Safety and Efficacy Study of Daclizumab High Yield Process (DAC HYP) to Treat Relapsing-Remitting Multiple Sclerosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of Daclizumab High Yield Process (DAC HYP) to Treat Relapsing-Remitting Multiple Sclerosis (NCT00390221), a randomized phase 2 study. The primary outcome is Adjusted Annualized Relapse Rate Between Baseline and Week 52.

2. Clinical Question

3. Trial Design

This was a completed, phase 2, randomized, parallel-group study of DAC HYP as monotherapy in relapsing-remitting multiple sclerosis. The official title describes a multicenter, double-blind, placebo-controlled, dose-ranging study. The registry record also describes masking as quadruple; it does not identify the roles covered by that designation. Total enrollment was 621. The record lists Biogen as sponsor, a start date of 2008-02, and primary completion in 2011-05.

Participants were assigned to placebo, 150 mg DAC HYP, or 300 mg DAC HYP. Each regimen involved 3 subcutaneous injections every 4 weeks for up to 52 weeks. The primary outcome was the adjusted annualized relapse rate from baseline through Week 52. The primary outcome population was defined as randomized participants who received at least 1 dose of study medication, excluding 21 participants from a single site because of a protocol violation in dosing. The registry record does not explain further how that exclusion was determined or handled in other analyses.

Secondary outcomes included new gadolinium-enhancing lesions, new or newly-enlarging T2 hyperintense lesions, the proportion of participants who relapsed, and change in the physical impact score of the Multiple Sclerosis Impact Scale (MSIS)-29. The registry record describes the trial as completed, but the protocol’s original sample-size assumptions, detailed analysis plan, and handling of missing outcome data are not reported in the registry record. The reported results should therefore be read alongside the definitions and populations stated for each outcome, rather than assumed to share one analysis population or method.

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: Intent to treat population: all randomized participants who received at least 1 dose of study medication (excluding 21 participants from a single site due to a protocol violation in dosing).

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 Adjusted Annualized Relapse Rate Between Baseline and Week 52, measured over Baseline through Week 52.

The primary endpoint was the adjusted annualized relapse rate between baseline and Week 52, expressed as relapses per person-years. The registry definition of relapse required new or recurrent neurologic symptoms that were not associated with fever or infection, lasted at least 24 hours, and were accompanied by new objective neurological findings on examination by the examining neurologist. The annualized rate was calculated from the total relapse count and total subject-years followed.

A rate endpoint is useful when participants may contribute different amounts of observation time. It relates the number of events to exposure time, rather than comparing event counts as if each participant had exactly the same follow-up. It also reflects repeated relapses, unlike a simple measure of whether a participant experienced any relapse. These are general features of rate outcomes, not additional details of this trial’s analysis.

The registry reports adjusted rates of 0.458 for placebo, 0.211 for 150 mg DAC HYP, and 0.23 for 300 mg DAC HYP, each in relapses per person-years. The outcome timeframe was baseline through Week 52. The registry identifies the primary population as randomized participants who received at least 1 dose, excluding 21 participants from a single site because of a protocol violation in dosing. The reason for choosing the adjustment variables, and the details of the adjustment model beyond the reported analysis, are not reported in the registry record.

7. Results Posted in the Registry

• 150 mg DAC HYP: 0.21 versus 0.46 (relapses per person-years) on control; rate ratio 0.46 (95% CI 0.32–0.67, derived from the posted confidence limits); p ≈ <0.001.
• 300 mg DAC HYP: 0.23 versus 0.46 (relapses per person-years) on control; rate ratio 0.50 (95% CI 0.35–0.72, derived from the posted confidence limits); p ≈ <0.001.

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.

Proportion of Participants Who Relapsed at Week 52

• 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:
  • 150 mg DAC HYP: 0.0% (0/201) versus 0.5% (1/196) on control; risk difference -0.5 percentage points (95% CI -1.5 to 0.5); unadjusted two-proportion z-test p = 0.311.
  • 300 mg DAC HYP: 0.0% (0/203) versus 0.5% (1/196) on control; risk difference -0.5 percentage points (95% CI -1.5 to 0.5); unadjusted two-proportion z-test p = 0.308.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 150 mg DAC HYP 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 300 mg DAC HYP and the control. The interval gives the range of effects that remain compatible with the data.

Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52

• 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 deviations.
• Result:
  • 150 mg DAC HYP: mean -1.00 versus 3.00 on control; difference -4.00 (95% CI -6.50 to -1.50), standardized effect d = -0.32; z-test p = 0.002.
  • 300 mg DAC HYP: mean 1.40 versus 3.00 on control; difference -1.60 (95% CI -4.25 to 1.05), standardized effect d = -0.12; z-test p = 0.237.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for 150 mg DAC HYP than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 300 mg DAC HYP and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the primary question beyond annualized relapse rate. They include relapse occurrence by Week 52, MSIS-29 physical impact, and measures of new gadolinium-enhancing and new or newly-enlarging T2 hyperintense lesions. The registry reports numerical analyses for relapse occurrence and MSIS-29 physical impact. Numerical results for the lesion outcomes are not reported in the registry record.

Across the posted secondary analyses, the relapse-occurrence results are reported as hazard ratios below 1 for both dose comparisons. For MSIS-29 physical impact, the sponsor-reported analysis differs by dose: one comparison has a reported p-value below 0.05 and the other does not. These outcomes use different scales and statistical methods from the primary annualized rate, so they are complementary rather than interchangeable evidence. The secondary results do not change the definition or analysis population of the primary endpoint.

Secondary findings generally carry less confirmatory weight when several outcomes or comparisons are examined and no multiplicity procedure is reported. Multiple testing increases the chance that at least one result may appear statistically unusual by chance. This is a general concern, not a claim that any particular finding is false. The registry record does not report a multiplicity adjustment or a hierarchy defining which secondary outcomes were confirmatory. Accordingly, secondary p-values are best read as outcome-specific evidence, with caution about treating them as independent confirmation of the primary result.

The registry lists imaging measures among the secondary objectives, but their numerical results are not reported in the registry record. Their absence limits assessment of how consistently the reported clinical endpoint findings corresponded to the planned lesion outcomes. No conclusion about those unreported results can be drawn from the outcomes that are posted.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Adjusted Mean Number of New Gadolinium (Gd)-Enhancing Lesions Between Week 8 and Week 24
• Adjusted Mean Number of New or Newly-enlarging T2 Hyperintense Lesions at Week 52
• Proportion of Participants Who Relapsed at Week 52
• Mean Change From Baseline in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Impact Score at Week 52

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports two types of analysis for the primary outcome. The sponsor’s own analyses used negative binomial regression and report rate ratios with 95% confidence intervals and p-values. The simple recalculations use posted group rates and a Poisson rate-ratio approach. These methods share a focus on event rates but make different assumptions about the variation in counts. The sponsor’s regression results are the trial’s reported analyses; the recalculations are an unadjusted check based on summary values.

What does a rate ratio express?

A rate ratio compares event rates between groups. A value of 1 represents equal estimated rates; a value below 1 represents a lower estimated rate in the numerator group than in the reference group, while a value above 1 represents a higher estimated rate. The reported primary comparisons use placebo as the reference and compare it with each DAC HYP dose. This interpretation is general; the estimates themselves are those reported for the trial.

The annualized relapse rate accounts for exposure time by relating relapse counts to person-years. Participants can contribute different amounts of observation time, so exposure-based rates can be more suitable than raw counts when follow-up varies. The registry defines the annualized rate as total relapses divided by total subject-years followed. The word “adjusted” appears in the endpoint title, but the registry record does not list the variables used for adjustment in the primary outcome.

Why can a negative binomial model be used?

Count data often vary more than a simple Poisson model allows. This extra variability is called over-dispersion. In general, a negative binomial model can accommodate over-dispersion by allowing count variation beyond the mean-based variation assumed by a basic Poisson model. That can affect estimated uncertainty and confidence intervals. The registry reports negative binomial regression for the sponsor’s primary analyses, but the registry record does not state whether over-dispersion was formally assessed or why this model was selected.

The recalculation from summary rates uses a Poisson assumption. This is a simpler, unadjusted calculation and does not reproduce the sponsor’s full regression model. Its purpose is a consistency check, not a replacement analysis. Agreement between the recalculated and sponsor-reported estimates is close in these comparisons, but the methods and the precision estimates are not identical. Because the registry’s discrepancy indicator is false, no material discrepancy is flagged between the posted results and the recalculation.

How should a confidence interval be read?

A confidence interval represents uncertainty around an estimate under the assumptions of its statistical method. For the primary rate ratios, the 95% intervals give a range of values compatible with the observed data and model at the stated confidence level. A narrower interval indicates greater precision than a wider interval, all else equal. An interval that includes 1 does not rule out equal rates at that confidence level; an interval excluding 1 is evidence against that value under the model. This general explanation does not make the interval a guarantee about the true value.

A p-value describes how unusual data at least as incompatible with the null hypothesis would be if the null model and analysis assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The sponsor reports p < 0.001 for 150 mg and p < 0.001 for 300 mg in the primary analyses. The recalculated, unadjusted p-values are both reported as p < 0.001. Different model specifications and rounding can yield different reported p-values.

What is different about the secondary analyses?

The posted secondary analyses use methods suited to different outcome types. The registry reports Cox proportional hazards analyses for the proportion of participants who relapsed by Week 52, with hazard ratios. A hazard ratio compares event rates over time among participants still at risk, under the model. The record also reports analysis of variance for MSIS-29 physical impact, a continuous score, with relative mean change as the reported parameter. For these outcomes, the registry’s sponsor-reported method and parameter should be distinguished from unadjusted recalculations from summary values.

The recalculated MSIS-29 comparisons use group means and standard deviations to estimate unadjusted mean differences and confidence intervals. They are not the same estimand as the sponsor’s reported relative mean change from an analysis of variance model. The secondary relapse summary values also do not support treating a simple binary proportion comparison as equivalent to the registry’s time-to-event analysis. The registry record does not report the complete analysis specifications for these outcomes.

Several outcome definitions, analysis populations, and statistical methods can coexist within a trial. A result’s meaning depends on its endpoint, timeframe, comparison, and model. General statistical principles can explain how these methods work, but details such as covariate selection, model diagnostics, missing-data handling, and adjustments for multiple testing are not reported in the registry record.

11. Confidence Intervals and Precision

The primary rate-ratio estimates are accompanied by 95% confidence intervals. For 150 mg DAC HYP, the sponsor reports a rate ratio of 0.461 with an interval from 0.318 to 0.668. For 300 mg DAC HYP, the reported rate ratio is 0.503 with an interval from 0.352 to 0.721. Both intervals exclude 1, the value corresponding to equal rates under a rate-ratio interpretation. Their widths indicate that the data do not determine a single exact relative-rate value; each interval contains a range of estimates compatible with the analysis.

The unadjusted recalculations give rate ratios of 0.461 and 0.502, with intervals from 0.317 to 0.670 and from 0.350 to 0.720, respectively. Those intervals are similar to, but not identical with, the sponsor’s intervals. The recalculations use a Poisson model on summary rates, whereas the registry reports negative binomial regression. Differences in modeling and rounding can produce small differences in estimates and precision.

Confidence intervals quantify statistical uncertainty under the specified model; they do not account automatically for every possible source of uncertainty. For example, a confidence interval does not resolve limitations in endpoint measurement, analysis population, missing-data handling, or multiplicity. The registry record does not report several of those analysis details. The intervals should therefore be read as model-based precision for the stated comparisons, not as a complete measure of uncertainty about all aspects of the trial.

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.

The sample-size figures are planning illustrations based on observed effects, not the trial’s original design calculations. For the comparisons listed, figures are participants per arm, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers detecting the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the model assumptions hold. The 90% power column describes the corresponding target for a 90% chance. These are design quantities, not probabilities that the trial’s result is correct or that a treatment effect exists. The figures are not observed power.

Rows for 100% of the observed effect use the effect estimated in the posted comparison; rows for 75% and 50% consider smaller effects. Smaller effects are harder to distinguish from random variation, so the illustration requires more participants per arm for the same target power. The figures should not be read as recommendations or as evidence that the trial was or was not adequately planned. They are conditional calculations based on the stated assumptions, while the actual trial design rationale is not reported in the registry record.

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 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, λ₀ and λ₁ are event rates per patient-year, and T is follow-up per participant in years. This assumes Poisson counts and equal follow-up.

Worked calculation for this trial

1. Control rate λ₀ = 0.4580; treatment rate λ₁ = 0.2110 events per patient-year; follow-up T = 1.00 years.
2. n = (1.96 + 0.842)² × (1/0.4580 + 1/0.2110) / (1.00 × [ln(0.461)]²) = 90.8, rounded up to 91 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
lambda0 <- 0.458                      # control rate, events per patient-year
lambda1 <- 0.211                      # treatment rate
tt      <- 0.996550402453047                       # follow-up per participant, years
n_per_arm <- function(power, frac = 1) {
  l1 <- lambda0 * (lambda1 / lambda0)^frac   # smaller effect = fraction of the observed log rate ratio
  ceiling(round((z_a + qnorm(power))^2 * (1 / lambda0 + 1 / l1) / (tt * log(l1 / lambda0)^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 = ",")))

# Simulation 1: Poisson counts. Simulation 2: over-dispersed counts (variance = 1.5 x mean), analysed with the matching variance.
set.seed(390221)
n    <- n_per_arm(0.80)
reps <- 20000
m0 <- lambda0 * n * tt; m1 <- lambda1 * n * tt
x0 <- rpois(reps, m0); x1 <- rpois(reps, m1)
z  <- log(x1 / x0) / sqrt(1 / x0 + 1 / x1)
cat(sprintf("Simulated power, Poisson counts, n = %s per arm: %.3f\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE)))
phi <- 1.5
y0 <- rnbinom(reps, mu = m0, size = m0 / (phi - 1)); y1 <- rnbinom(reps, mu = m1, size = m1 / (phi - 1))
z2 <- log(y1 / y0) / sqrt(phi * (1 / y0 + 1 / y1))
cat(sprintf("Simulated power, over-dispersed counts (phi = 1.5), same n: %.3f\n", mean(abs(z2) > z_a, na.rm = TRUE)))

Output from running the code

100% of observed effect: n per arm = 91 (80% power), 122 (90% power)
 75% of observed effect: n per arm = 142 (80% power), 190 (90% power)
 50% of observed effect: n per arm = 284 (80% power), 380 (90% power)
Simulated power, Poisson counts, n = 91 per arm: 0.823
Simulated power, over-dispersed counts (phi = 1.5), same n: 0.651

The first simulation draws Poisson counts and should land close to the target power. The second allows extra variability (variance 1.5 times the mean, a purely illustrative value), which lowers the power at the same sample size, so rate trials usually need more participants than the Poisson formula suggests.

14. Analyses Reported by the Sponsor

The sponsor’s primary analyses are reported as negative binomial regression rate ratios. For the 150 mg comparison, the sponsor reports 0.461 with a 95% confidence interval of 0.318 to 0.668 and p < 0.001. For the 300 mg comparison, the reported estimate is 0.503 with a 95% confidence interval of 0.352 to 0.721 and p < 0.001.

The simple recalculations from posted summary rates give rate ratios of 0.461 and 0.502, with 95% confidence intervals of 0.317 to 0.670 and 0.350 to 0.720. These are unadjusted Poisson-based recalculations, not a reproduction of the sponsor’s regression analysis. Their close correspondence with the sponsor’s estimates offers a consistency check, while the small differences are compatible with the use of different methods and rounding. The recalculated p-values are reported as p < 0.001 for both comparisons.

The registry record does not flag a discrepancy between the posted results and recalculation. The sponsor’s model-based results remain the reported trial analyses; the recalculations help readers understand the comparison using the posted group rates but do not supersede the sponsor’s analysis.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates multiple outcomes, treatment groups, or statistical comparisons. The chance of at least one apparently notable result can increase as the number of tests grows. Trial analysis plans commonly address this through prespecified hierarchies or statistical adjustments, but whether such procedures were used for this study is not reported in the registry record. The posted p-values should therefore be understood as outcome-specific results; the record does not establish that they control an overall error rate across all analyses.

The registry identifies five outcome measures and ten analyses. It lists primary and secondary outcomes, but the detailed strategy for prioritizing hypotheses and handling multiple comparisons is not reported in the registry record. The presence of multiple doses and secondary measures makes that information relevant when weighing the secondary findings. This does not invalidate the reported analyses; it limits how strongly nominal p-values can be interpreted across the full set of outcomes.

The primary outcome population is described as randomized participants who received at least 1 dose, excluding 21 participants from a single site because of a protocol violation in dosing. This definition is narrower than a description of all randomized participants. The registry record does not report additional details about the handling of missing data, withdrawal, incomplete follow-up, or whether other analysis populations were used for particular outcomes. It also does not provide the full protocol or statistical analysis plan.

These omissions matter because analysis choices can affect estimates and their uncertainty. Missing-data methods, treatment of follow-up time, covariate adjustment, and the population included can influence interpretation. The endpoint-specific results remain informative as posted, but the registry record does not allow a full audit of every analysis decision or of whether all planned analyses are represented.

16. 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: multiple sclerosis relapse (21.6%), leukocytosis (0.5%), angina unstable (0.5%), atrial fibrillation (0.5%), diabetes insipidus (0.5%).

The registry reports participants with serious adverse events by group. The serious adverse event figures are 53 among 204 participants at risk in the placebo group, 32 among 208 at risk in the 150 mg DAC HYP group, and 36 among 209 at risk in the 300 mg DAC HYP group. The registry also reports a Total Active group with 68 among 417 at risk. These are counts of participants affected and the corresponding group sizes at risk as recorded; they are not a complete description of event timing, duration, severity, or causal attribution.

The listed serious adverse event terms include multiple sclerosis relapse at 21.6%, followed by leukocytosis, unstable angina, atrial fibrillation, diabetes insipidus, and gastritis, each at 0.5%. The registry record does not provide further context in this summary for interpreting those percentages or comparing individual terms across arms. Death counts are not reported in the registry record.

These figures describe reported safety events in the registry record. They do not, on their own, establish whether an event was caused by a study intervention or provide a complete benefit-risk assessment. The definitions, collection procedures, exposure-adjusted event rates, and detailed event narratives are not reported in the registry record.

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

The primary registry results show lower adjusted annualized relapse-rate estimates in both DAC HYP groups than in the placebo group over baseline through Week 52. The sponsor-reported rate ratios are below 1, and their 95% confidence intervals exclude 1. This is evidence from the stated analysis that the group rates differed over the measured timeframe. It is not a guarantee of an exact effect size, nor does it establish how the result would generalize beyond the trial population and follow-up.

The endpoint concerns relapses meeting the trial’s neurologic symptom and examination definition, expressed per person-years. It is not a measure of every aspect of multiple sclerosis, and a rate comparison is distinct from comparing the proportion of participants who relapsed or measuring quality of life. The registry reports some secondary analyses, but other listed outcome results are not reported in the registry record. Those outcomes cannot be inferred from the primary result.

The findings do not by themselves establish the safety profile or causal attribution of adverse events. The safety summary gives serious adverse event counts, but not a full account of event characteristics or causal assessments. The registry record also does not report the detailed missing-data strategy, original sample-size justification, full analysis plan, or multiplicity approach. These omissions constrain assessment of robustness and the context for secondary p-values.

The posted statistics are evidence about group-level comparisons under the reported methods. They do not determine an individual outcome, substitute for clinical judgment, or support advice about treatment. Interpretation should stay tied to the population definition, endpoint, timeframe, and statistical methods that the registry reports.

18. Why This Trial Matters Statistically

This trial illustrates how the choice of endpoint shapes the statistical question. An annualized relapse rate uses event counts relative to person-time and can represent repeated events, whereas a binary relapse outcome asks whether a participant experienced a relapse within a defined period. The two measures address related but different aspects of the data and are analyzed with different statistical approaches.

It also provides a practical comparison between a sponsor-reported negative binomial regression and a simple Poisson recalculation from summary rates. The close agreement in the primary rate-ratio estimates is reassuring as a numerical check, while the method distinction remains important: an unadjusted calculation does not reproduce the sponsor’s regression model. Confidence intervals make the uncertainty around each estimate visible, rather than reducing interpretation to whether a p-value crosses a threshold.

Finally, the record highlights why analysis populations, multiplicity, and reporting completeness matter. The primary analysis excludes 21 participants from a single site because of a dosing protocol violation, and the record does not detail the full missing-data or multiplicity strategy. Secondary outcomes include different measurement types, and numerical results for the lesion measures are not reported in the registry record. Statistical interpretation therefore depends not just on estimates, but also on the definitions, methods, and limitations accompanying them.

19. 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.
• Rate comparisons use a Poisson approximation unless the sponsor posted confidence limits; real event counts are often over-dispersed.

Several trial-specific limitations affect interpretation. The primary outcome population excludes 21 participants from a single site because of a protocol violation in dosing. The registry record does not describe further details about the violation, the basis for the exclusion, or the sensitivity of results to including those participants. The stated population is randomized participants who received at least 1 dose, rather than an unqualified analysis of everyone randomized.

The primary endpoint covers baseline through Week 52. The registry record does not report longer-term results in the information summarized for this outcome, so the primary estimate should not be extended to a different follow-up period. Although the official title describes a multicenter study, the record does not give further site-level results in this information.

The record does not report the original sample-size justification, detailed statistical analysis plan, adjustment variables for the primary rate, missing-data methods, or multiplicity procedures. Those details are important for evaluating prespecification, robustness, and interpretation of secondary p-values. Numerical results for the listed lesion outcomes are also not reported in the registry record, limiting evaluation of those planned outcome domains.

The primary recalculation is unadjusted and uses a Poisson approach, whereas the sponsor reports negative binomial regression. The recalculation is therefore not a full independent reproduction of the sponsor analysis. Safety reporting is also limited in this summary: serious adverse event counts and selected terms are listed, but death counts and detailed causal assessments are not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of Daclizumab High Yield Process (DAC HYP) to Treat Relapsing-Remitting Multiple Sclerosis — NCT00390221.
• Registry record last updated 2016-07-11; status last verified 2016-05.
• Results first posted 2016-07-11.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The registry record describes a completed phase 2 randomized, parallel-group, placebo-controlled, dose-ranging trial of DAC HYP in relapsing-remitting multiple sclerosis. Enrollment was 621. The primary outcome was adjusted annualized relapse rate from baseline through Week 52, measured as relapses per person-years in the defined treated randomized population, with 21 participants from a single site excluded because of a dosing protocol violation.

The sponsor reports negative binomial rate ratios of 0.461 for 150 mg DAC HYP versus placebo and 0.503 for 300 mg DAC HYP versus placebo. Both reported 95% confidence intervals exclude 1. Simple recalculations from posted summary rates are close but use a different, unadjusted method. Secondary findings cover relapse occurrence and MSIS-29 physical impact; numerical results for the listed lesion outcomes are not reported in the registry record.

The record does not report the original sample-size rationale, full analysis plan, missing-data strategy, or multiplicity procedures. Safety results include serious adverse event counts by group, but death counts are not reported in the registry record.