Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment (NCT02530996), a randomized phase 1, phase 2 study. The primary outcome is Flow Mediated Dilatation (FMD)-Diameter of Artery.

2. Clinical Question

The registry frames the study around SSc vasculopathy and the need to understand potential approaches to monitoring and treatment. The primary endpoint is a physiological measure of vascular response, rather than a clinical outcome such as digital ulcers, pulmonary arterial hypertension, renal crisis, or disease progression. The record does not report those outcomes as trial endpoints.

Because this is a crossover study, each participant was intended to receive both treatments. The treatment comparison therefore concerns measurements under two periods in the same group of participants, rather than outcomes from two entirely separate participant groups. The registry lists 12 participants in each treatment condition, consistent with the crossover descriptions, and reports an enrollment of 12.

The clinical question is narrow: whether the recorded FMD artery diameter differs between the BH4 and placebo periods. The record does not establish a broader claim about clinical benefit, long-term effects, or outcomes beyond the measures collected during the study.

3. Trial Design

The registry identifies this as a randomized, quadruple-masked, crossover study in phase 1 and phase 2. The sponsor was the VA Office of Research and Development. Enrollment was 12, and the study status is completed. The registry lists a start date of 2016-01-01 and a primary completion date of 2016-06-01.

Participants received BH4 and placebo in different sequences. Six participants received placebo before BH4, and six received BH4 before placebo. Each treatment was oral and listed at 10 mg/kg. The description says measurements were taken after the treatment periods, with a five-day washout before crossing over to the other treatment. FMD was measured in both periods, and blood samples were collected for oxidative stress assessments.

A crossover design lets participants serve as their own comparator, which can reduce the influence of stable differences between people when comparing treatment periods. The comparison also depends on the periods being adequately separated and on the analysis accounting appropriately for the repeated measurements within each participant. The registry confirms a five-day washout, but it does not report a rationale for that duration or describe how possible period or carryover effects were assessed.

The record labels masking as quadruple but does not identify which roles were masked or describe how masking was maintained. It also does not report the randomization sequence-generation method, allocation concealment procedures, protocol deviations, participant flow by period, or the original statistical analysis plan. These design details are not reported in the registry record.

The trial's small enrollment and crossover structure are important when interpreting the results. The two treatment-condition summaries refer to the same enrolled group across different periods; they should not be read as evidence that 24 distinct people took part. The registry record reports 12 participants under each treatment condition and 12 enrolled overall.

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: While 32 participants were intended, this study was concluded after 12 participants due to budgetary restrictions.

First Intervention

Washout (5 Days)

Second Intervention

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 Flow Mediated Dilatation (FMD)-Diameter of Artery, measured over FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period..

The primary endpoint was flow-mediated dilatation artery diameter, measured in millimeters. FMD is a vascular assessment based on the change in an artery in response to increased blood flow. In this record, the stated outcome is the artery diameter, and the registry describes a higher value as better. It is a physiological measure intended to reflect vascular function, rather than a direct count of clinical complications.

FMD is relevant to this study because systemic sclerosis can involve vascular dysfunction. Measuring artery diameter in the placebo and BH4 periods gives a way to compare the vascular response under each condition. The registry states that FMD was obtained on a single day at two time points, after placebo and after the intervention, with a five-day washout period.

The posted mean diameter was 3.79 mm after placebo and 3.78 mm after BH4. The posted mean difference for BH4 compared with placebo was -0.01 mm. These summaries describe the endpoint as measured; they do not show whether the difference corresponds to a meaningful change in symptoms or future clinical events. The record does not report a threshold for clinical importance or a minimum change considered meaningful.

FMD is one way to characterize vascular function, but it does not by itself represent all aspects of SSc vasculopathy. The trial's primary endpoint does not directly measure digital ulcers, pulmonary arterial hypertension, renal crisis, or disease progression. Those outcomes should not be inferred from the FMD result.

7. Results Posted in the Registry

• 12 Participants With BH4: mean 3.78 versus 3.79 on control; difference -0.01 (95% CI -0.58 to 0.56), standardized effect d = -0.01; z-test p = 0.972.

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.

Oxidative Stress Measurement-MDA: Malondialdehyde

• 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 errors.
• Result:
  • 12 SSc Patients Oxidative Stress After BH4: mean 2.90 versus 2.80 on control; difference 0.10 (95% CI -0.34 to 0.54), standardized effect d = 0.18; z-test p = 0.655.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 12 SSc Patients Oxidative Stress After BH4 and the control. The interval gives the range of effects that remain compatible with the data.

Oxidative Stress Measurement-catalase (CAT)

• 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 errors.
• Result:
  • 12 SSc Patients Oxidative Stress After BH4: mean 78.00 versus 86.00 on control; difference -8.00 (95% CI -33.55 to 17.55), standardized effect d = -0.25; z-test p = 0.539.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 12 SSc Patients Oxidative Stress After BH4 and the control. The interval gives the range of effects that remain compatible with the data.

Oxidative Stress Measurement- Protein Carbonyl

• 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 errors.
• Result:
  • 12 SSc Patients Oxidative Stress After BH4: mean 0.16 versus 0.17 on control; difference -0.01 (95% CI -0.04 to 0.02), standardized effect d = -0.29; z-test p = 0.480.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 12 SSc Patients Oxidative Stress After BH4 and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists oxidative stress outcomes including malondialdehyde (MDA), catalase (CAT), protein carbonyl, ferric reducing ability of plasma (FRAP), superoxide dismutase (SOD), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP). Numerical comparisons are posted for MDA, CAT, and protein carbonyl. Results for the other listed markers are not reported in the registry record.

Across the numerical secondary comparisons, the estimated directions are not uniform: the MDA estimate is positive, while the CAT and protein carbonyl estimates are negative. The confidence intervals for these comparisons include zero. This broad pattern does not provide a clear, consistent signal across the reported markers, and the estimates are uncertain. It should not be treated as a biological explanation for the primary result.

These outcomes relate to the primary FMD measure because they assess oxidative stress markers alongside a vascular-function measurement. They address different aspects of the study question, however. Changes in blood-marker measurements do not directly establish a change in artery diameter or a clinical outcome, and the primary FMD result does not determine what happened to every oxidative stress marker.

The secondary comparisons are unadjusted. When multiple outcomes are examined, the chance of observing apparently notable results by chance can increase. If several markers are tested, the results should be viewed as exploratory unless a prespecified testing strategy controls the overall error rate or otherwise addresses multiplicity. The registry does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes.

Accordingly, the secondary findings carry less evidential weight than a single prespecified primary outcome, particularly when the study is small and the analysis plan is not described. The posted results can identify what was measured and the direction and uncertainty of the available estimates, but they do not establish a pattern of treatment effects across all oxidative stress pathways.

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

• Oxidative Stress Measurement-MDA: Malondialdehyde
• Oxidative Stress Measurement-catalase (CAT)
• Oxidative Stress Measurement- Protein Carbonyl
• Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP)
• Oxidative Stress Measurement- Superoxide Dismutase (SOD)
• Oxidative Stress Measurement- Interleukin 6 (IL-6)
• Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α,
• Oxidative Stress Measurement- C-reactive Protein (CRP)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is a continuous measurement, so the registry reports means and standard errors for each treatment condition and a mean difference between conditions. A mean describes the central value of a set of measurements. A standard error describes the statistical uncertainty in an estimated mean; it is not the same quantity as the spread of individual participant measurements.

What does the mean difference represent?

The reported comparison is BH4 minus placebo. The means are 3.78 mm for BH4 and 3.79 mm for placebo, and the mean difference is -0.01 mm. A negative value therefore indicates that the estimated mean was lower in the BH4 condition than in the placebo condition. This is a direction-of-comparison convention, not a statement about whether the size of the estimate is clinically important.

The comparison also gives a confidence interval, from -0.578 to 0.558, and an unadjusted p-value of 0.972. A confidence interval describes uncertainty around an estimate under the method used to construct it. A p-value is a measure of compatibility between the observed data and a specified null model. Neither statistic independently establishes clinical importance or equivalence.

Why does the crossover design matter?

In a crossover study, each participant receives more than one treatment in separate periods. Measurements from the same person can be correlated because individual characteristics persist across periods. An analysis that uses the paired structure can incorporate that within-person relationship. The registry record describes the crossover sequences and washout but does not report the statistical model or whether the primary comparison accounts for pairing, period, sequence, or carryover effects.

The posted means and standard errors alone do not reveal the within-person covariance. That covariance is relevant to the precision of a paired treatment contrast. Without participant-level data or a clearly described paired analysis, readers cannot verify how the comparison reflects the crossover design. The reported comparison should therefore be interpreted with this reporting limitation in mind.

What do standard errors and confidence intervals tell readers?

Standard errors quantify uncertainty in estimated means. Confidence intervals combine an estimate with its uncertainty to indicate a range of values compatible with the data and the chosen statistical method. A narrow interval generally indicates greater precision than a wide interval, provided the methods and assumptions are appropriate. Here, the primary interval crosses zero and extends in both directions, so the estimate does not precisely determine the direction or size of the treatment contrast.

The record reports standard errors for the primary and secondary continuous outcomes. It does not provide standard deviations for individual participant values in the outcome summaries, although derived comparisons include pooled standard deviation estimates. No patient-level data are reported, limiting independent assessment of distributional features, outliers, and within-person relationships.

How should the p-value be read?

The unadjusted p-value of 0.972 does not mean there is a 97.2% probability that the treatments are the same. It describes how compatible the data are with a null model under the analysis used. A large p-value can arise when the estimated difference is small, when the data are variable, or both. It is not an equivalence test, and the record does not report an equivalence margin or a non-inferiority margin.

General statistical interpretation: a failure to find strong evidence against a null model is not the same as evidence that the null model is exactly true. To support equivalence, a study would generally need a prespecified margin and an analysis designed to test whether the entire uncertainty interval lies within that margin. Such a margin and analysis are not reported in the registry record.

What can be inferred from the reported analysis details?

The record lists one primary outcome analysis and does not describe the analysis model, covariate adjustment, missing-data handling, or analysis population. It does not report whether the displayed p-value was prespecified, whether any interim analyses occurred, or how the original sample size was justified. These matters are not reported in the registry record. The posted summary statistics can be described, but they do not allow a full audit of the original analysis.

General statistical explanation: for repeated measurements, accounting for the dependence between observations can improve or change estimates of uncertainty. For a crossover study, the analysis may also need to distinguish treatment effects from period and sequence effects. These are general considerations, not claims about procedures used in this trial; the registry does not report those procedures.

11. Confidence Intervals and Precision

The primary mean difference is -0.01 mm, with a confidence interval from -0.578 to 0.558. The interval spans zero, so the posted estimate is compatible with a difference in either direction. Its breadth relative to the point estimate signals substantial uncertainty about the size and direction of the contrast.

Precision is the degree to which the data constrain the plausible values for an effect. A point estimate alone cannot show precision: the interval is needed to understand the range of uncertainty. In this case, the estimated difference is close to zero, but the interval extends well beyond that point in both directions. It therefore does not rule out differences of appreciable size on the scale of the endpoint.

The interval should not be read as a range that contains the true effect with certainty. It is produced by a statistical method and relies on assumptions. The registry does not report the method used to construct the interval or the treatment of the crossover pairing. That reporting gap matters because within-person dependence can affect uncertainty estimates in a crossover design.

The number of participants is small: 12 enrolled, with 12 listed in each treatment condition because participants crossed over. Repeated observations from the same participants do not provide the same information as observations from additional independent people. The reported interval communicates uncertainty in the posted comparison, but it cannot resolve limitations arising from small enrollment or unreported analysis details.

The interval and p-value should be interpreted together with the endpoint's clinical meaning. The registry does not give a threshold for a clinically important FMD change. Consequently, the interval cannot be classified as excluding or including a clinically meaningful effect using a trial-specific criterion. The record supports describing the numerical estimate and its uncertainty, but not a claim of equivalence or a definitive conclusion about clinical impact.

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 estimates describe hypothetical future sample sizes under the stated assumptions; they are not the number of participants who took part in this study. For these continuous outcomes, the estimates are participants per arm, not total event counts. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect.

The 80% power column gives the estimated participants per arm for a future study to have an 80% chance of detecting the selected effect if that effect is real and the planning assumptions hold. The 90% power column gives the corresponding estimate for a 90% chance. These are design targets, not guarantees; actual performance depends on the true effect, variability, analysis, and other design features.

The rows use planning for 100% of the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect. A smaller effect is harder to distinguish from random variation, so detecting a smaller effect generally requires more participants. The calculations use the observed effect as their starting point; when that estimate is close to zero, the resulting sample-size estimates can become very large.

For the primary outcome, the observed mean difference is -0.01 mm, and the planning estimates are correspondingly very large. These numbers should be read as illustrations of how the estimated effect and assumptions influence planning, not as recommendations for a new study. They also do not account for details that are not reported, including any crossover-specific planning or analysis assumptions from the original protocol. The trial's own original sample-size justification and design assumptions are not reported in the registry record.

This is not observed power. Observed power would attempt to describe power using the effect estimated from the completed study and does not provide a useful substitute for interpreting the estimate and its confidence interval. The planning figures instead show hypothetical sample-size requirements under explicit assumptions.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.010; pooled standard deviation σ = 0.710.
2. n = 2 × (1.96 + 0.842)² × 0.710² / -0.010² = 79,210.9, rounded up to 79,211 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
delta <- -0.0100000000000002                      # observed difference in means
sigma <- 0.710352025407122                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2530996)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 79,211 (80% power), 106,041 (90% power)
 75% of observed effect: n per arm = 140,820 (80% power), 188,518 (90% power)
 50% of observed effect: n per arm = 316,844 (80% power), 424,164 (90% power)
power.t.test: 79211.9 
Simulated power at n = 79,211 per arm: 0.808 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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

Several statistical reporting details are not available in the registry record. The record lists one primary outcome and multiple secondary oxidative stress outcomes, but does not describe a prespecified strategy for handling multiple comparisons. It does not report whether any adjustment was made, whether the primary outcome had priority in a testing hierarchy, or how secondary results were intended to be interpreted. Without such information, the unadjusted secondary p-values should be treated cautiously.

Multiplicity matters because testing several outcomes can increase the chance of at least one apparently unusual result even when there is no underlying effect. This is a general statistical concern, not a finding about the trial. The posted secondary comparisons are unadjusted, and no adjusted estimates or p-values are reported. The primary comparison is also identified as unadjusted.

The registry record does not report the handling of missing outcome measurements, the number of participants with complete data for each period, or any imputation method. It reports 12 participants in each treatment condition, but that summary does not establish that every participant had complete paired measurements or that no data were missing. Missing-data methods and reasons for missingness are not reported in the registry record.

The analysis population is also not described. It is not reported whether the analysis followed an intention-to-treat, per-protocol, or other population definition. The record does not provide participant flow, exclusions from analysis, protocol deviations, or a detailed account of how participants were handled if they did not complete both treatment periods.

For a crossover study, period and sequence effects, carryover, and within-person correlation can affect estimation and uncertainty. The record states that a five-day washout was used, but does not report how these issues were assessed in the analysis. It also does not report whether any interim analyses were conducted, how the original sample size was justified, or a complete statistical analysis plan. Those details are not reported in the registry record, so the posted summaries cannot answer these questions.

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.

The registry reports serious adverse events, other adverse events, and deaths separately for the placebo and BH4 conditions. In each condition, 12 participants were listed as at risk. The record reports 0 serious adverse events, 0 other adverse events, and 0 deaths in each condition.

These figures describe the events recorded in the registry for this study. They do not establish that no adverse events occurred outside the recorded categories or observation period. The registry does not provide event definitions, severity grading details, exposure duration beyond the treatment descriptions, or a narrative account of safety monitoring.

Because the trial used a crossover design, the same participants contributed to both treatment conditions. The two sets of at-risk figures should not be read as 24 separate people. The small enrollment also limits how much the absence of recorded events can establish about uncommon events. The safety record is therefore best read as a count of events reported for each condition in this study, not as a general estimate of risk.

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

The posted primary result is a mean FMD artery diameter of 3.78 mm after BH4 and 3.79 mm after placebo, with an estimated mean difference of -0.01 mm. The confidence interval extends from -0.578 to 0.558, and the unadjusted p-value is 0.972. Taken together, these statistics show an estimate close to zero with substantial uncertainty around it.

The result does not demonstrate that BH4 and placebo are equivalent. Equivalence requires a prespecified margin defining how much difference would be considered acceptably small, together with an analysis designed to evaluate that margin. Such a margin and analysis are not reported in the registry record. A non-small p-value alone cannot establish equivalence.

The result also does not show that a clinically important difference is absent. The confidence interval includes values on both sides of zero, and the registry does not report a threshold for a clinically meaningful FMD change. Nor does the endpoint directly measure patient symptoms or the complications named in the study description, including digital ulcers, pulmonary arterial hypertension, and renal crisis.

The study is small and uses a crossover design. Although the crossover allows participants to receive both treatments, interpretation depends on paired analysis and appropriate consideration of period and carryover effects. The registry does not report the model used to analyze these features. It also does not report missing-data handling or analysis-population definitions.

The most defensible reading is limited to the posted measurement: the means were very similar, but the estimated contrast is imprecise. The result is not a definitive estimate of long-term effects, clinical outcomes, or safety beyond the events recorded during the trial. It neither establishes a treatment benefit nor proves the absence of one.

17. Why This Trial Matters Statistically

This study is statistically informative because it illustrates the difference between a small point estimate and a precise estimate. The primary difference is close to zero, but the confidence interval is wide and includes values on either side. Focusing only on the point estimate could make the evidence look more conclusive than it is; considering the interval shows how much uncertainty remains.

The crossover structure is another important feature. Each participant received both BH4 and placebo, which can make within-person comparisons useful when analyzed appropriately. At the same time, the repeated observations require attention to pairing, period effects, and possible carryover. The registry reports the design and washout but does not report the analysis methods used to address these features. This makes transparent analysis reporting particularly important.

The study also demonstrates why a non-significant result should not be equated with proof of no effect. The posted p-value is 0.972, but the confidence interval does not confine the effect to a narrow, prespecified equivalence range. The absence of a reported clinical-importance threshold further limits what can be concluded about the practical meaning of the estimate.

Finally, the oxidative stress outcomes show why multiple outcomes require a clear interpretation plan. The record includes several markers, while numerical results are available for only some. Unadjusted secondary results can generate hypotheses, but they are not as strong a basis for confirmatory conclusions as a prespecified primary analysis with a reported multiplicity strategy.

These statistical considerations do not negate the value of a small early-phase study. They clarify what the posted data can support: a descriptive comparison, an indication of uncertainty, and identification of important reporting needs for future evaluation.

18. Limitations

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

The enrollment was 12, limiting the amount of information available for estimating the primary treatment contrast and for assessing variability across participants. The crossover design means the treatment-condition summaries refer to measurements from the same group across periods, but the registry does not report a paired analysis or participant-level data. It is therefore not possible to assess how the within-person relationship was handled.

The record does not report important details of the randomization and masking procedures, including the roles masked and how the allocation sequence was generated. It also does not report participant flow through both periods, completeness of paired measurements, protocol deviations, or analysis-population definitions. These omissions make it difficult to evaluate possible sources of bias or the influence of missing observations.

Although a five-day washout is described, the registry does not report evidence that carryover was assessed or the reasoning for the washout duration. Period and sequence effects are also not discussed. Those issues are specific to the interpretation of a crossover comparison and are not resolved simply by knowing that a washout occurred.

The primary endpoint is a physiological measure and no clinical-importance threshold is reported. The registry does not report long-term follow-up or the clinical complications discussed in the study rationale as measured outcomes. The listed oxidative stress outcomes cover multiple markers, but numerical results are not reported for every listed measure, and no multiplicity strategy is described.

Finally, the registry does not report the trial's original sample-size justification, complete statistical analysis plan, missing-data methods, or whether interim analyses occurred. These limitations constrain evaluation of the precision and robustness of the posted results, beyond the uncertainty already evident in the primary interval.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment — NCT02530996.
• Registry record last updated 2021-04-05; status last verified 2021-04.
• Results first posted 2021-04-05.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

NCT02530996 is a completed randomized, quadruple-masked crossover study listed in phase 1 and phase 2. It enrolled 12 participants with systemic sclerosis and compared oral BH4 10 mg/kg with placebo 10 mg/kg, using different treatment sequences and a five-day washout.

The primary outcome was FMD artery diameter in millimeters. The posted means were 3.79 mm after placebo and 3.78 mm after BH4; the mean difference was -0.01 mm, with a confidence interval from -0.578 to 0.558 and an unadjusted p-value of 0.972. These data show a small estimated difference with considerable uncertainty.

The record also lists oxidative stress outcomes and reports numerical results for some of them. Safety figures list 0 serious adverse events, 0 other adverse events, and 0 deaths in each treatment condition. Details of the statistical plan, paired analysis, missing-data handling, and multiplicity procedures are not reported in the registry record.