Safety and Tolerability of PF-06649751 in Parkinson's Disease Patients With Motor Fluctuations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Tolerability of PF-06649751 in Parkinson's Disease Patients With Motor Fluctuations (NCT03185481), a randomized phase 2 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (All Causalities).

2. Clinical Question

The study concerns an open-label extension, according to its official title, following an earlier study in participants with Parkinson’s disease and motor fluctuations. The registry’s primary endpoint focuses on adverse events after treatment begins. It counts an event if it occurs after treatment starts, or if an event that began earlier increases in severity after treatment starts. The description explicitly says that an event need not have a causal relationship with the study treatment.

The registry record does not provide a comparator for the primary endpoint. It also does not report estimates of treatment effects or analyses comparing dose pathways. The listed intervention descriptions include escalation and maintenance pathways, but the posted primary outcome data are for a single PF-06649751 15 mg group. Thus, the clinical question supported by the posted data is descriptive: what adverse-event counts were recorded in that group during the stated observation period?

The record lists additional outcomes concerning diary-based daily OFF time and ON time, and scores on the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale. Results for those outcomes are not reported in the registry record. Consequently, the primary endpoint does not answer whether motor symptoms changed, and the presence of those secondary outcome measures does not establish that changes were measured or analyzed in the posted results.

3. Trial Design

The registry identifies this as a Phase 2 study, with randomized allocation, triple masking, and a parallel model. Its official title, however, describes a Phase 2 open-label extension study. These descriptors do not align on masking: “open label” ordinarily indicates that treatment assignment is known, while “triple” masking indicates that multiple groups involved in a trial are masked. The registry record does not explain this discrepancy, so the actual masking arrangements for the extension cannot be established from the record alone.

The study was intended to investigate long-term safety and tolerability of PF-06649751 in people with Parkinson’s disease and motor fluctuations. The record gives enrollment as 5 and status as terminated. It lists a start date of 2017-07-06 and a primary completion date of 2017-10-24. The reason for termination is not reported in the registry record. The stated primary outcome timeframe is baseline to the last visit after termination, up to approximately 3 months.

The intervention listings describe several dose pathways. Some participants were listed as escalating from lower doses to 15 mg QD, while other pathways describe remaining at 15 mg QD or reaching or remaining at 7 mg QD. Several of these pathways depend on dose changes in the parent study. The registry’s intervention and arm-description text is not fully consistent for the pathway involving de-escalation from 15 mg to 7 mg: one description says participants remain at 7 mg, while an arm description says they remain at 15 mg. The record does not clarify the discrepancy.

Although the design descriptors identify randomization and a parallel model, the primary outcome result is reported for one PF-06649751 15 mg group, and the registry notes that the primary outcome has fewer than two arms. No comparator outcome or arm-to-arm estimate is reported. The design labels therefore should not be mistaken for evidence that the posted primary endpoint supports a randomized comparison. The record does not report the allocation procedure, the groups’ assignment details, or how the masking descriptors relate to the open-label extension title.

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: The study population included all participants who received at least 1 dose of study medication during the study period.

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 Treatment-Emergent Adverse Events (All Causalities), measured over Baseline to last visit after termination (up to approximately 3 months).

The primary endpoint is the number of participants with treatment-emergent adverse events of all causalities. It counts participants who had at least one qualifying event; it is not a count of every event occurrence. The registry defines an adverse event as an untoward medical occurrence in a participant administered a product or medical device, whether or not the occurrence is considered related to treatment or use.

An event qualifies as treatment-emergent if it occurs after treatment starts, or if it occurred before treatment but increases in severity afterward. The endpoint’s timeframe is baseline to the last visit after termination, up to approximately 3 months. Its stated population includes all participants who received at least 1 dose of study medication during the study period.

Counting participants with events is a straightforward way to describe how many people in the analyzed group experienced an adverse event during the specified period. It avoids treating repeated events in the same participant as separate affected participants. However, a participant count alone does not describe event frequency, duration, severity, or the number of recurrent events. Nor does “all causalities” establish that treatment caused an event. The endpoint is therefore a safety description, not a causal estimate of treatment risk. The registry record does not report a comparative analysis that would quantify an excess or reduction in events relative to another group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

For a binary outcome such as whether a participant experienced an event, each participant is classified according to whether the event occurred during the defined observation period. A count of affected participants describes the number meeting that outcome definition. It does not count repeated occurrences as additional affected participants, and it does not convey how often events recurred. Here, the primary endpoint is explicitly a participant count for treatment-emergent adverse events of all causalities.

The denominator is also important. It indicates how many participants were considered at risk for the reported outcome. The registry’s primary population definition includes participants who received at least 1 dose of study medication. The adverse-event summary reports 5 at risk for the group. A count should be interpreted alongside its stated denominator and observation period, rather than as an isolated figure. No new percentage or comparative estimate is necessary to describe the posted counts.

Why does the event definition matter?

Safety endpoints depend on operational definitions. The record defines a treatment-emergent event by timing and change in severity: an event begins after treatment starts, or an earlier event becomes more severe after treatment starts. This definition makes the treatment period relevant to classification, but it does not establish causation. “All causalities” expressly allows events to be counted without deciding that the study treatment caused them. General statistical interpretation should keep event occurrence, timing, severity, and causal attribution separate.

The primary endpoint counts participants with any qualifying event. The serious adverse-event summary is a distinct safety description. A serious event is not interchangeable with an event count for all adverse events, and the posted registry descriptions do not provide a complete account of how seriousness was adjudicated. The serious-event count should therefore be reported as the registry reports it, without inferring additional classifications or details.

What would a comparison require?

General: an estimated difference between treatment groups requires outcome information for each group and a defined comparison. A confidence interval can express the statistical uncertainty around an estimate; it does not guarantee that the underlying value lies within its limits, and its width depends on the amount and variability of information. A hypothesis test can assess compatibility with a specified null hypothesis under stated assumptions, but it does not establish clinical importance or causality by itself.

For this primary outcome, the registry identifies a single group and states that there are fewer than two arms. It does not report a comparator result, an estimated difference, a confidence interval, or a p-value. Therefore, no between-group inference is available from the posted primary outcome. The broader registry design labels—randomized allocation, triple masking, and parallel model—do not supply missing outcome data or create a comparison where the primary result is reported for only one group.

What is the role of statistical models?

General: models can account for features such as different follow-up times, repeated observations, or variation between participants. A model’s estimates depend on its assumptions and on the data used to fit it. For event counts, over-dispersion can matter when the observed variability exceeds what a simple model assumes; accounting for it may produce more realistic uncertainty. These are general considerations, not a description of analyses performed in this study. The registry record does not report a statistical model, an over-dispersion assessment, or an adjusted analysis.

The primary outcome is a participant-level event indicator, not a reported rate of recurrent events over person-time. The record does not provide individual follow-up times or recurrent-event counts. Consequently, a time-to-event analysis or a recurrent-event model cannot be reconstructed from the posted summary. The timeframe states baseline to last visit after termination, up to approximately 3 months, but that alone is not enough to recover the timing of individual outcomes.

How should planning illustrations be understood?

General: sample-size planning uses assumptions about the effect to detect, the statistical error rate, allocation, and analysis method. A planning illustration answers a hypothetical design question; it is not evidence that a study had that level of power after it was conducted. The registry record does not report the study’s own sample-size justification or statistical plan. Any planning illustration based on an observed effect is not the trial’s original design rationale and should never be called observed power.

The stated assumptions for planning illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect specified as a fraction of the observed effect. The notes distinguish participant-per-arm outputs from total-event outputs for time-to-event settings. These assumptions describe an illustrative calculation framework, not a reported study analysis. Since the primary outcome has fewer than two arms and the registry reports no outcome analyses, such planning assumptions do not create an observed treatment comparison.

Why does precision remain limited?

General: sparse event data often produce substantial uncertainty, and a small study may be unable to distinguish chance variation from a treatment-related pattern. A single observed count can be informative as a description of what was recorded while remaining imprecise as an estimate of what might occur in a wider population. The registry does not report confidence intervals for these event counts. No recalculated comparison is available; in particular, there is no sponsor analysis to set against a simple unadjusted re-calculation.

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-06649751 15 mg")
n      <- c(5)
events <- c(3)
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-06649751 15 mg  5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the primary safety endpoint and secondary outcomes concerning Hauser Participant Diary data and MDS-UPDRS scores. It reports 0 analyses. The presence of multiple outcomes makes multiplicity relevant in principle: when several hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan addresses that issue. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified approach to interpreting multiple tests.

Because no analyses are reported, there are no posted p-values or estimated effects across the outcome set to interpret as a family of statistical tests. This absence should not be treated as proof that no analyses were carried out; it means that analysis results and methods are not reported in the registry record. The listed outcomes describe what was intended for measurement, not what was necessarily collected or analyzed.

Missing-data handling is not reported in the registry record. The primary endpoint population is stated as participants who received at least 1 dose of study medication, but the record does not explain how incomplete adverse-event follow-up, missing visits, or other missing observations were handled. It also does not provide participant-level completion information or clarify whether the endpoint’s last-visit timeframe was observed for every participant.

The record does not describe an intention-to-treat analysis population, a per-protocol population, or a sensitivity analysis. Nor does it provide a statistical analysis plan from which to assess whether outcome definitions and analysis choices were set before results were known. The specified treated-participant population is the only primary population definition. These gaps limit assessment of potential selection, missing-data, and multiplicity effects, without establishing that any particular bias occurred.

12. 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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hip fracture (20.0%).

The serious adverse-event summary reports 1 affected participant among 5 at risk in the PF-06649751 15 mg group. The separate other-adverse-event summary reports 3 affected participants among 5 at risk. The registry reports 0 deaths. These figures are counts of participants, not totals of event episodes, and the record does not provide enough detail to determine whether an individual could contribute to more than one category.

Hip Fracture is listed as a top serious adverse event term, with a reported value of 20.0%. That term-level percentage should be preserved as reported; it does not establish that treatment caused the event. The primary endpoint explicitly includes events of all causalities. The registry does not provide details about event onset, duration, outcome, investigator attribution, or clinical circumstances.

These summaries cover the stated period from baseline to the last visit after termination, up to approximately 3 months. They are descriptive and do not compare PF-06649751 with another group. With no comparator result or reported statistical analysis, the counts cannot show whether event risk differed under another treatment. “Other” is the category label in the safety summary; the record does not clarify its precise relationship to the serious-event category.

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

The primary result establishes what the registry reports for its recorded group: participants experienced treatment-emergent events during the stated observation period, and the record separately gives counts for serious and other adverse events. The endpoint includes events regardless of causal relationship to treatment. These observations are relevant to describing the safety data collected in the study, but a descriptive count is not itself a causal conclusion.

The result does not show whether PF-06649751 increased or decreased adverse-event risk compared with another treatment, placebo, or no treatment. The primary outcome is reported for a single group, and the record notes fewer than two arms for that outcome. There is no reported comparative estimate, confidence interval, or hypothesis test. Randomized allocation in the general design descriptors does not substitute for outcome data in a comparison group.

The counts also do not establish the event rate that would occur in a broader population. The registry reports enrollment 5, and the primary endpoint population includes participants who received at least 1 dose. Small and limited observations can be useful descriptions of what was recorded but do not provide precise estimates for uncommon events or for populations not represented in the record. No confidence intervals are reported.

The study status is terminated, and the stated primary completion date is 2017-10-24. The reason for termination and details of the follow-up completed by each participant are not reported in the registry record. The endpoint timeframe extends to the last visit after termination, up to approximately 3 months, so these data should not be interpreted as an exhaustive account of long-term safety beyond that stated window.

Finally, the record lists outcomes for motor diaries and MDS-UPDRS scores, but their results are not reported in the registry record. The safety endpoint does not establish a change in motor symptoms, and the listed secondary outcomes cannot be used to infer such a change without posted results. The appropriate conclusion is limited to the descriptive safety information actually recorded.

14. Why This Trial Matters Statistically

This trial illustrates the distinction between a study’s design labels and the evidence available for a particular endpoint. The registry describes randomized allocation, a triple-masked design, and a parallel model, while the official title calls the study an open-label extension. The record does not reconcile those descriptions. More importantly for interpreting the primary result, the outcome is reported for a single group and the registry notes fewer than two arms for that endpoint. A design label alone cannot support a comparative conclusion.

It also illustrates why endpoint definitions matter in safety reporting. The primary outcome counts participants with treatment-emergent events of all causalities, using a timing-and-severity definition. That is not equivalent to counting every event, identifying treatment-caused events, or estimating a comparative risk. Keeping these concepts separate prevents descriptive safety counts from being overstated.

The record further demonstrates how a small enrollment and absent analysis details constrain interpretation. Event counts can be stated accurately, but their precision and generalizability remain limited when there is no reported interval estimate, model, comparator, or analysis plan. The number of outcome measures and lack of reported analyses also mean that multiplicity and missing-data handling cannot be assessed from the record.

Finally, extension studies can have intervention pathways linked to treatment in a parent study. Here, the listed dose pathways include escalation and maintenance choices, and one de-escalation description is inconsistent across the registry text. Such details affect how clearly readers can identify the treatment exposure being summarized. Statistical interpretation depends not only on numbers, but also on well-defined populations, interventions, endpoints, and analysis methods. Where the record does not report those elements, conclusions should remain correspondingly limited.

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 registry record has several limitations specific to interpreting this study. First, it is marked terminated, but the reason for termination is not reported. The record gives enrollment as 5, but does not describe the circumstances of enrollment or provide participant-level follow-up. The primary endpoint timeframe ends at the last visit after termination, up to approximately 3 months; the duration actually observed for each participant is not reported.

Second, the design descriptors are not internally clear. The official title calls the study an open-label extension, whereas the registry descriptors identify triple masking. The record does not explain how these labels apply to the extension. It also identifies randomized allocation and a parallel model but reports the primary endpoint for a single group, with fewer than two arms for that outcome. No comparative primary result is reported.

Third, the dose-pathway descriptions are not fully consistent. The intervention text for the pathway involving de-escalation from 15 mg to 7 mg indicates remaining at 7 mg, while the corresponding arm description indicates remaining at 15 mg. The record does not resolve this discrepancy. These descriptions also refer to dose decisions in the parent study, but the details needed to reconstruct each participant’s exposure are not reported.

Fourth, the registry reports 0 analyses and does not report a statistical analysis plan, confidence intervals, hypothesis tests, missing-data methods, or multiplicity procedures. Results for the listed diary and MDS-UPDRS outcomes are not reported. The safety summaries do not include event timing, recurrence, duration, or detailed causal assessments. These omissions limit evaluation of precision, completeness, and the clinical context of the recorded events; they do not establish that any particular method or event was absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Tolerability of PF-06649751 in Parkinson's Disease Patients With Motor Fluctuations — NCT03185481.
• Registry record last updated 2019-04-12; status last verified 2019-04.
• Results first posted 2019-04-12.
• 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

NCT03185481 is a Phase 2 study of PF-06649751 in people with Parkinson’s disease and motor fluctuations. Its official title describes an open-label extension focused on long-term safety and tolerability. The registry identifies randomized allocation, triple masking, and a parallel model, but does not explain the discrepancy between the masking descriptor and the open-label title.

The record gives enrollment as 5, status as terminated, a start date of 2017-07-06, and a primary completion date of 2017-10-24. The primary endpoint counts participants with treatment-emergent adverse events of all causalities, from baseline to the last visit after termination, up to approximately 3 months. The posted primary outcome is for a PF-06649751 15 mg group and has fewer than two arms.

The record reports adverse-event counts and lists additional diary and MDS-UPDRS outcomes, but reports 0 analyses. The reason for termination, comparative results, missing-data methods, and statistical analysis plan are not reported in the registry record. The available primary results are descriptive and do not establish comparative treatment effects.