Minocycline as add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif®) in Relapsing-Remitting Multiple Sclerosis [RRMS]: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Minocycline as add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif®) in Relapsing-Remitting Multiple Sclerosis [RRMS] (NCT01134627), a randomized phase 2 study. The primary outcome is Number of Participants Who Experienced First Documented Relapse.

2. Clinical Question

3. Trial Design

This was a Phase 2 randomized, double-blind, parallel-group trial comparing minocycline with placebo as an add-on to interferon beta-1a (Rebif®) in people with relapsing-remitting multiple sclerosis. The registry describes the study as multicentre. Enrollment is listed as 305. The record lists 149 participants in the Rebif® plus minocycline arm and 155 in the Rebif® plus placebo arm for the primary outcome. These arm counts are stated as posted; they should not be treated as a recalculation of enrollment.

The trial started in 2006-02, had primary completion in 2011-04, and is listed as terminated. The reason for termination is not reported in the registry record. The registry does not report the planned allocation ratio, the identities of the people masked, or the details of the randomization procedure. The arm descriptions do not provide further treatment schedules.

The primary outcome was the number of participants who experienced a first documented relapse, assessed from baseline through 96 weeks (+/- 1 week) or early termination. The primary outcome population is described as the intention-to-treat population, including randomized participants who received study medication. Secondary outcomes listed include documented relapses, new or enlarging lesions on T2-weighted MRI, and changes in brain volume measured by MRI. Numeric summaries are posted for the lesion and brain-volume outcomes, but a numeric secondary result for documented relapses is not reported in the registry record.

The record identifies a Phase 2 study but does not report the original sample-size justification or the assumptions used to plan the trial. The planning illustrations associated with the posted results are based on observed effects and should not be confused with the trial's original design.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: One out of 305 participants was randomized by mistake and did not receive study medication.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intention to Treat (ITT) population included all the participants who were randomized and received study medication.

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 Number of Participants Who Experienced First Documented Relapse, measured over Baseline up to 96 weeks (+/- 1 week) or early termination (ET).

The primary endpoint counts participants who experienced a first documented relapse. It is a binary outcome at the participant level: a participant either had a documented first relapse during the specified follow-up or did not. The outcome is not the total number of relapses, the duration of relapses, or a time-to-event estimate.

The registry defines a documented relapse as the development of new neurological symptoms or worsening of existing symptoms persisting for >48 hrs, with a prior period of >30 days in a stable or improving condition. The definition also requires a specified change in functional-system scoring or in the expanded disability status scale. The registry describes that scale as assessing disability across 8 functional systems, with an overall score from 0 (normal) to 10 (death due to multiple sclerosis).

A participant count is useful because it expresses how many people in each group met the defined event criterion during follow-up. Comparing the groups can describe the observed difference in the proportion experiencing a first relapse. It does not, by itself, explain when relapses occurred, how often participants relapsed after the first event, or whether other clinical measures changed. Early termination is included as a possible endpoint assessment time, so follow-up was not necessarily identical for every participant.

7. Results Posted in the Registry

• Rebif®+ Minocycline: 21.5% (32/149) versus 25.2% (39/155) on control; risk difference -3.7 percentage points (95% CI -13.2 to 5.8), risk ratio 0.85 (0.57–1.29); unadjusted two-proportion z-test p = 0.448.

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.

Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI)

• 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:
  • Rebif®+ Minocycline: mean 3.00 versus 3.00 on control; difference 0.00 (95% CI -2.20 to 2.20), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Rebif®+ Minocycline and the control. The interval gives the range of effects that remain compatible with the data.

Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI)

• 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:
  • Rebif®+ Minocycline: mean -2,997 versus 5,835 on control; difference -8,832 (95% CI -22,067 to 4,402), standardized effect d = -0.38; z-test p = 0.191.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Rebif®+ Minocycline and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes address related but different aspects of relapsing-remitting multiple sclerosis: documented relapses, new or enlarging MRI lesions, and changes in brain volume. In the posted numeric results, the lesion group means are the same, while the brain-volume means differ; both unadjusted confidence intervals include zero. A numeric secondary result for documented relapses is not reported in the registry record. The secondary evidence therefore does not give a consistent, precise pattern that independently settles the primary comparison.

The primary outcome concerns whether a participant experienced a first documented relapse. MRI measures are distinct outcomes and should not be treated as substitutes for that endpoint. They may provide complementary information, but an MRI comparison cannot by itself establish what happened to the primary clinical outcome. Likewise, the absence of a numeric secondary relapse result means that outcome cannot be used to cross-check the primary result from the posted record.

The secondary summaries are based on fewer participants than the primary-outcome summaries. The reason for those smaller denominators and the handling of missing measurements are not reported in the registry record. This limits how confidently the MRI results can be compared with the primary finding.

Multiplicity is another consideration. When several outcomes are examined, the chance of observing an apparently notable result by chance can increase. General statistical explanation: prespecified adjustment procedures can address that issue, but no multiplicity procedure is reported in the registry record. The secondary p-values are unadjusted and should carry less weight than a confirmatory result from a prespecified analysis with a documented testing strategy. They are best read as descriptive evidence that helps characterize the trial, rather than as separate proof for or against the primary result.

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

• Number of Participants With Documented Relapses
• Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI)
• Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI)

9. Statistical Interpretation

10. Statistical Methods Explained

The posted comparisons use different statistical summaries because the outcomes have different forms. The primary endpoint is a participant count for an event, while the MRI outcomes are continuous measurements summarized by means and standard deviations. The comparisons are unadjusted recalculations from the posted summary statistics. The registry record does not report a sponsor statistical analysis for these comparisons.

How should the primary risk difference be read?

General statistical explanation: a risk difference compares the proportion with an event in one group with the proportion in the other group. A value of zero represents no difference between the group proportions. A negative value means the event proportion is lower in the group placed first in the comparison than in the comparator group. For this trial, the posted estimate is -0.037. Its confidence interval crosses zero, so the data are compatible with no difference and with differences in either direction. The interval should be considered alongside the estimate rather than treating the estimate as a precise measure of the true effect.

The primary outcome is a count of participants with an event, not a rate calculated per unit of follow-up. Follow-up was described as baseline through 96 weeks (+/- 1 week) or early termination. The record does not provide participant-level event times or a time-to-event analysis. Thus, the primary comparison does not use the timing of a first relapse in the way a survival analysis would.

What do the p-values describe?

General statistical explanation: a p-value measures how incompatible the observed data are with a specified null model, under the assumptions of the calculation. A larger p-value is not proof that the null model is true, and it does not quantify the probability that a treatment effect exists. The primary unadjusted p-value is 0.448. The secondary unadjusted p-values are 1.0 for the lesion comparison and 0.191 for the brain-volume comparison. These are descriptive unadjusted results; the registry record does not report adjustment for testing multiple outcomes.

For the continuous MRI outcomes, the reported comparison is a difference between group means. General statistical explanation: a mean difference describes the separation between average measurements, while the standard deviation describes how spread out individual measurements are within a group. A mean difference close to zero can coexist with substantial variability among participants. The lesion summaries show a mean of 3.0 in both groups, while the brain-volume summaries have a broad confidence interval around their mean difference. These statistics do not describe every participant's outcome or the shape of the underlying measurements.

Why do participant counts and outcome counts differ?

The primary outcome denominators are 149 and 155. The secondary MRI summaries use smaller denominators: 23 and 27 participants for lesion counts, and 23 and 26 for brain-volume change. These are the denominators reported for those outcomes; they should not be presumed to represent the full primary-outcome population. The registry record does not report why the secondary denominators are smaller, how missing values were handled, or whether any imputation was used. Without such details, it is not possible to determine from the record whether the missing outcome data could affect the comparisons.

The registry defines the primary intention-to-treat population as randomized participants who received study medication. The record does not describe an additional analysis population or provide an account of exclusions from the outcome summaries. General statistical explanation: analysis-population definitions matter because they determine which participants contribute to a result. The available definition is useful, but it does not answer every question about participant flow or missing data.

What is the role of the confidence intervals?

General statistical explanation: a confidence interval describes the uncertainty around an estimated effect under a statistical procedure and its assumptions. A narrower interval indicates greater precision; a wider interval indicates less precision. An interval that includes zero does not establish equivalence or rule out effects that may matter. The primary interval extends to both negative and positive differences. The MRI intervals also permit a range of possible mean differences, with the brain-volume interval particularly broad. These intervals make clear that the posted estimates should not be read as exact values.

The record does not report whether the trial used interim analyses, a prespecified covariate-adjusted model, or a formal multiplicity strategy. The absence of these details in the registry record does not establish what was or was not done outside the posted record. No conclusion about the trial's original statistical plan can be drawn from the unadjusted recalculations alone.

11. Confidence Intervals and Precision

The primary risk-difference estimate is -0.037. Its 95% confidence interval runs from -0.132 to 0.058. Because the interval includes zero and extends to negative and positive values, the observed estimate is not precise enough to determine the direction or size of the underlying difference with confidence. The unadjusted p-value of 0.448 is consistent with this uncertainty, but the interval gives more direct information about the range of effects compatible with the calculation.

A confidence interval is not a range that guarantees where the true effect lies. General statistical explanation: it is an interval produced by a method that, under its assumptions, has a stated long-run coverage property. Its interpretation depends on the design, the analysis, and the quality of the underlying data. Here, the interval is based on posted group counts, and the registry does not provide a sponsor analysis to compare with that recalculation.

The secondary estimates also have uncertainty. For lesion counts, the mean difference is 0.0 and the 95% confidence interval ranges from -2.198 to 2.198. For brain-volume change, the mean difference is -8832.0 cubic millimeter and the interval ranges from -22070.0 to 4402.0. Both intervals include zero. The brain-volume interval permits a wide range of possible differences, so its point estimate should not be treated as precise. The secondary MRI outcome denominators are much smaller than the primary-outcome denominators, and the registry record does not explain the difference.

Confidence intervals do not address every source of uncertainty. They do not account for unreported analysis choices, possible bias from missing outcome data, or multiplicity unless those features are incorporated into the method. Those details are not reported in the registry record. The uncertainty in the posted intervals should therefore be considered together with the gaps in the record, rather than read as a complete account of all uncertainty.

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 illustrations translate an observed effect into hypothetical planning requirements. For these comparisons, the figures are participants per arm, not total events. The record's planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each illustration uses the stated fraction of the observed effect. The original trial's own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed for an 80% chance of detecting the specified effect under its assumptions. The 90% power column gives the corresponding planning estimate for a 90% chance. These are planning probabilities for a hypothetical repeated study under the model, not probabilities that the posted result is correct. The calculations are not observed power.

The rows that plan for 100%, 75%, or 50% of the observed effect illustrate how the assumed effect size changes the planning requirement. A smaller effect is harder to distinguish from random variation, so it requires more participants to reach the same target power under the same assumptions. This relationship is a general feature of statistical planning, not evidence that the smaller effect is the true effect.

The sample-size illustrations are not the enrollment plan used for this trial. They are derived from observed effects after the trial and are sensitive to those estimates. Because the observed effects themselves are uncertain, the planning figures should be treated as examples of scale under stated assumptions, not as a recommendation or as proof that a future study will achieve the listed power.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.252; treatment proportion p₁ = 0.215; average p̄ = 0.233.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5980 = 1.1721.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5974 = 0.5028.
4. n = (1.1721 + 0.5028)² / (-0.0368)² = 2,066.2, rounded up to 2,067 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
p0 <- 0.251612903225806                          # control proportion
p1 <- 0.214765100671141                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1134627)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 2,067 (80% power), 2,766 (90% power)
 75% of observed effect: n per arm = 3,725 (80% power), 4,986 (90% power)
 50% of observed effect: n per arm = 8,492 (80% power), 11,368 (90% power)
power.prop.test: 2066.2 
Simulated power at n = 2,067 per arm: 0.803 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 multiple outcomes, including the primary first documented relapse endpoint and secondary outcomes involving documented relapses, MRI lesions, and brain volume. It does not report a multiplicity adjustment or a hierarchy specifying how the outcomes were to be tested. The posted secondary p-values are unadjusted. When several outcomes are tested, interpreting each result as though it were the only test can overstate the strength of evidence; without a reported strategy, the secondary findings are more appropriately treated as exploratory.

The record reports 0 posted analyses. This means that a sponsor analysis is not available in the registry record for comparison with the unadjusted recalculations. It does not establish whether analyses were conducted outside the record. The record also does not report an interim-analysis plan, covariate adjustment, or a detailed statistical analysis plan. Those details cannot be inferred from the outcome summaries.

The primary outcome population is defined as randomized participants who received study medication. This identifies the stated population for the primary endpoint, but the registry record does not provide a detailed participant-flow account or explain the smaller denominators for secondary MRI outcomes. It does not report how missing outcomes were handled, whether any participants were excluded from specific analyses, or whether imputation was used. These omissions make it difficult to assess whether incomplete outcome data could have affected the posted comparisons.

The trial is listed as terminated, but the reason for termination is not reported in the registry record. The record does not state whether the termination affected follow-up, outcome collection, or the planned analysis. These limitations should be understood as gaps in the posted record, not as proof that particular procedures were or were not used.

15. 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: breast cancer (1.3%), syncope (0.7%), testis cancer (0.7%), hysterectomy (0.7%), lymphadenopathy (0.7%).

The registry reports serious adverse events affecting 11 of 149 participants in the Rebif® plus minocycline group and 21 of 155 participants in the Rebif® plus placebo group. It also reports other adverse events affecting 51 of 149 participants in the minocycline group and 35 of 155 in the placebo group. These figures describe the posted participant counts and denominators; they do not establish that an intervention caused an event or show the timing, duration, or severity of every event.

The registry lists serious-event terms and percentages, including breast cancer at 1.3%, and syncope, testis cancer, hysterectomy, lymphadenopathy, and neutropenia, each at 0.7%. The record does not connect these listed terms to a specific treatment group in the posted terms. Death counts are not reported in the registry record.

Safety counts need context, including definitions, follow-up, and whether participants could have experienced more than one event. Those details are not fully described in the posted summary. The counts should therefore be read as descriptive registry data, not as a complete comparison of risk or evidence of causation.

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

The posted primary results show 32 participants with a first documented relapse in the Rebif® plus minocycline arm and 39 in the Rebif® plus placebo arm. The unadjusted risk-difference estimate is negative, but its confidence interval includes zero and extends in both directions. The primary p-value is 0.448. Together, these statistics indicate that the posted data do not provide a precise estimate of the difference between groups.

This does not demonstrate that the groups are equivalent. A result that does not establish a difference may reflect uncertainty, including the range of effects compatible with the data. Nor does the numerical direction of the point estimate establish that minocycline reduced relapse occurrence. The confidence interval allows for effects on either side of no difference, and no medical conclusion should be drawn from the estimate alone.

The secondary MRI results do not remove that uncertainty. Their confidence intervals also include zero, and the outcome summaries use smaller denominators. The registry record does not provide a numeric secondary result for documented relapses or an account of the missing MRI measurements. The unadjusted nature of the secondary comparisons and the absence of a reported multiplicity strategy further limit their confirmatory weight.

The safety counts describe adverse events recorded in the registry and should not be interpreted as proof that an intervention caused or prevented those events. The registry record does not report deaths, the reason for termination, or enough detail to fully assess missing outcomes and analysis choices. Overall, the posted results characterize this trial's observed comparisons but do not establish a definitive effect of adding minocycline to Rebif®.

17. Why This Trial Matters Statistically

This trial illustrates why a difference between observed group counts is not, on its own, a reliable guide to the size or direction of an underlying effect. The primary estimate is numerically negative, but its confidence interval includes no difference and extends in both directions. Reading the estimate together with its uncertainty avoids treating a point estimate as a settled conclusion.

It also shows the distinction between a clinical endpoint and supporting measurements. The primary outcome is whether a participant experienced a first documented relapse, while MRI lesion and brain-volume outcomes capture different dimensions. Secondary results can contribute context, but unadjusted analyses across several outcomes do not automatically provide independent confirmation of the primary finding.

The registry record also illustrates the value of transparent reporting. Knowing the defined primary population is helpful, but interpretation is limited when the record does not explain the smaller secondary denominators, missing-data handling, multiplicity strategy, original sample-size justification, or reason for termination. These details affect how confidently readers can assess the results and their precision.

Finally, planning calculations based on observed effects are not the same as a trial's original design or its observed power. Their assumptions should be visible and interpreted as illustrations. Separating the posted observations, unadjusted recalculations, and hypothetical planning estimates helps keep statistical evidence in proportion to what the record supports.

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 lists the trial as terminated, but the reason is not reported. Without that information, the record does not establish whether termination affected follow-up, completion of outcome assessments, or the analysis. Primary follow-up could end at early termination, and the registry does not provide individual follow-up durations or event times.

The secondary MRI outcome summaries have smaller denominators than the primary outcome. The reason is not reported in the registry record, and missing-data methods are not described. This makes it difficult to judge whether the MRI comparisons represent the randomized groups or could be affected by missing measurements. The registry also does not report a detailed participant-flow account or additional analysis populations.

There is no posted sponsor analysis among the registry analyses, and the comparisons available are unadjusted recalculations from summary statistics. The record does not report a statistical analysis plan, multiplicity procedure, covariate-adjusted model, or interim-analysis plan. It also does not provide the original sample-size justification. These gaps constrain interpretation of the estimates and the planning illustrations.

The primary outcome is reported as a participant count with a first documented relapse, not as a time-to-event result or total relapse count. The trial's posted result therefore does not describe timing or recurrent events. Safety reporting is also limited: deaths are not reported, and the listed serious-event terms are not assigned to treatment groups in the posted term list. These record-specific limitations do not establish that the relevant information was unavailable to investigators, only that it is not reported in the registry record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Minocycline as add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif®) in Relapsing-Remitting Multiple Sclerosis [RRMS] — NCT01134627.
• Registry record last updated 2013-12-27; status last verified 2013-12.
• Results first posted 2012-09-05.
• 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

NCT01134627 is a Phase 2 randomized, double-blind, placebo-controlled, parallel-group study of minocycline added to Rebif® for relapsing-remitting multiple sclerosis. Enrollment is listed as 305; the registry lists 149 participants in the minocycline arm and 155 in the placebo arm for the primary outcome. The study started in 2006-02, had primary completion in 2011-04, and is listed as terminated.

The primary outcome was the number of participants with a first documented relapse through 96 weeks (+/- 1 week) or early termination. The posted unadjusted comparison has a risk difference of -0.037, a 95% confidence interval from -0.132 to 0.058, and p = 0.448. The interval includes no difference, leaving the estimated group contrast uncertain. Secondary MRI comparisons are also unadjusted and imprecise. Important details, including the termination reason, missing-data handling, and multiplicity strategy, are not reported in the registry record.