-10 mild, 11-20 moderate, 21-30 severe and 31-40 very severe.
The registry’s endpoint description states that a decrease of 10 or more points in mean change corresponds to improvement by one severity rank and has clinical importance. That rationale gives context for interpreting the size of score changes. It does not mean that the group mean change alone identifies how many individual participants reached a clinically important improvement, nor does the primary endpoint description report an individual responder analysis as the primary measure.
The posted mean changes were -12.3 points for 0.25 mg, -12.5 points for 0.5 mg and -11.8 points for 0.75 mg. Each is a group-level estimate with a standard error of 1.1 points. The endpoint captures average change over the blinded period; it does not by itself describe the distribution of individual responses, durability after week 6, or longer-term outcomes. The registry lists longer-term IRLS outcomes separately for the open-label period.
7. Results Posted in the Registry
- Pramipexole 0.5mg Group: mean -12.50 versus -12.30 on control; difference -0.20 (95% CI -3.25 to 2.85), standardized effect d = -0.03; z-test p = 0.898.
- Pramipexole 0.75mg Group: mean -11.80 versus -12.30 on control; difference 0.50 (95% CI -2.55 to 3.55), standardized effect d = 0.06; z-test p = 0.748.
Mean difference: Pramipexole 0.5mg Group
95% CI: -3.25 to 2.85
Recalculated from the posted summary statistics
8. Secondary Efficacy Endpoints
The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| IRLS Responder | Binary Endpoint | Risk difference | -1.9 pts (-21.1 to 17.2) | 10,200 per arm |
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 6 Weeks | Continuous Endpoint | Mean difference | 0.00 (-1.11 to 1.11) | n/a |
| Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 6 Weeks | Continuous Endpoint | Mean difference | -0.40 (-1.93 to 1.13) | 1,488 per arm |
IRLS Responder
- Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
- Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
- Result:
- Pramipexole 0.5mg Group: 58.5% (31/53) versus 60.4% (29/48) on control; risk difference -1.9 percentage points (95% CI -21.1 to 17.2), risk ratio 0.97 (0.70–1.34); unadjusted two-proportion z-test p = 0.844.
- Pramipexole 0.75mg Group: 49.1% (26/53) versus 60.4% (29/48) on control; risk difference -11.4 percentage points (95% CI -30.7 to 7.9), risk ratio 0.81 (0.57–1.16); unadjusted two-proportion z-test p = 0.252.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.5mg Group and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.75mg Group and the control. The interval gives the range of effects that remain compatible with the data.
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 6 Weeks
- Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
- Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
- Result:
- Pramipexole 0.5mg Group: mean -3.20 versus -3.20 on control; difference 0.00 (95% CI -1.11 to 1.11), standardized effect d = 0.00; z-test p = 1.000.
- Pramipexole 0.75mg Group: mean -2.50 versus -3.20 on control; difference 0.70 (95% CI -0.41 to 1.81), standardized effect d = 0.26; z-test p = 0.216.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.5mg Group and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.75mg Group and the control. The interval gives the range of effects that remain compatible with the data.
Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 6 Weeks
- Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
- Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
- Result:
- Pramipexole 0.5mg Group: mean -3.00 versus -2.60 on control; difference -0.40 (95% CI -1.93 to 1.13), standardized effect d = -0.10; z-test p = 0.609.
- Pramipexole 0.75mg Group: mean -2.30 versus -2.60 on control; difference 0.30 (95% CI -1.36 to 1.96), standardized effect d = 0.07; z-test p = 0.724.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.5mg Group and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pramipexole 0.75mg Group and the control. The interval gives the range of effects that remain compatible with the data.
The registry lists secondary outcomes spanning IRLS responder status, sleep quality, sleepiness, global impressions, safety measures and longer-term IRLS outcomes. These address different aspects of participant status and extend beyond the primary question about average IRLS score change during the blinded period. The outcome list therefore supplies broader context, but it does not make every secondary measure an equally strong basis for inference.
The posted secondary summaries do not suggest a clear, consistent separation across the dose groups. Some measures are continuous changes from baseline, while responder and impression outcomes are categorical. Their effect estimates and uncertainty are consequently expressed in different ways. The registry record includes results for secondary outcomes, but does not report a complete analysis plan or a correction for the number of outcomes and contrasts examined.
Secondary results can help assess whether the primary pattern is accompanied by changes in related domains. They should be interpreted alongside the primary endpoint rather than as independent confirmation. If many outcomes are examined without an adjustment strategy, some apparently notable findings may occur by chance. Unadjusted estimates and p-values therefore carry less inferential weight than results from a prespecified, fully described analysis, particularly when confidence intervals are broad.
The short blinded comparison and the open-label long-term outcomes also answer different questions. In an open-label period, participants and investigators are not masked in the same way as during the blinded phase, and the registry lists different numbers at risk across open-label dose groups. Long-term results can describe what was recorded during that period, but they do not have the same randomized, blinded comparison structure as the primary six-week endpoint. The registry record does not report details sufficient to assess how those outcomes were analyzed or how missing observations were handled.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- IRLS Responder
- Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 6 Weeks
- Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 6 Weeks
- Clinical Global Impression Global Improvement (CGI-I) Responder
- Patient Global Impression (PGI) Responder
- Clinically Significant Abnormalities in Vital Signs (Blood Pressure and Pulse Rate in Both Supine and Standing Positions), ECG, Laboratory Tests - Double Blind Period.
- Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 52 Weeks for Open-Label Period
- IRLS Responder for Open-label Period
9. Statistical Interpretation
The primary results show reductions in mean IRLS score from baseline in each dose group at week 6. The posted least-squares mean changes are -12.3 points for 0.25 mg, -12.5 points for 0.5 mg and -11.8 points for 0.75 mg, each with a standard error of 1.1. These are within-group changes; the dose contrasts address whether the average change differed between randomized groups.
Compared with 0.25 mg, the estimated mean difference for 0.5 mg is -0.2 points, with a 95% confidence interval from -3.249 to 2.849 and an unadjusted p-value of 0.898. The estimated mean difference for 0.75 mg is 0.5 points, with a 95% confidence interval from -2.549 to 3.549 and an unadjusted p-value of 0.748. Both intervals include zero and extend in both directions. Thus, the posted unadjusted comparisons are compatible with either direction of a difference, as well as with little or no difference between these dose groups.
The small estimated contrasts should not be read as proof that the doses are identical. A failure to distinguish groups in these summaries is not an equivalence finding: the registry record does not report an equivalence or non-inferiority framework, its margin, or an analysis addressing such a question. Nor do the within-group reductions establish what would have occurred without pramipexole, because the posted primary comparison is among active dose groups.
The registry describes a decrease of 10 or more points in mean change as clinically important. The reported group means are reductions of that scale, but this does not establish that every participant, or any particular proportion, experienced that amount of improvement. Individual outcomes and the primary group mean answer different questions.
The p-values are unadjusted comparisons derived from posted summary statistics, not a reported sponsor analysis. The registry record does not list a multiplicity strategy for the two dose contrasts or the many secondary outcomes. The primary results therefore warrant descriptive interpretation, with attention to the breadth of the confidence intervals and the absence of a reported analysis plan. The evidence in these posted summaries is about the observed six-week dose-group changes; it does not settle broader questions about long-term comparative effects, individual response, or the meaning of the trial for other populations.
10. Statistical Methods Explained
The primary outcome is continuous: it records change in an IRLS total score rather than placing participants into a simple yes-or-no category. A group mean summarizes the average change, while a standard error describes the estimated precision of that mean. The posted least-squares means are -12.3, -12.5 and -11.8 points for the three fixed-dose groups, with a standard error of 1.1 in each group. Least-squares means are adjusted means in many statistical settings, but the registry record does not describe the model or covariates used to obtain these particular values. The label is reported; the underlying analysis details are not reported in the registry record.
What does a mean difference represent?
A mean difference compares the average change in one group with the average change in the reference group. The posted reference is the 0.25 mg group. The estimate of -0.2 points for 0.5 mg is the contrast between its reported mean change and the reference mean; the estimate of 0.5 points for 0.75 mg is the corresponding contrast for that dose. The sign depends on the order of subtraction. It should not be interpreted without checking which group is the reference and how the contrast is defined.
These contrasts are not the same as the change from baseline within an individual group. A large change in each group can coexist with a small difference between groups when the groups’ average changes are similar. In this trial, the primary comparative question concerns differences among three active dose groups, not change relative to an untreated control.
How should the p-values be read?
A p-value describes how compatible the observed contrast is with a specified null model, under the assumptions of the analysis. It does not state the probability that the null hypothesis is true, measure the size or clinical importance of an effect, or show that the groups are equivalent. The unadjusted p-values are 0.898 for the 0.5 mg comparison and 0.748 for the 0.75 mg comparison. Since these are unadjusted recalculations from posted summary statistics, they should not be mistaken for results of a fully described sponsor model. The registry record does not report the sponsor’s detailed statistical method for the primary endpoint.
Why are the confidence intervals important?
A confidence interval gives a range of values compatible with the observed data under a statistical procedure and its assumptions. For the 0.5 mg contrast, the interval is -3.249 to 2.849 points; for the 0.75 mg contrast, it is -2.549 to 3.549 points. Both include zero, the value corresponding to no mean difference. Their width also matters: estimates on either side of zero remain compatible with the posted data. A point estimate alone would hide that uncertainty.
The comparisons are simple, unadjusted recalculations from the posted group summaries. For these continuous-outcome calculations, the standard errors were used to approximate standard deviations. This approach allows a basic comparison from the reported summaries, but it does not recreate a model-based analysis that may have accounted for baseline score, site, repeated observations, or other features. Whether such methods were used by the sponsor is not reported in the registry record. The recalculated intervals and p-values should therefore be treated as approximate descriptive comparisons.
What does over-dispersion mean in general?
In general, over-dispersion occurs when the observed variability in data is greater than the variability assumed by a statistical model. It can make standard errors too small if the extra variation is ignored, which can in turn make confidence intervals too narrow and p-values too small. It is especially relevant to some count and binary outcome models. The primary outcome is continuous, and the registry record does not report a model diagnostic or an over-dispersion assessment. This general concern should not be mistaken for evidence that over-dispersion occurred in this trial.
What details are not available?
The registry record does not report the original sample-size justification, the sponsor’s full statistical analysis plan, the model specification for the primary least-squares means, or how missing primary outcome data were handled. It also does not report an analysis population definition beyond naming the Full Analysis Set for the primary endpoint. Without those details, the posted summaries permit interpretation of the reported estimates and their approximate uncertainty, but not a full audit of the analysis decisions.
11. Confidence Intervals and Precision
Precision concerns the range of values that remain compatible with an estimate, not merely how many digits appear in the estimate. The primary mean difference comparing 0.5 mg with 0.25 mg is -0.2 points, with a 95% confidence interval from -3.249 to 2.849. The comparison of 0.75 mg with 0.25 mg is 0.5 points, with a 95% confidence interval from -2.549 to 3.549. Both intervals cross zero and include values on either side of it.
These intervals indicate that the estimated differences are not sharply determined by the posted summaries. Their ranges include a possible advantage in either direction, as defined by the contrast, and do not establish that the dose groups have the same mean change. The point estimates are close to zero, but point estimates alone are not a measure of precision. The interval width is essential to understanding how much uncertainty remains.
The group mean changes are reported with standard errors of 1.1 points. A standard error describes precision of a mean estimate, whereas individual participants’ scores may vary more widely. The registry record does not report confidence intervals for the three group means themselves. The contrast intervals are approximate, unadjusted recalculations from the posted summaries, with standard deviations approximated from the standard errors. They are not a substitute for an analysis using the sponsor’s full participant-level data and specified model.
Precision also depends on the question. The intervals describe differences in average score change between dose groups at week 6. They do not quantify uncertainty about individual response, long-term effects, or comparisons with placebo. The registry record does not report a prespecified equivalence margin, so these intervals cannot establish equivalence.
12. 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.
| Effect to detect | Participants per arm, 80% power | Participants per arm, 90% power |
|---|---|---|
| 100% of the observed effect | 24,041 | 32,184 |
| 75% of the observed effect | 42,739 | 57,215 |
| 50% of the observed effect | 96,161 | 128,733 |
The planning illustrations express required sample sizes as participants per arm for the continuous and binary outcomes. They are not total trial enrollment figures or total event counts. 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 the stated fraction of the observed effect. The registry record does not report the trial’s original sample-size assumptions or justification.
The 80% power column describes the planned sample size per arm for a hypothetical study designed to have an 80% chance of detecting the specified effect under those planning assumptions. The 90% power column gives the corresponding per-arm planning size for a higher chance of detection. These are prospective planning quantities based on the stated assumptions, not descriptions of the participants enrolled in this trial.
The illustrations include planning for 100%, 75% and 50% of the observed effect. Detecting a smaller effect requires more participants, because a smaller signal is harder to distinguish from random variation. The very large or small-looking sample estimates should be read in light of the observed effects used to generate them and the assumptions underlying the normal approximation. They do not establish that an effect is real, clinically important, or likely to recur.
These figures are planning illustrations, not observed power. Observed power is not a useful substitute for interpreting the estimated effects and confidence intervals after a study; the intervals communicate the uncertainty in the posted comparisons more directly.
13. 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 z1−α/2 = 1.960) and the desired power (z1−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
- Observed difference Δ = -0.200; pooled standard deviation σ = 7.827.
- n = 2 × (1.96 + 0.842)2 × 7.8272 / -0.2002 = 24,040.2, rounded up to 24,041 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 <- -0.199999999999999 # observed difference in means
sigma <- 7.82673480947054 # 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(390689)
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 = 24,041 (80% power), 32,184 (90% power)
75% of observed effect: n per arm = 42,739 (80% power), 57,215 (90% power)
50% of observed effect: n per arm = 96,161 (80% power), 128,733 (90% power)
power.t.test: 24041.2
Simulated power at n = 24,041 per arm: 0.803 (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.
14. Multiplicity, Missing Data and Analysis Populations
The registry record lists a primary endpoint and multiple secondary outcomes, including several comparisons across dose groups. Examining many endpoints and contrasts creates a multiplicity issue: even when there is no underlying difference, a collection of tests can produce apparently notable results by chance. A prespecified hierarchy, adjustment procedure, or other strategy can address that concern, but the registry record does not report such a strategy. The posted p-values described for the recalculated comparisons are unadjusted.
The registry record also does not report a detailed analysis plan, the original sample-size justification, or the sponsor’s full statistical model for the primary endpoint. It names the Full Analysis Set for the primary result, but does not define the population in detail or state how participants entered that set. It does not report whether analyses followed intention-to-treat principles or how deviations from assigned treatment were handled. These details matter because the analysis population and analytic choices can affect the estimate and its uncertainty.
Missing data handling is not reported in the registry record. The available outcome group sizes are listed, but the record does not explain why the numbers contributing to each result differ, whether missing observations were imputed, or whether sensitivity analyses were performed. Missingness can affect interpretation if the availability of an outcome is related to participant status or treatment group. Without a description of the approach, the posted estimates cannot show how robust they are to missing data assumptions.
The record’s use of least-squares means and standard errors signals summary quantities, but the model that generated them is not described. The simple recalculations accompanying the posted summaries do not incorporate unreported modeling choices or multiplicity procedures. These limitations do not invalidate the descriptive results; they constrain how strongly formal statistical claims can be made from the registry record.
15. 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 |
|---|---|---|---|
| Pramipexole 0.25mg (Double-blind) | 0 | 48 | 0.0% |
| Pramipexole 0.50mg (Double-blind) | 2 | 53 | 3.8% |
| Pramipexole 0.75mg (Double-blind) | 0 | 53 | 0.0% |
| Pramipexole 0.125mg (Open Label) | 1 | 8 | 12.5% |
| Pramipexole 0.25mg (Open Label) | 5 | 140 | 3.6% |
| Pramipexole 0.50mg (Open Label) | 0 | 97 | 0.0% |
| Pramipexole 0.75mg (Open Label) | 0 | 41 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Pramipexole 0.25mg (Double-blind) | 32 of 48 |
| Pramipexole 0.50mg (Double-blind) | 42 of 53 |
| Pramipexole 0.75mg (Double-blind) | 42 of 53 |
| Pramipexole 0.125mg (Open Label) | 5 of 8 |
| Pramipexole 0.25mg (Open Label) | 58 of 140 |
| Pramipexole 0.50mg (Open Label) | 50 of 97 |
Most frequent serious adverse event terms
| Event term | Organ system | Pramipexole 0.25mg (Double-blind) | Pramipexole 0.50mg (Double-blind) | Pramipexole 0.75mg (Double-blind) | Pramipexole 0.125mg (Open Label) | Pramipexole 0.25mg (Open Label) | Pramipexole 0.50mg (Open Label) |
|---|---|---|---|---|---|---|---|
| Gastroenteritis bacterial | Infections and infestations | 0 of 48 | 1 of 53 | 0 of 53 | 0 of 8 | 0 of 140 | 0 of 97 |
| Colon cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 48 | 1 of 53 | 0 of 53 | 0 of 8 | 0 of 140 | 0 of 97 |
| Breast cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Hepatic neoplasm malignant | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Maculopathy | Eye disorders | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Asthma | Respiratory, thoracic and mediastinal disorders | 0 of 48 | 0 of 53 | 0 of 53 | 1 of 8 | 0 of 140 | 0 of 97 |
| Pancreatitis acute | Gastrointestinal disorders | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Fall | Injury, poisoning and procedural complications | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Spinal compression fracture | Injury, poisoning and procedural complications | 0 of 48 | 0 of 53 | 0 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Pramipexole 0.25mg (Double-blind) | Pramipexole 0.50mg (Double-blind) | Pramipexole 0.75mg (Double-blind) | Pramipexole 0.125mg (Open Label) | Pramipexole 0.25mg (Open Label) | Pramipexole 0.50mg (Open Label) |
|---|---|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 6 of 48 | 13 of 53 | 6 of 53 | 4 of 8 | 32 of 140 | 29 of 97 |
| Nausea | Gastrointestinal disorders | 6 of 48 | 22 of 53 | 25 of 53 | 1 of 8 | 11 of 140 | 15 of 97 |
| Somnolence | Nervous system disorders | 10 of 48 | 15 of 53 | 9 of 53 | 0 of 8 | 9 of 140 | 11 of 97 |
| Headache | Nervous system disorders | 5 of 48 | 10 of 53 | 2 of 53 | 0 of 8 | 11 of 140 | 4 of 97 |
| Constipation | Gastrointestinal disorders | 7 of 48 | 3 of 53 | 3 of 53 | 0 of 8 | 4 of 140 | 1 of 97 |
| Vomiting | Gastrointestinal disorders | 0 of 48 | 4 of 53 | 5 of 53 | 1 of 8 | 3 of 140 | 5 of 97 |
| Dizziness | Nervous system disorders | 2 of 48 | 3 of 53 | 4 of 53 | 1 of 8 | 2 of 140 | 5 of 97 |
| Palpitations | Cardiac disorders | 3 of 48 | 3 of 53 | 1 of 53 | 0 of 8 | 2 of 140 | 2 of 97 |
| Stomach discomfort | Gastrointestinal disorders | 2 of 48 | 4 of 53 | 4 of 53 | 0 of 8 | 1 of 140 | 0 of 97 |
| Abdomial pain upper | Gastrointestinal disorders | 1 of 48 | 2 of 53 | 1 of 53 | 1 of 8 | 1 of 140 | 4 of 97 |
Serious events with the highest arm-level rate: asthma (12.5%), gastroenteritis bacterial (1.9%), colon cancer (1.9%), breast cancer (0.7%), hepatic neoplasm malignant (0.7%).
During the double-blind period, serious adverse events were reported for 0 participants among 48 at risk in the 0.25 mg group, 2 among 53 at risk in the 0.5 mg group, and 0 among 53 at risk in the 0.75 mg group. Other adverse events were reported for 32, 42 and 42 participants in those respective groups. These are counts of participants affected, not counts of every event occurrence.
The open-label groups are reported separately: serious adverse events affected 1 of 8 at risk at 0.125 mg, 5 of 140 at risk at 0.25 mg, 0 of 97 at risk at 0.50 mg, and 0 of 41 at risk at 0.75 mg. Other adverse events affected 5, 58, 50 and 29 participants, respectively. The open-label groups have different numbers at risk and do not have the same blinded randomized comparison structure as the primary analysis.
Deaths are not reported in the registry record. The record lists serious adverse event terms including asthma at 12.5%, gastroenteritis bacterial and colon cancer at 1.9% each, and breast cancer, hepatic neoplasm malignant and maculopathy at 0.7% each. The registry record does not provide enough detail in these summaries to infer comparative risk or causation. Safety counts describe what was recorded; they are not, by themselves, a determination of whether an event was caused by treatment.
16. What the Result Does, and Does Not, Mean
The posted primary results describe mean IRLS score reductions from baseline in all three fixed-dose groups over the six-week blinded period. The dose-group means are close to one another, and the estimated differences relative to 0.25 mg are small. The confidence intervals include zero and span values in both directions, so the posted comparisons do not precisely establish a difference between the dose groups.
That interpretation is narrower than saying the doses are identical. The registry record does not report an equivalence or non-inferiority design, a margin for defining similarity, or an analysis intended to establish either. An interval crossing zero means the data do not rule out no difference under the comparison; it does not prove no difference.
The endpoint is a group average. The registry describes a 10-point or greater decrease in mean change as clinically important, but a group mean cannot show how many individual participants reached that threshold. The primary endpoint also does not answer whether the observed within-group reductions would have occurred without pramipexole, because the listed primary comparisons are between active dose groups rather than against placebo or no treatment.
The six-week results do not establish the pattern of outcomes over the subsequent open-label period. That period has a different design, and its registry-listed safety groups have different numbers at risk. Nor do these results alone resolve whether changes in sleep or global impression measures align with the primary outcome; secondary analyses require their own context and are subject to multiplicity and reporting limitations.
Overall, the registry record supports a descriptive account of the posted score changes and their approximate comparative precision. It does not provide all information needed to reconstruct the sponsor’s statistical analysis, assess missing-data sensitivity, or make broad claims beyond the trial’s recorded population, outcomes and periods.
17. Why This Trial Matters Statistically
This trial illustrates why the within-group change and the between-group contrast answer different statistical questions. Each dose group had a reduction in mean IRLS score, while the primary dose comparisons estimate the difference between those average reductions. Reading only the direction or size of the group changes would miss the comparative uncertainty central to a randomized dose study.
It also shows why confidence intervals matter when point estimates are close to zero. The primary contrasts have intervals that include no difference and allow values on either side. The results therefore call for careful language: the estimates do not clearly separate the doses, but they do not establish equivalence. Distinguishing those statements is important in clinical-trial interpretation.
The registry provides a useful example of the limits of summary-level reanalysis. Least-squares means and standard errors are posted, but the model specification and full statistical plan are not. Simple unadjusted calculations can aid interpretation of scale and precision, while remaining distinct from a sponsor’s participant-level analysis. The absence of reported details about multiplicity, missing data and original planning assumptions further demonstrates how registry reporting affects the strength of statistical conclusions.
Finally, the blinded and open-label periods should not be conflated. The primary endpoint addresses the six-week randomized dose comparison; open-label outcomes extend the observation period but are not the same type of comparison. Keeping the endpoint, design period and estimand aligned is essential to reading the results accurately.
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 primary comparisons are reconstructed as unadjusted calculations from posted summary statistics, with standard deviations approximated from the reported standard errors. They may not reproduce the sponsor’s model-based analysis. The registry record does not report the model specification, covariate adjustment, detailed analysis plan, or original sample-size justification, so the analysis cannot be fully audited from these summaries.
The comparison is among three active doses, with the 0.25 mg group as the reference. No placebo or untreated comparator is described for the posted primary results. Consequently, the within-group score reductions do not isolate the change attributable to treatment relative to an untreated course. The confidence intervals are broad enough to include differences in either direction, and no equivalence margin is reported.
The record does not report how missing outcome data were handled, the detailed definition of the Full Analysis Set, or sensitivity analyses. It also does not report a multiplicity strategy despite the presence of multiple secondary outcomes and comparisons. The secondary summaries should therefore be treated as supportive and exploratory rather than as a set of independently definitive findings.
For safety, the open-label groups have differing numbers at risk and are not directly comparable with the randomized double-blind groups. The registry record does not report deaths, which should not be interpreted as evidence that none occurred. The serious adverse event term percentages are listed without enough context in these summaries to support causal or comparative conclusions. These limitations apply to interpretation of the registry record and do not establish that the underlying trial lacked additional analyses or documentation.
19. Related Tutorials
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: A Randomised, Comparing Fixed Doses of Pramipexole to Investigate the Efficacy and Safety in Patients With RLS. — NCT00390689.
- Registry record last updated 2014-07-02; status last verified 2014-04.
- Results first posted 2009-08-25.
- 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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22. Record Summary
NCT00390689 is a completed randomized, quadruple-masked, parallel-group phase 3 study of fixed-dose pramipexole in idiopathic restless legs syndrome. The official title describes a six-week double-blind comparison of 0.25 mg, 0.5 mg and 0.75 mg, followed by a 46-week open-label study. The registry lists enrollment of 154 and identifies change from baseline in IRLS total score at week 6 as the primary endpoint.
The posted primary group mean changes were -12.3, -12.5 and -11.8 points, respectively. The unadjusted dose contrasts against 0.25 mg have confidence intervals that include zero. The registry also lists secondary outcomes and safety results, but does not report the detailed statistical plan, missing-data methods, multiplicity strategy or original sample-size justification. Interpretation is therefore best kept to the recorded outcomes, study periods and uncertainty in the posted comparisons.