Safety of Intravenous Neridronic Acid in CRPS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Intravenous Neridronic Acid in CRPS (NCT02972359), a na phase 3 study. The primary outcome is Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE).

2. Clinical Question

This is a safety question within a treated group, not a question about the difference between neridronic acid and another treatment or a control condition. The registry also lists secondary outcomes covering permanent treatment discontinuation due to an adverse event, current pain intensity, pain-response thresholds, Patient Global Impression of Change, and pain interference. Those outcomes broaden the topics recorded for assessment, but their presence does not establish that results or analyses for them are available. The number of outcome measures is reported as 8, while the number of analyses is reported as 0. A separate primary-endpoint analysis result is not reported in the registry record.

3. Trial Design

The record describes a Phase 3, open-label, single-group trial of intravenous neridronic acid in people with CRPS. It was not a randomized comparison: allocation is listed as not applicable, masking as none, and the study model as single group. Consequently, the study can describe events recorded among treated participants, but it has no concurrent control group for estimating how those events compare with another treatment or with no study treatment.

The registry reports enrollment of 580. The primary endpoint specifies the Safety Set, and the posted safety figures use 316 participants at risk. The record does not explain the difference between enrollment and the safety population, or give further detail about inclusion in that analysis population. These counts should therefore be understood as belonging to distinct registry descriptions rather than reconciled by an assumed reason.

The treatment schedule was 100 mg of neridronic acid on Day 1, Day 4, Day 7, and Day 10, with a total dose of 400 mg. The brief description divides the trial into a 60-day enrollment period, treatment consisting of 4 infusions over 10 days, and follow-up of approximately 50 weeks, with visits at Week 2, Week 6, Week 12, Week 26, Week 39, and Week 52. The primary endpoint timeframe is Day 1 to Week 52.

The study started on 2016-12-20, had primary completion on 2019-01-09, and is listed as completed. The registry does not report the rationale for the enrollment target, a sample-size justification, or further details of the operational procedures beyond the summary and schedule.

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: A total of 580 participants signed an informed consent form, 318 participants hereof were allocated to treatment. Two of the allocated participants did not meet inclusion criteria/met exclusion criteria, thus 316 participants received treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Set

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 With Occurrence of Any Treatment Emergent Adverse Event (TEAE), measured over Day 1 to Week 52.

The primary endpoint is the number of participants with occurrence of any treatment-emergent adverse event (TEAE), recorded from Day 1 to Week 52 in the Safety Set. The endpoint description makes the participant-level outcome binary: each participant either experienced at least one TEAE during the stated period or did not. It is a count of participants meeting that definition, not a count of all adverse-event episodes.

General statistical context: a binary safety endpoint provides a straightforward way to describe how many people experienced an event during a defined observation period. The timeframe matters because events outside that period are not part of the endpoint as specified. A participant-level measure also avoids treating repeated events in one person as though they represented separate participants.

For an open-label, single-group safety trial, this endpoint can characterize the recorded event experience in the defined population. It cannot by itself distinguish events caused by treatment from events that would have occurred for other reasons, nor can it estimate a treatment-versus-control difference. The registry describes the endpoint and its analysis population, but a separate primary-endpoint result is not reported in the registry record. The posted safety counts should not be assumed to be an exact result for this primary endpoint unless the registry explicitly identifies them that way.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context: the choice of method depends on the endpoint, the study design, and the way observations were collected. The registry describes a binary participant-level safety endpoint in a single-group study. It does not report a statistical analysis for that endpoint, so an estimated event proportion, confidence interval, or hypothesis test should not be inferred from the endpoint definition alone.

What a binary endpoint represents

For this primary endpoint, each participant is classified according to whether any TEAE occurred within the stated timeframe. A count of participants with an event is distinct from a count of event episodes: a participant with repeated events still contributes one participant to an any-event count. General statistical context: when a complete denominator and numerator are available, the proportion with an event can describe the observed frequency in the analysis population. An uncertainty interval can indicate how imprecise that estimate may be, but it does not address whether events were caused by treatment or what would have happened under a comparator.

The registry names the Safety Set but does not report its full definition. It also does not provide a separately identified primary endpoint count or a confidence interval. The safety summary does report 316 participants at risk and other adverse-event counts, but it does not explicitly say that the 275 participants with other adverse events are the primary endpoint numerator. Maintaining that distinction avoids presenting a safety-summary category as though it were an explicitly reported primary result.

What the design allows

The study is listed as single-group, open-label, and without randomized allocation or masking. General statistical context: a single-group study can describe what was observed among treated participants, but it lacks a concurrent comparison that would separate treatment-associated patterns from background events or other influences. Randomization, when present, can help balance measured and unmeasured factors between groups; it is not present in this design. The registry does not report a comparator or a planned comparative test.

Open-label status means treatment was not masked. General statistical context: knowledge of treatment can affect reporting, attention to symptoms, or assessment, depending on the outcome and study procedures. The record does not describe whether or how these possibilities were addressed. They should be treated as methodological considerations, not as evidence that event reporting was biased.

Uncertainty and interpretation

General statistical context: a confidence interval gives a range of values compatible with the observed data under a specified statistical method and assumptions. It communicates sampling uncertainty; it is not a guarantee that the true value lies within the interval, and it does not account automatically for bias, incomplete follow-up, or limitations of the design. No confidence interval for the primary endpoint is reported in the registry record.

A p-value, when used, describes how unusual data would be under a specified null hypothesis and model. It is not the probability that the null hypothesis is true, nor a direct measure of clinical importance. No primary-endpoint p-value or test is reported in the registry record. Without a comparator and a stated analysis, there is no reported treatment contrast to interpret.

Planning calculations are not trial results

The registry describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. For non-time-to-event outcomes, such illustrations are described as participants per arm for 80% or 90% power; time-to-event calculations are described as total event counts. These are planning conventions, not outcomes observed in this single-group trial, and they do not establish that the trial was designed with those assumptions. The actual numerical planning results and the observed effect needed to interpret them are not reported in the registry record. Such illustrations should not be called observed power or mistaken for evidence of a treatment effect.

Event categories and repeated observations

The safety summary separates serious adverse events from other adverse events and provides selected serious-event terms. General statistical context: seriousness is a classification of an adverse event and is not the same as severity or proof of a causal relationship. A list of terms and participant counts can support descriptive safety reporting, but interpretation depends on the event definitions, observation rules, and denominator. The registry does not report enough detail to determine whether event categories overlap or how every category maps to the primary any-TEAE endpoint.

The record lists secondary outcomes involving pain intensity, pain-response thresholds, global impression of change, pain interference, and permanent discontinuation due to an adverse event. The registry does not report analyses for these outcomes. General statistical context: repeated measurements and multiple outcomes can require explicit plans for handling missing observations, selecting time points, and interpreting multiple comparisons. Those plans are not reported in the registry record, so no assumptions about them should be made.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures, including the primary safety endpoint and secondary outcomes concerning adverse-event discontinuation, pain intensity, response thresholds, global impression of change, and pain interference. It reports 0 analyses. The statistical plan, including any strategy for handling multiple outcomes or repeated time points, is not reported in the registry record. General statistical context: testing or interpreting several outcomes can increase the chance of emphasizing a result that appears notable by chance. A prespecified multiplicity approach can clarify how such results are interpreted, but no such approach is described in this record.

Missing-data handling is not reported in the registry record. The brief description gives follow-up visits through Week 52, but it does not describe participant retention, completeness at each visit, imputation, or other rules for missing observations. General statistical context: missingness can affect estimates when the likelihood of having an observed outcome is related to participant characteristics or outcome status. Without the analysis rules and follow-up details, the direction or size of any such effect cannot be determined.

The primary endpoint names the Safety Set, while the safety summary reports 316 participants at risk and the enrollment figure is 580. The record does not explain the Safety Set definition or reconcile these populations. It also does not describe how participants with incomplete safety follow-up were handled. No analysis population should be inferred beyond the populations explicitly named in the registry.

These omissions limit assessment of whether the reported safety counts use consistent denominators across outcomes and time points. They also limit evaluation of outcome multiplicity, missingness, and population selection. The absence of reported details is not evidence that a particular procedure was or was not used; the relevant information is not reported in the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chest pain (0.6%), pneumonia (0.6%), fall (0.6%), osteoarthritis (0.6%), syncope (0.6%).

The safety summary reports 316 participants at risk in the Neridronic Acid group, with 27 participants affected by serious adverse events and 275 affected by other adverse events. It also reports 1 death. The record lists chest pain, pneumonia, fall, osteoarthritis, syncope, and suicide attempt as the leading serious adverse-event terms, each at 0.6%. These are descriptive safety figures, not comparisons between treatment groups.

The record does not state whether participants with serious events are also included among those with other adverse events, or whether the event categories are mutually exclusive. The counts therefore should not be added to create a total. The figures also should not be interpreted as event counts: they are reported as participants affected, and the primary endpoint itself is defined as a participant-level occurrence measure.

General statistical context: a serious adverse event is classified by seriousness criteria; this does not by itself establish that the event was severe in intensity or caused by the study treatment. The record does not report causal attribution for the listed terms. The 0.6% figures should be read as the registry’s reported values, without inferring a different denominator or recalculating them. The separate primary endpoint result for any TEAE is not reported in the registry record.

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

The record establishes that this was a completed, open-label, single-group Phase 3 safety trial of intravenous neridronic acid in participants with CRPS. It specifies a treatment schedule of 100 mg on Day 1, Day 4, Day 7, and Day 10, and identifies occurrence of any TEAE from Day 1 to Week 52 as the primary endpoint. It also reports selected safety counts and serious-event terms. These details allow readers to understand the intended safety question and the treatment and follow-up schedule recorded in the registry.

The posted results do not give a separate analysis of the primary endpoint, a confidence interval, or a test result. The reported adverse-event counts cannot be treated as a comparative estimate, because there is no control group. They also do not demonstrate that an event was caused by neridronic acid. No conclusion about efficacy or comparative benefit follows from the safety descriptions.

General statistical context: observed events in a treated group are important for describing what was recorded, but causal interpretation usually requires a suitable comparison and clear methods for collecting and analyzing outcomes. Even a precise estimate of the frequency within a treated group would not, by itself, show how that frequency differs from what might have occurred in another setting. In this record, the endpoint result and uncertainty are not reported, which further limits quantitative interpretation.

Enrollment of 580 and the safety summary denominator of 316 are both recorded, but the reason for their difference is not reported in the registry record. The analysis population definition, missing-data procedures, and handling of outcome multiplicity are also not reported. The record therefore supports a limited descriptive reading of its listed design and safety information, not a complete assessment of the trial’s analysis or the comparative safety of treatment.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a safety description and a comparative treatment estimate. Its design is single-group and open-label, while its stated primary endpoint is whether a participant experienced any TEAE over a defined period. Such an endpoint is clinically interpretable as a participant-level safety measure, but the absence of a comparator constrains what can be inferred from the observed counts.

The record also illustrates why denominator definitions matter. Enrollment is reported as 580, while the safety summary gives 316 participants at risk and the primary endpoint identifies the Safety Set. The record does not explain how those populations relate. Without that explanation, readers cannot determine from the registry alone why the reported safety population differs from enrollment or whether the same population was used for every safety summary.

The registry includes multiple secondary outcomes and a follow-up schedule extending to Week 52, yet reports 0 analyses. Statistical plans for multiple outcomes, missing observations, and population definitions are not reported. General statistical context: these details help readers judge which estimates were intended, how incomplete data were handled, and how to interpret a collection of outcome results. Their absence from the registry record limits that assessment.

The listed serious adverse-event counts and terms remain useful as descriptive information, provided they are not mistaken for causal or comparative evidence. This case highlights the value of separating the stated endpoint, reported safety summaries, and unreported analysis results. That separation keeps interpretation aligned with what the registry actually records.

14. 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.

Several limitations specific to this trial constrain interpretation of the posted record. The study had a single treatment group, no randomized allocation, and no masking. As a result, the safety information is descriptive and cannot estimate a treatment-versus-control difference. The record does not identify a comparator, so comparative safety cannot be assessed from these data.

The primary endpoint is clearly described as any TEAE from Day 1 to Week 52 in the Safety Set, but a separate result for that endpoint is not reported in the registry record. The registry lists 0 analyses. The summary count of 275 participants with other adverse events is not explicitly identified as the primary endpoint count, and the record does not explain the relationship between that category and any TEAE. The reported serious and other event counts may overlap; that relationship is not stated.

The enrollment figure is 580, while the safety summary reports 316 participants at risk. The reason for this difference and the Safety Set definition are not reported in the registry record. The record also does not describe participant-level follow-up completion, missing-data methods, or whether denominators changed across outcomes and visits.

The listed secondary outcomes cover several domains and time points, but no analysis results or multiplicity approach are reported. The statistical plan, sample-size justification, interim analyses, and detailed event-classification procedures are not reported in the registry record. This means the posted record does not permit evaluation of those design and analysis choices. The limitations concern the detail and design available for interpretation; they do not establish that an unreported procedure was absent from the trial itself.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety of Intravenous Neridronic Acid in CRPS — NCT02972359.
• Registry record last updated 2019-11-21; status last verified 2019-11.
• Results first posted 2019-11-04.
• 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.

18. Record Summary

NCT02972359 is a completed Phase 3, open-label, single-group safety trial of intravenous neridronic acid in participants with CRPS. The registry reports enrollment of 580 and a treatment schedule of 100 mg on Day 1, Day 4, Day 7, and Day 10, for a total dose of 400 mg. The primary endpoint is occurrence of any TEAE from Day 1 to Week 52 in the Safety Set.

The safety summary reports 316 participants at risk, 27 with serious adverse events, 275 with other adverse events, and 1 death. Six listed serious-event terms are each reported at 0.6%. A separate result for the primary endpoint, inferential analyses, and explanations of the enrollment-to-safety-population distinction are not reported in the registry record.