Study of CVN424 in Parkinson's Disease Patients With Motor Fluctuations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of CVN424 in Parkinson's Disease Patients With Motor Fluctuations (NCT04191577), a randomized phase 2 study. The primary outcome is Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Study Drug.

2. Clinical Question

3. Trial Design

This was a phase II, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of CVN424 in participants with Parkinson disease and motor fluctuations. The registry lists three arms: placebo, CVN424 50 mg, and CVN424 150 mg. Enrollment was 136, and the study status is completed. The study start date was 2019-12-02, and primary completion was 2021-11-06.

The low-dose group was assigned CVN424 once daily. The high-dose schedule began with low-dose CVN424 once daily from day 1 to day 7, followed by the full high dose once daily beginning on day 8. The placebo arm received placebo once daily. The registry's masking entry is quadruple, while the official title describes the study as double-blind; further explanation of this terminology is not reported in the registry record.

The primary outcome was assessed in the Safety Analysis Set over a timeframe of up to Day 35. The registry reports percentages by arm and the numbers of participants with related treatment-emergent adverse events. It also lists secondary outcomes concerning laboratory parameters, 12-lead ECG findings, vital signs, and change in 2-day average OFF time. Quantitative results are posted for change in OFF time; results for the other listed secondary outcomes are not reported in the registry record.

Details such as the randomization method, allocation concealment, the trial's original sample-size justification, and the statistical analysis plan are not reported in the registry record. The registry lists no reported analyses. The posted pairwise comparisons are unadjusted recalculations from the reported summary statistics, rather than a substitute for a sponsor analysis.

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: Safety Analysis 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.

Population: Safety Analysis Set comprised of all participants who were enrolled and received at least 1 dose of study drug, classified according to the treatment they actually received.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Study Drug, measured over Up to Day 35.

The primary endpoint is the percentage of participants with treatment-emergent adverse events related to study drug, assessed up to Day 35. The registry defines an adverse event as an untoward medical occurrence temporally associated with study treatment, regardless of whether it is considered related to that treatment. A treatment-emergent event is one with onset during or after the first dose of active treatment or placebo. The primary endpoint title narrows the reported outcome to events considered related to study drug.

This endpoint describes the proportion of participants in each arm who experienced at least one qualifying event. It is a binary outcome at the participant level: each participant either met the event definition or did not. It therefore provides a direct descriptive comparison of the frequency of reported related events across the randomized groups over the specified timeframe.

Adverse-event outcomes are used to characterize safety and tolerability during a study, but a percentage alone does not describe the event's severity, duration, clinical course, or causal certainty. The registry separately reports serious adverse events and deaths. Those are different summaries and should not be treated as interchangeable with the primary endpoint. Further detail about event severity and how relatedness was determined is not reported in the registry record.

7. Results Posted in the Registry

• CVN424 50 mg: 17.8% (8/45) versus 9.1% (4/44) on control; risk difference 8.7 percentage points (95% CI -5.3 to 22.7), risk ratio 1.96 (0.63–6.03); unadjusted two-proportion z-test p = 0.230.
• CVN424 150 mg: 19.1% (9/47) versus 9.1% (4/44) on control; risk difference 10.1 percentage points (95% CI -4.0 to 24.2), risk ratio 2.11 (0.70–6.35); unadjusted two-proportion z-test p = 0.171.

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.

Change From Baseline in 2-day Average OFF Time

• 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:
  • CVN424 50 mg: mean -1.34 versus -0.46 on control; difference -0.88 (95% CI -2.20 to 0.44), standardized effect d = -0.30; z-test p = 0.190.
  • CVN424 150 mg: mean -1.56 versus -0.46 on control; difference -1.10 (95% CI -2.28 to 0.08), standardized effect d = -0.40; z-test p = 0.068.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CVN424 50 mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CVN424 150 mg and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes spanning laboratory parameters, ECG findings, vital signs, and change in 2-day average OFF time. Quantitative results posted in the record include the OFF-time outcome; the results for the other listed secondary outcomes are not reported in the registry record. Accordingly, the overall secondary-outcome pattern cannot be evaluated across all listed measures from the posted numerical data.

For OFF time, the arm-specific mean changes were more negative in both CVN424 groups than in placebo. The unadjusted recalculated differences have confidence intervals that include zero, so the available summaries leave uncertainty about the magnitude and direction of the between-arm differences. This secondary outcome does not replace the primary safety endpoint: it asks a different question, uses a different outcome scale, and was assessed at Day 27 rather than over the primary outcome's timeframe of up to Day 35.

Secondary outcomes are useful for describing additional aspects of a trial, but they ordinarily require cautious interpretation. When many outcomes or comparisons are examined, the chance of apparently notable results arising by chance can increase. The registry record does not report a multiplicity strategy, a hierarchy for testing outcomes, or sponsor analyses for the listed secondary outcomes. The posted unadjusted results therefore carry less inferential weight than a clearly prespecified, multiplicity-controlled analysis would.

The secondary results should be considered alongside the primary safety findings, rather than as confirmation of them. They concern distinct questions and the record does not report enough analysis detail to establish how the outcomes were intended to support one another. The absence of numerical results for some listed measures also prevents a full assessment of the breadth of the secondary findings.

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

• Percentage of Participants With Clinically Significant Abnormal Laboratory Parameters
• Percentage of Participants With Clinically Significant Changes 12-Lead Electrocardiogram (ECG) Findings
• Percentage of Participants With Clinically Significant Abnormal Vital Signs
• Change From Baseline in 2-day Average OFF Time

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: a participant either experienced a treatment-emergent adverse event related to study drug during the stated timeframe or did not. A natural summary is the percentage of participants with an event in each arm. The posted figures are 9.1% for placebo, 17.8% for CVN424 50 mg, and 19.1% for CVN424 150 mg. Arm-specific percentages describe the observed groups; they do not by themselves quantify uncertainty about the differences between groups.

A risk difference expresses the difference in event probability between two groups. Positive values in these comparisons mean that the estimated event probability was higher in the active-dose arm than in placebo, under the stated ordering of the comparison. The recalculated risk differences are 0.087 for CVN424 50 mg versus placebo and 0.101 for CVN424 150 mg versus placebo. They are unadjusted calculations from the posted summary counts and denominators. No covariate adjustment is reflected in these estimates.

A confidence interval gives a range of values compatible with the data under the method used to calculate it. Wider intervals indicate less precision. For the primary comparisons, the intervals include zero and extend to both negative and positive values. This means the posted results do not sharply distinguish between a possible lower event probability, little or no difference, or a possible higher event probability. The interval is not a guarantee that the true value lies within its endpoints, and it does not measure the probability that a treatment is beneficial or harmful.

The unadjusted p-value evaluates how unusual the observed data, or data more extreme, would be under a statistical null model of no difference, subject to the assumptions of the calculation. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry lists p-values of 0.23 and 0.171 for the primary comparisons. The record does not report a prespecified testing procedure, adjustment for multiple comparisons, or a sponsor analysis for these comparisons; interpretation should therefore remain descriptive.

The secondary OFF-time outcome is continuous and reported as a mean change from baseline, in hours, at Day 27. A mean difference compares the average change in one arm with the average change in placebo. The recalculated differences are -0.88 hours for CVN424 50 mg and -1.101 hours for CVN424 150 mg. Negative estimates indicate a more negative mean change in the active arm under the stated comparison direction. Their confidence intervals include zero, reflecting uncertainty about the difference. The reported standard deviations describe participant-to-participant variability in the arm-specific changes; they are not confidence intervals for the means.

These recalculated comparisons use the posted arm-level means, standard deviations, and sample sizes. They are simple, unadjusted comparisons. In general, analyses of continuous outcomes may use models that account for baseline values or other design features, but whether such an approach was prespecified or used in the sponsor's analysis is not reported in the registry record. The calculations should not be read as evidence that no such analysis was conducted outside the posted record.

For a binary endpoint, relatively few events can make estimates imprecise. A change in the event status of a small number of participants can have a noticeable effect on a group percentage, especially when group sizes are modest. In general, uncertainty depends on both the number of events and the number of participants contributing data. Percentages and risk differences are complementary: percentages describe each arm, while the risk difference describes the absolute contrast between arms.

Why does over-dispersion matter?

Over-dispersion is a general concern when observed variation is greater than a statistical model expects. For binary participant-level outcomes, dependence among observations or unmodeled differences in risk can make a simple model understate uncertainty. This trial's posted primary comparison is a simple unadjusted recalculation; the registry record does not report an over-dispersion assessment or a model addressing it. The concept is relevant as a general consideration, not a finding about this study.

What does the absence of a reported analysis mean?

The registry lists no reported analyses, and its primary outcome entries contain arm-level percentages and counts. The recalculated effect estimates and p-values provide a transparent, unadjusted way to describe those summaries, but they do not reveal the sponsor's planned estimand, analysis population rules beyond the stated Safety Analysis Set, handling of missing observations, or any model-based adjustment. Such details are not reported in the registry record. If a sponsor analysis is available elsewhere, it may use methods not represented by these recalculations.

The statistical methods should therefore be read as descriptive comparisons based on posted summaries, not as a reconstruction of an unreported trial analysis plan. The size and direction of an estimate, its interval, and the underlying outcome definition all matter; no single p-value provides a complete account of the evidence.

11. Confidence Intervals and Precision

The primary risk-difference confidence intervals are broad relative to their point estimates. For CVN424 50 mg versus placebo, the recalculated risk difference is 0.087, with an interval from -0.053 to 0.227. For CVN424 150 mg versus placebo, it is 0.101, with an interval from -0.040 to 0.241. Each interval includes zero and also includes values on either side of zero. The data therefore leave substantial uncertainty about the direction and size of the difference.

Precision is limited in part because the primary outcome counts were 4 in the placebo arm, 8 in the 50 mg arm, and 9 in the 150 mg arm. With a binary endpoint, the estimate can be sensitive to a small number of event classifications. The point estimates should not be treated as exact measures of an underlying event probability difference.

The secondary mean-difference intervals are also wide. For CVN424 50 mg versus placebo, the recalculated mean difference in OFF-time change is -0.88 hours, with an interval from -2.197 to 0.437. For CVN424 150 mg versus placebo, the mean difference is -1.101 hours, with an interval from -2.285 to 0.083. Both intervals include zero. Thus, the secondary estimates do not precisely establish the size or direction of a between-arm difference.

In general, an interval's width conveys precision, not clinical importance. A narrow interval can still include effects of different practical relevance, and a broad interval can include both little difference and meaningful differences. The registry record does not report a clinical threshold for interpreting these outcomes, nor does it report a sponsor analysis that would alter the unadjusted recalculations.

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 planning figures are illustrations based on the observed effects, not the trial's original design calculations. For these binary and continuous outcomes, the displayed figures are participants per arm, rather than total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial's original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm that would be needed under those assumptions for an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column gives the corresponding planning figure for a 90% chance. These are conventional design targets, not guarantees about the results of a future study. Higher target power generally requires more participants under otherwise comparable assumptions.

The planning rows use the full observed effect, 75% of the observed effect, and 50% of the observed effect. Smaller effects need more participants to detect, which is why the planning figures rise as the assumed effect becomes a smaller fraction of the observed estimate. The results can differ substantially by endpoint and comparison because the observed effect and variability differ.

These sample-size figures are not observed power. They are forward-looking planning illustrations based on effects estimated in this trial, and the observed-effect estimate itself is uncertain. They should not be read as proof that the trial was adequately or inadequately sized under its original design, which is not reported in the registry record.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.091; treatment proportion p₁ = 0.178; average p̄ = 0.134.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4823 = 0.9452.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4783 = 0.4026.
4. n = (0.9452 + 0.4026)² / (0.0869)² = 240.7, rounded up to 241 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 <- 0.0909090909090909                          # control proportion
p1 <- 0.177777777777778                          # 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(4191577)
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 = 241 (80% power), 322 (90% power)
 75% of observed effect: n per arm = 400 (80% power), 534 (90% power)
 50% of observed effect: n per arm = 831 (80% power), 1,112 (90% power)
power.prop.test: 240.7 
Simulated power at n = 241 per arm: 0.806 (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 record reports comparisons of each CVN424 dose with placebo for the primary safety endpoint and for the posted OFF-time outcome. It does not report a multiplicity adjustment, a testing hierarchy, or a prespecified strategy for controlling the family-wise error rate across these comparisons and outcomes. When a study examines multiple hypotheses, unadjusted p-values can overstate the strength of evidence if interpreted as though each were the only test. This is a general statistical concern; the registry record does not establish which approach the trial team used.

The primary comparisons have unadjusted p-values, and the secondary comparisons also have unadjusted p-values. They are useful descriptive summaries but should not be treated as multiplicity-controlled confirmatory tests. The registry lists no reported analyses, so whether adjusted analyses were performed is not reported in the registry record.

The primary endpoint specifies the Safety Analysis Set. The record does not give further details about the population rules, such as how participants were included in the analysis if they discontinued, missed assessments, or had incomplete event data. Missing-data handling for the secondary OFF-time outcome is also not reported in the registry record. The arm-specific denominators in the reported outcome summaries may differ from the enrollment count, but the reasons and rules behind outcome-specific availability are not reported.

Other important elements of an analysis plan are not reported in the registry record, including the planned model, covariate adjustment, handling of protocol deviations, and whether analyses were interim or final. These omissions limit the ability to determine how closely the recalculated summaries correspond to the trial's planned inferential analysis. The recalculated comparisons should therefore be interpreted as unadjusted statistical descriptions of the posted summary data, not as evidence that a particular sponsor analysis was or was not conducted.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac arrest (2.1%).

The serious adverse event summary reports 0 participants with a serious event in the placebo arm, 0 in the CVN424 50 mg arm, and 1 in the CVN424 150 mg arm. The reported deaths were 0, 0, and 1, respectively. These figures are distinct from the primary endpoint, which concerns treatment-emergent adverse events related to study drug and is not limited to serious events.

The record lists cardiac arrest at 2.1% among the top serious adverse event terms. The posted summary does not provide enough detail to connect that term to a particular arm or to establish a causal relationship to treatment. A serious event occurring during a trial does not, by itself, establish that study treatment caused it.

Counts this small offer limited precision and should be interpreted descriptively. The registry record does not report further details about event narratives, timing, severity beyond seriousness, or adjudication. These summaries alone cannot characterize the full safety profile.

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

The posted results show that the percentage of participants with treatment-emergent adverse events related to study drug was numerically higher in each CVN424 arm than in the placebo arm. The unadjusted risk-difference intervals include zero and span both negative and positive values. Thus, the results do not precisely determine the size or direction of a difference. The record also reports one serious adverse event and one death in the 150 mg arm, with none reported in the other arms; those events should be described as observed events, not attributed to treatment on these data alone.

The secondary OFF-time results show more negative average changes in the active arms than in placebo, but the unadjusted mean-difference intervals include zero. These results are not sufficiently precise to establish a between-arm difference from the posted summaries. The registry does not report quantitative results for the other listed secondary outcomes.

These findings do not establish that CVN424 is safe or unsafe, nor do they establish a benefit or lack of benefit for Parkinson disease symptoms. The trial's primary endpoint is a safety outcome, and the posted secondary data are limited. The estimates describe this study's observed groups over the recorded timeframes; they do not settle what would occur in other populations, with other schedules, or over longer periods.

Interpretation is also constrained by missing analysis details. The registry does not report the original sample-size justification, multiplicity plan, sponsor analyses, or the handling of missing outcome data. The recalculated comparisons are unadjusted, and the confidence intervals show appreciable uncertainty. A reader should distinguish the observed arm percentages and means from causal conclusions or claims about clinical importance, neither of which is established by these summaries alone.

17. Why This Trial Matters Statistically

Statistically, this study illustrates the distinction between arm-specific outcome percentages and a comparative effect estimate. The percentages describe the observed frequency of the primary event in each randomized group; risk differences express the contrast between an active-dose group and placebo. Reporting both kinds of information helps readers see the absolute pattern and the uncertainty around the comparison.

The trial also illustrates why confidence intervals matter alongside p-values. The primary risk-difference estimates are positive, but their intervals include zero and extend into negative values. The secondary OFF-time estimates have the same broad uncertainty about the direction of the difference. A point estimate alone can appear more definitive than the data warrant, while an interval makes the range of compatible effects more visible.

Another statistical issue is that a trial may report several outcomes and comparisons. Without a reported multiplicity plan, individual unadjusted results should not be treated as definitive evidence across all endpoints. The registry's limited reporting of secondary outcomes and absence of listed analyses make it especially important to separate observed summaries from a confirmatory analysis.

Finally, the planning illustrations make clear that sample-size requirements depend on the effect a future study aims to detect. Smaller target effects require more participants under the stated assumptions. Because the observed estimates are uncertain, planning from them should be viewed as illustrative rather than as a definitive design recommendation.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The posted primary endpoint is a short-term safety outcome assessed up to Day 35. It does not provide a long-term safety assessment. The record does not report longer-term follow-up for this outcome, and the listed study timeframe does not establish what might happen after the assessed period.

The primary event counts are limited, which contributes to uncertainty in the risk-difference estimates. The confidence intervals include zero and a range of negative and positive values. The posted comparisons are unadjusted recalculations, while the registry record does not report the sponsor's analysis plan or analyses. Consequently, the results cannot be checked against a reported prespecified inferential method.

The registry lists several secondary safety outcomes, but quantitative data are posted for change in OFF time and not for the laboratory, ECG, and vital-sign outcomes. This restricts assessment of the secondary safety pattern. The OFF-time outcome also has incomplete arm-specific denominators relative to the primary endpoint summaries; reasons for outcome availability and missing-data handling are not reported in the registry record.

The record does not report the original sample-size justification, planned multiplicity procedure, details of randomization, or the basis for classifying events as related to study drug. It also does not report sufficient information to judge clinical importance thresholds for the outcome estimates. These are limitations of the registry record and should not be interpreted as proof that the study team did not collect or analyze such information elsewhere.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study of CVN424 in Parkinson's Disease Patients With Motor Fluctuations — NCT04191577.
• Registry record last updated 2024-07-03; status last verified 2024-06.
• Results first posted 2024-07-03.
• 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

NCT04191577 is a completed phase II randomized, double-blind, placebo-controlled, multicenter parallel-group study of CVN424 in Parkinson disease participants with motor fluctuations. Enrollment was 136. The primary endpoint was the percentage with treatment-emergent adverse events related to study drug, assessed up to Day 35 in the Safety Analysis Set.

The reported primary percentages were 9.1% for placebo, 17.8% for CVN424 50 mg, and 19.1% for CVN424 150 mg. Unadjusted recalculated risk-difference confidence intervals include zero. Quantitative secondary results are posted for change in 2-day average OFF time; its unadjusted mean-difference intervals also include zero. The registry record does not report sponsor analyses, the original sample-size justification, or a multiplicity plan.