Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men. (NCT01293487), a na phase 1 study. The primary outcome is Number of Participants With Dose-Limiting or Intolerable Treatment Related Adverse Events (AEs).

2. Clinical Question

The trial’s stated purpose was to determine the safety and tolerability of RN564 in women with osteopenia and healthy men. Its official title also identifies immunogenicity, pharmacokinetics and pharmacodynamics as areas of evaluation. Those aims indicate a broad early-phase assessment, rather than a trial framed around a clinical benefit comparison. The listed secondary outcomes focus on drug exposure and disposition, including concentration measures, clearance, distribution and half-life. Numerical results for those outcomes are not reported in the registry record.

For the primary safety question, the endpoint combines a count of participants with a definition of dose-limiting or intolerable treatment-related adverse events. It considers specified types of events and permits the Investigator and Sponsor to judge a dose intolerable when the type, frequency or severity of adverse events becomes unacceptable. That definition is important when interpreting the endpoint: it is not simply a count of all adverse events, and it includes both listed criteria and a judgment-based component.

The registry record reports an overall enrollment of 68, but enrollment is not necessarily the same as the Safety Analysis Set, which requires receipt of at least 1 dose. The number actually included in that endpoint population is not reported in the registry record. Nor does the available record state how the observed endpoint counts varied by population or dose. Consequently, the clinical question is clear, but its primary answer cannot be recovered from the endpoint information recorded.

3. Trial Design

The study is identified as Phase 1 and completed. Its title describes escalating doses of RN564 in women with osteopenia and healthy men, and the design is classified as sequential. The registry record gives an enrollment of 68. The study began on 2011-04-01, and primary completion was recorded as 2012-05-24. These details place the study within early clinical evaluation, but the record does not give a full schedule of cohorts, dose-escalation rules or decision criteria.

Masking is listed as quadruple. The registry record does not identify which groups of people were masked, how masking was implemented, or whether masking applied in the same way across all dose groups. Allocation is listed as NA. The record also states that this was not a randomized comparison and that the groups are not a like-for-like control comparison. Although placebo is among the adverse-event groups, its presence alone does not make the dose groups randomized or establish a valid comparative design.

The intervention is named RN564, while adverse-event groups are labelled PF-04840082 at 0.3 mg/kg, 1.0 mg/kg, 6.0 mg/kg, 24.0 mg/kg, 3.0 mg/kg, 12.0 mg/kg and 18.0 mg/kg, as well as placebo. The registry record does not explain the relationship between the intervention name and those group labels. It also does not provide arm descriptions. The listed groups include different numbers at risk for adverse-event reporting, so raw counts across groups must be read with their own denominators rather than compared as if group sizes were the same.

The record lists osteopenia, osteoporosis and bone disease as conditions. The study purpose specifically names women with osteopenia and healthy men; further eligibility criteria, recruitment details and the distribution of participants between those populations are not reported in the registry record. The design information does not establish how the sequential structure governed dose decisions. Protocol details such as cohort progression, stopping rules and any dose-escalation committee arrangements are not reported in the registry record. The design can therefore be characterized as a masked, sequential Phase 1 evaluation with several dose groups and a placebo group, but not reconstructed in finer operational detail.

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.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set: All participants who received at least 1 dose of 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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting or Intolerable Treatment Related Adverse Events (AEs), measured over Day 1 to Day 85.

The primary endpoint is the number of participants with dose-limiting or intolerable treatment-related adverse events during Day 1 to Day 85. The listed population is the Safety Analysis Set: participants who received at least 1 dose of study medication. The outcome is expressed as a participant count, so its intended unit is people meeting the endpoint definition rather than the total number of adverse-event episodes.

The definition includes serious adverse events; increased liver transaminases; increased bilirubin in the absence of ALT/AST elevations; allergic or hypersensitivity reactions; vasculitis; musculoskeletal pain; increased serum creatinine; diarrhea, enteritis or nausea; prolongation of the QTcF interval; and other criteria considered appropriate by the Medical Monitor and Investigator. It also states that a dose level would be considered intolerable if the Investigator and Sponsor judged the type, frequency or severity of adverse events unacceptable. The listed criteria and clinical judgment therefore both contribute to the endpoint.

This kind of endpoint is used in early-phase evaluation to characterize tolerability and help identify safety concerns as doses are studied. It differs from an endpoint that measures a clinical outcome such as disease progression or symptom improvement. The registry record does not report the number of participants meeting this primary definition, a result by dose group, or a statistical estimate. The endpoint’s purpose and definition can be described, but its observed result cannot be interpreted from the information recorded.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a participant-count primary outcome and defines a Safety Analysis Set as participants who received at least 1 dose of study medication. The endpoint counts participants with dose-limiting or intolerable treatment-related adverse events during Day 1 to Day 85. These details establish the type of outcome, observation period and stated analysis population. The endpoint result itself is not reported in the registry record.

What does a participant-count endpoint represent?

A binary outcome assigns each participant to a category according to whether the defined event occurred. Summarizing such an outcome as a count describes how many participants met the criterion; the count is ordinarily interpreted alongside the number of participants assessed. It is not the same as counting every episode, because a participant with multiple events may still contribute as a participant meeting the endpoint. The primary outcome is described as a count, but no endpoint count or denominator by group is available in the registry record. The separate adverse-event summary includes participants at risk and participants affected, but those figures do not substitute for the primary endpoint result.

The endpoint definition has multiple components. It names specific events and allows other criteria when considered appropriate by the Medical Monitor and Investigator. It also describes a dose as intolerable when the Investigator and Sponsor judge the type, frequency or severity of adverse events unacceptable. A reader therefore needs the operational rules and the recorded event determinations to understand how participants were classified. The registry record does not report participant-level determinations, adjudication procedures or details about how judgment-based criteria were applied.

Why does the study design matter?

The design is classified as sequential, and the title describes escalating doses. In a sequential dose study, information from earlier cohorts may inform what happens next, depending on the protocol. That is a general description, not a statement about the specific rules used in this study. The registry record does not report dose-escalation criteria, stopping rules, cohort progression decisions or interim review procedures. Those details should not be inferred from the design label alone.

Masking is recorded as quadruple, while allocation is NA. Masking can reduce the influence of expectations on assessments, but its practical meaning depends on who was masked and how the procedure was maintained. The registry record does not identify masked roles or describe implementation. It explicitly notes that the study was not a randomized comparison and that the groups were not a like-for-like control comparison. Thus, the existence of a placebo group does not justify interpreting differences between group counts as randomized treatment effects.

How should adverse-event counts be read?

The adverse-event summary reports participants at risk and participants affected for serious and other adverse events. A count should be read with its corresponding group denominator. For serious adverse events, the record reports no affected participants in most listed dose groups, 1 affected participant among 8 at risk in the 12.0 mg/kg group, and 1 among 20 at risk in placebo. These are descriptive observations. They do not give a precise estimate of the frequency that would apply in a wider population, and they do not establish whether any event was caused by the study intervention.

General statistical point: small samples tend to provide limited precision for uncommon outcomes. A confidence interval can express uncertainty around an estimated event frequency, while a comparison model can account for differences between groups only if its assumptions and design support that comparison. No confidence intervals, comparative estimates or tests for these adverse-event figures are reported in the registry record. The percentages attached to the top serious terms are listed without enough information to establish their denominators or how events were counted.

What statistical analyses are documented?

The registry record lists zero analyses and 39 outcome measures. The listed secondary measures include AUClast, Cmax, Tmax, Vss, CL, terminal elimination half-life, AUC (0 - Inf) and Vz/F. These names describe pharmacokinetic measures, but numerical results and analysis details for them are not reported in the registry record. The absence of registered analysis entries does not establish that no analysis was performed outside the registry.

General statistical point: an analysis plan commonly specifies how outcomes will be summarized, which populations will be analyzed, how missing observations will be handled, and whether adjustments are needed when many outcomes are tested. The registry record does not report those details. No sample-size justification is reported in the registry record, and no interim-analysis plan or multiplicity strategy is reported. Without those details or the primary endpoint result, there is no basis for assessing whether the study’s planned analysis was followed, whether precision met a target, or how multiple outcome assessments were interpreted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("PF-04840082 0.3 mg/kg", "PF-04840082 1.0 mg/kg", "PF-04840082 6.0 mg/kg", "PF-04840082 24.0 mg/kg", "PF-04840082 3.0 mg/kg", "PF-04840082 12.0 mg/kg")
n      <- c(6, 6, 6, 6, 8, 8)
events <- c(0, 0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  PF-04840082 0.3 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  PF-04840082 1.0 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  PF-04840082 6.0 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  PF-04840082 24.0 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  PF-04840082 3.0 mg/kg  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  PF-04840082 12.0 mg/kg  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 39 outcome measures, including the primary safety endpoint and secondary pharmacokinetic measures. It lists zero analyses. No multiplicity strategy is reported in the registry record. General statistical point: when many outcomes or comparisons are examined, the chance of finding an apparently notable result by chance can increase; methods for addressing this depend on the aims and analysis plan. The registry record does not state whether outcomes were ranked, whether tests were adjusted, or whether analyses were intended to be descriptive.

Missing-data methods are not reported in the registry record. The information recorded does not explain how participants who stopped treatment, missed assessments or lacked evaluable measurements were handled. The Safety Analysis Set is defined as participants who received at least 1 dose of study medication, but the number included in that set and the handling of incomplete follow-up are not stated. The overall enrollment of 68 should not be assumed to be the number analyzed for every endpoint.

The primary outcome population is the Safety Analysis Set. Other analysis populations are not reported in the registry record. The record also does not specify an analysis model, statistical test, confidence-interval method or missing-data assumptions for the primary endpoint. It does not report an interim-analysis plan, sample-size justification or statistical analysis plan. These omissions limit assessment of the intended control of false-positive findings, the handling of incomplete data, and the precision or robustness of any conclusions. They do not establish that no such procedures existed outside the registry record.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: clostridium difficile colitis (12.5%), atrial flutter (5.0%).

The serious adverse-event summary reports participants at risk and participants affected within each group. No affected participants are recorded in the groups labelled PF-04840082 0.3 mg/kg, 1.0 mg/kg, 6.0 mg/kg, 24.0 mg/kg and 18.0 mg/kg. The record reports 1 affected participant among 8 at risk in the PF-04840082 12.0 mg/kg group, and 1 among 20 at risk in placebo. The denominators are group-specific and should remain attached to the counts.

The record lists Clostridium difficile colitis (12.5%) and atrial flutter (5.0%) as top serious terms. The denominator and event-level basis for these percentages are not reported in the registry record. They should not be interpreted as comparative rates for particular doses without that context. The death fields are null, so the record does not report a death count; null should not be read as zero.

These are descriptive observations, not evidence of a causal relationship or a reliable comparison between groups. The trial is not a randomized comparison, and the registry record cautions that the groups are not like-for-like controls. The small group counts also leave substantial uncertainty about uncommon events. Serious adverse-event counts do not represent the primary endpoint, which includes a broader definition of dose-limiting or intolerable treatment-related events.

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

The registry record supports a limited description of the study: it was a completed Phase 1, sequential study of RN564 in women with osteopenia and healthy men, with an enrollment of 68 and several dose-labelled adverse-event groups. It also records a definition for the primary safety endpoint and descriptive counts for serious and other adverse events. Those details are useful for understanding the intended safety assessment and the kinds of data recorded.

They do not establish the primary endpoint result. The number of participants with dose-limiting or intolerable treatment-related adverse events from Day 1 to Day 85 is not reported in the registry record. Nor are numerical results for the listed secondary outcomes reported. Without those results, the central safety question cannot be answered from the posted registry information.

The serious adverse-event counts do not show a randomized comparison. The record identifies allocation as NA and explicitly cautions that the groups are not a like-for-like control comparison. The counts cannot by themselves establish that an event was caused by treatment, that one dose is safer than another, or that placebo provides a valid estimate for comparison. The listed serious terms also lack denominator and event-level context in the record.

General statistical point: observed event counts are affected by sample size and follow-up, and sparse counts can be imprecise. A lack of recorded events in a group is not proof that the underlying event risk is absent. Likewise, the enrollment figure is not automatically the number analyzed for every outcome. The endpoint analysis set is defined by receipt of at least 1 dose, but its size and missing-data handling are not reported.

The record does not report a statistical analysis plan, multiplicity approach, sample-size justification, interim analyses or inferential estimates. Those details would be needed to understand the planned statistical framework and the precision of outcome estimates. The available information describes study structure and some observed adverse-event counts; it does not support claims of efficacy, definitive safety, or a comparative treatment effect.

14. Why This Trial Matters Statistically

This study illustrates why early-phase safety questions need to be separated from questions of treatment benefit. The registered primary endpoint focuses on dose-limiting or intolerable treatment-related adverse events, with a defined observation period and a Safety Analysis Set. Those choices orient the assessment toward tolerability during dose evaluation. They do not make the study an efficacy comparison, and the registry record does not report an efficacy result.

The design also matters to interpretation. The trial is described as sequential and involving escalating doses, but allocation is NA and the record says the groups are not a like-for-like control comparison. A placebo group appears in the adverse-event summary, yet that alone does not support randomized comparisons. Dose groups can be informative descriptively, but their counts should not be treated as estimates of a causal dose effect.

Another statistical lesson is the distinction between an endpoint’s definition and its observed result. The registry gives a detailed primary endpoint definition, including specified adverse events and judgment about whether the type, frequency or severity of events is unacceptable. However, the endpoint count is not reported. A detailed outcome definition cannot substitute for the numerical result needed to answer the study’s central question.

Finally, adverse-event counts in small groups require careful attention to denominators and uncertainty. The record reports few serious-event participants, but does not report confidence intervals or comparative analyses. It also lists secondary pharmacokinetic outcomes without their numerical results. The record is therefore useful for understanding the study’s aims, design labels and selected safety observations, while highlighting how missing outcome and analysis information limits statistical interpretation.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint result is not reported in the registry record. This is the central limitation for interpreting the study’s stated safety question: the record defines the outcome and time period, but does not give the number of participants meeting the definition. Numerical results for the listed secondary pharmacokinetic measures are also not reported.

The overall enrollment is 68, but the number in the Safety Analysis Set is not reported. The number at risk differs across the adverse-event groups, and the registry record does not provide enough information to reconstruct participant flow or determine whether all enrolled participants contributed to each outcome. The handling of incomplete follow-up and missing measurements is not reported.

The groups are not randomized like-for-like controls, according to the record. Dose-group and placebo counts should not be used to infer comparative effects. Arm descriptions are blank, and the record does not explain the relationship between the RN564 intervention name and the PF-04840082 labels used for adverse-event groups. The detailed operation of the sequential design, escalation criteria and stopping rules is not reported.

The serious-event term percentages are listed without denominator or event-level context. Death fields are null, which does not establish a zero count. No confidence intervals or inferential analyses are reported, and the record lists zero analyses. Statistical methods, sample-size justification, multiplicity handling and interim analyses are not reported in the registry record. These limitations restrict assessment of precision, completeness and planned analysis; they do not show whether additional information exists outside the registry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men. — NCT01293487.
• Registry record last updated 2024-09-24; status last verified 2024-06.
• Results first posted 2024-09-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01293487 is a completed Phase 1 study of RN564, described as a sequential evaluation of safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics in women with osteopenia and healthy men. Enrollment was 68. The study began on 2011-04-01, with primary completion recorded as 2012-05-24. Masking is listed as quadruple; allocation is NA.

The primary endpoint is the number of participants with dose-limiting or intolerable treatment-related adverse events from Day 1 to Day 85, in the Safety Analysis Set. The primary endpoint result is not reported in the registry record. Adverse-event groups include PF-04840082 dose labels and placebo; the record cautions that this was not a randomized, like-for-like comparison. Serious-event counts are descriptive, and the listed death fields are null.

The record lists 39 outcome measures and zero analyses. It does not report numerical results for the secondary pharmacokinetic outcomes, a statistical analysis plan, missing-data methods, multiplicity handling, or sample-size justification.