This page separates reported trial results from statistical interpretation. The numerical results and trial characteristics presented here are restricted to the ClinicalTrials.gov record for FREEDOM-C.
1. Trial at a Glance
FREEDOM-C was a randomized, parallel-group, quadruple-masked phase 3 treatment trial with 354 participants and two study arms. The primary endpoint was change in six minute walk distance (6MWD) from Baseline to Week 16, analyzed using ANCOVA with a reported Hodges-Lehmann effect estimate.
| Feature | FREEDOM-C |
|---|---|
| Trial | FREEDOM-C |
| ClinicalTrials.gov identifier | NCT00325442 |
| Therapeutic area | Pulmonology |
| Condition | Pulmonary Hypertension |
| Phase | Phase 3 |
| Status | COMPLETED |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | QUADRUPLE |
| Primary purpose | TREATMENT |
| Enrollment | 354 |
| Interventions | Oral treprostinil (UT-15C) sustained release tablets; placebo |
| Lead sponsor | United Therapeutics |
| Sponsor type | INDUSTRY |
2. Clinical Question
The primary statistical question was whether oral treprostinil produced a different change in six minute walk distance from Baseline to Week 16 compared with placebo. The registered endpoint describes placebo-corrected change in 6MWD as an objective measure of patient functional status and notes its relationship to the historical clinical standard for assessing functional status in pulmonary arterial hypertension.
Population
Participants in a phase 3 treatment trial for pulmonary hypertension, with background pulmonary arterial hypertension therapy represented by endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor subgroups in the reported analyses.
Intervention
Oral treprostinil (UT-15C) sustained-release tablets.
Comparator
Placebo.
Primary question
Does oral treprostinil improve the change in 6MWD from Baseline to Week 16 relative to placebo?
3. Trial Design
Oral treprostinil
- Oral treprostinil (UT-15C)
- Sustained-release tablets
- Compared with placebo
Placebo
- Placebo tablets
- Parallel comparison
- Used as the reference group for the reported analyses
The registry identifies the allocation as randomized and the design model as parallel. Masking is listed as quadruple. The trial was intended to evaluate treatment rather than a diagnostic or prevention question, and the registered hypothesis type for the posted analyses is superiority.
4. Endpoints
| Role | Outcome measure | Time frame | Type | Reported method |
|---|---|---|---|---|
| Primary | Six Minute Walk Distance (6MWD) | Baseline and 16 Weeks | Continuous | ANCOVA |
| Secondary | Borg Dyspnea Score | Baseline and 16 Weeks | Continuous | Wilcoxon rank-sum test |
| Secondary | Dyspnea-Fatigue Index | Baseline and 16 Weeks | Continuous | Wilcoxon sum-rank test |
| Secondary | Six Minute Walk Distance (6MWD) | Baseline and 12 weeks | Continuous | ANCOVA |
| Secondary | Six Minute Walk Distance (6MWD) | Baseline and 8 weeks | Continuous | ANCOVA |
| Secondary | Six Minute Walk Distance (6MWD) | Baseline and 4 weeks | Continuous | ANCOVA |
| Secondary | Clinical Worsening Assessment | Baseline and 16 Weeks | Binary | Fisher Exact |
The registered primary endpoint is defined as placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16. The registry describes 6MWD as correlating with the historical clinical standard for assessing patient functional status in pulmonary arterial hypertension and as an objective measure of patient functional status by the American Thoracic Society.
5. Statistical Methodology
| Endpoint / analysis | Statistical method | Effect measure | Hypothesis |
|---|---|---|---|
| Primary 6MWD, Week 16 | ANCOVA | Hodges-Lehmann | Superiority |
| Borg Dyspnea Score, Week 16 | Wilcoxon rank-sum test | Hodges-Lehmann | Superiority |
| Dyspnea-Fatigue Index, Week 16 | Wilcoxon sum-rank test | Hodges-Lehmann | Superiority |
| 6MWD, Week 12 | ANCOVA | Hodges-Lehmann | Superiority |
| 6MWD, Week 8 | ANCOVA | Hodges-Lehmann | Superiority |
| 6MWD, Week 4 | ANCOVA | Hodges-Lehmann | Superiority |
| Clinical Worsening Assessment | Fisher Exact | Not reported | Superiority |
The statistical-method profile is notably different from a time-to-event trial. There is no hazard ratio or Kaplan-Meier analysis in the statistical analyses posted on ClinicalTrials.gov. The principal continuous endpoint was analyzed with ANCOVA, while several patient-reported or scale-based measures were analyzed with a Wilcoxon procedure. The binary Clinical Worsening Assessment used Fisher's exact test.
Primary endpoint analysis
For the primary 6MWD analysis, the registry reports ANCOVA and an effect measure of Hodges-Lehmann. The reported comparison is between the placebo arm and the active arm, with change in 6MWD from Baseline to Week 16 as the analysis target.
95% two-sided confidence interval: 0 to 22 meters; P = 0.072.
ANCOVA is a linear-model approach for comparing continuous outcomes while accounting for relevant baseline information. For a change-from-baseline endpoint, this is important because participants can begin at different baseline levels of functional capacity. Adjusting for baseline information can reduce residual variability and produce a more informative between-group comparison than simply comparing raw post-treatment means.
6. Primary Endpoint Result: Six Minute Walk Distance
The primary endpoint was Six Minute Walk Distance (6MWD), measured at Baseline and 16 Weeks. The outcome was continuous and measured in meters.
Hodges-Lehmann estimate for change in 6MWD
95% CI: 0 to 22 meters · P = 0.072
ANCOVA; placebo arm vs active arm; superiority hypothesis.
| Primary endpoint | Reported result |
|---|---|
| Outcome | Six Minute Walk Distance (6MWD) |
| Time frame | Baseline and 16 Weeks |
| Outcome unit | meters |
| Comparison | Placebo Arm vs Active |
| Method | ANCOVA |
| Effect measure | Hodges-Lehmann |
| Estimate | 11.0 |
| 95% CI | 0 to 22 |
| P-value | 0.072 |
| Hypothesis | Superiority |
The reported Hodges-Lehmann estimate of 11.0 meters represents the estimated difference associated with the active-versus-placebo comparison for change in 6MWD from Baseline to Week 16 under the reported analysis.
The estimate does not mean that every participant receiving oral treprostinil increased their walking distance by exactly 11.0 meters, nor does it describe an individual patient's expected change. It is a group-level effect estimate from the randomized comparison.
The two-sided 95% confidence interval of 0 to 22 meters indicates the statistical uncertainty around the reported estimate. Because the lower endpoint is exactly 0, the interval reaches the null difference.
The P-value of 0.072 is a measure of compatibility with the null hypothesis under the specified testing framework; it is not a measure of the magnitude or clinical importance of the effect. A P-value should therefore not be substituted for the estimated 11.0-meter effect or its confidence interval.
Finally, the registry reports ANCOVA as the method and Hodges-Lehmann as the effect measure. The ClinicalTrials.gov record does not provide the model's complete covariate specification or additional analysis-population details, so the statistical interpretation should remain limited to what was reported.
7. Secondary Endpoint Results
The posted statistical analyses include six secondary comparisons. These extend the assessment beyond the primary 16-week 6MWD analysis to dyspnea, fatigue, earlier 6MWD measurements, and clinical worsening.
Borg Dyspnea Score
Change from Baseline to Week 16
95% CI: -1.0 to 0.0 · P = 0.062
Wilcoxon rank-sum test; Hodges-Lehmann estimate.
One subject in the placebo arm did not have a Baseline Borg score value. The analysis compared the placebo and active groups using the Wilcoxon rank-sum test.
The Hodges-Lehmann estimate was 0.0, with a two-sided 95% confidence interval from -1.0 to 0.0. The P-value was 0.062. The estimate describes the reported group comparison; it does not establish that individual patients had no change in dyspnea. The confidence interval is also more informative than the P-value alone because it shows the range of effect estimates compatible with the analysis.
Dyspnea-Fatigue Index
Change from Baseline to Week 16
95% CI: 0.0 to 1.0 · P = 0.011
Wilcoxon sum-rank test; Hodges-Lehmann estimate.
Five subjects in the placebo arm and three subjects in the active arm did not have a Baseline dyspnea-fatigue index score. The reported comparison used the Wilcoxon sum-rank test.
The reported Hodges-Lehmann estimate was 0.0, with a 95% confidence interval of 0.0 to 1.0 and P = 0.011. The statistical result should be interpreted in the context of the scale's direction and the exact construction of the change variable; the ClinicalTrials.gov record does not provide enough information to assign a clinical direction to the numerical value independently. The P-value indicates evidence against the null hypothesis used for the reported superiority comparison, but it does not quantify the magnitude of benefit.
Six Minute Walk Distance at Week 12
Change from Baseline to Week 12
95% CI: 3.0 to 23.0 meters · P = 0.015
ANCOVA; Hodges-Lehmann estimate.
The reported estimate of 13.0 meters is the between-group effect estimate for change in 6MWD from Baseline to Week 12. The 95% confidence interval, 3.0 to 23.0 meters, does not include 0. The P-value of 0.015 indicates evidence against the null hypothesis under the reported superiority analysis. It should not, however, be interpreted as saying that 98.5% of the effect is real or that the probability of the treatment hypothesis being true is 98.5%.
Six Minute Walk Distance at Week 8
Change from Baseline to Week 8
95% CI: 0.0 to 18.0 meters · P = 0.051
ANCOVA; Hodges-Lehmann estimate.
The estimated difference was 9.0 meters, with a two-sided 95% confidence interval from 0.0 to 18.0 meters and P = 0.051. The estimate suggests a positive between-group difference in the reported analysis, while the confidence interval reaches the null value. This illustrates why an effect estimate and confidence interval should be reported alongside a P-value rather than converting the result into a binary label based solely on whether P is above or below a threshold.
Six Minute Walk Distance at Week 4
Change from Baseline to Week 4
95% CI: -2.4 to 12.0 meters · P = 0.238
ANCOVA; Hodges-Lehmann estimate.
The Week 4 estimate was 4 meters. Its 95% confidence interval ranged from -2.4 to 12.0 meters, crossing 0, and the P-value was 0.238. The result is therefore compatible with a range of underlying differences that includes both a small negative difference and a positive difference. It would be inappropriate to interpret the P-value as evidence that the treatment has exactly zero effect.
Clinical Worsening Assessment
Baseline to Week 16
95% confidence level reported · Fisher Exact
Binary outcome; placebo arm vs active; superiority hypothesis.
The registry reports Clinical Worsening Assessment as a binary endpoint involving participants. The posted analysis used Fisher Exact testing, with P = 0.491. No effect estimate is reported in the ClinicalTrials.gov record for this analysis.
Fisher's exact test is appropriate for a comparison of categorical outcomes when exact inference is useful, particularly when sample counts may be limited. Here, the reported P-value of 0.491 summarizes the evidence from the reported exact test; it does not quantify the difference in clinical-worsening probabilities because no effect estimate is provided in the ClinicalTrials.gov record.
8. Secondary Results Summary
| Endpoint | Time frame | Method | Estimate | 95% CI | P-value |
|---|---|---|---|---|---|
| Borg Dyspnea Score | Baseline and 16 Weeks | Wilcoxon rank-sum | 0.0 | -1.0 to 0.0 | 0.062 |
| Dyspnea-Fatigue Index | Baseline and 16 Weeks | Wilcoxon sum-rank | 0.0 | 0.0 to 1.0 | 0.011 |
| 6MWD | Baseline and 12 weeks | ANCOVA | 13.0 | 3.0 to 23.0 | 0.015 |
| 6MWD | Baseline and 8 weeks | ANCOVA | 9.0 | 0.0 to 18.0 | 0.051 |
| 6MWD | Baseline and 4 weeks | ANCOVA | 4 | -2.4 to 12.0 | 0.238 |
| Clinical Worsening Assessment | Baseline and 16 Weeks | Fisher Exact | Not reported | 95% confidence level reported | 0.491 |
9. Post-Hoc 6MWD Analyses by Baseline 6MWD Quartile
The registry contains four post-hoc analyses dividing the study population into quartiles according to Baseline 6MWD. Each comparison used ANCOVA and reported a Hodges-Lehmann estimate for change in 6MWD from Baseline to Week 16.
| Baseline 6MWD subgroup | Estimate | 95% CI | P-value |
|---|---|---|---|
| Quartile 1: 126-302 Meters | 24 | 0 to 45 | 0.121 |
| Quartile 2: 303-362 Meters | 15 | -7 to 41 | 0.069 |
| Quartile 3: 363-397 Meters | 4 | -15 to 24 | 0.889 |
| Quartile 4: 398-450 Meters | 0 | -23 to 24 | 0.966 |
The estimates vary across the four baseline-distance groups, from 24 meters in Quartile 1 to 0 meters in Quartile 4. The confidence intervals are relatively wide, particularly compared with the primary analysis, which is expected when a randomized population is divided into smaller subgroups.
A subgroup-specific estimate does not by itself demonstrate that treatment effects differ between subgroups. To establish effect modification, one generally needs a formal treatment-by-subgroup interaction analysis. The ClinicalTrials.gov record does not report such an interaction analysis, so these four estimates should be viewed as post-hoc descriptive comparisons rather than proof of differential treatment effect across baseline 6MWD quartiles.
10. Post-Hoc Analyses by Lowest Dose Strength Available at Randomization
Three post-hoc analyses examined 6MWD according to the lowest study-drug dose strength available at randomization. Each used ANCOVA and a Hodges-Lehmann effect estimate for change from Baseline to Week 16.
| Dose-strength subgroup | Estimate | 95% CI | P-value |
|---|---|---|---|
| Smallest Dose Available 1 mg | 5 | -16 to 28 | 0.853 |
| Dose Strength 0.5 mg | 7 | -7 to 21 | 0.327 |
| Study Drug Dose 0.25 mg | 29.5 | 1 to 73 | 0.085 |
The registry defines these subgroups by the minimum tablet strength available for initiation of study-drug dosing and dose titration. The estimates are 5, 7, and 29.5 meters, respectively. Their confidence intervals differ substantially in width, with the 0.25-mg subgroup having a particularly wide interval of 1 to 73 meters.
These analyses are post-hoc subgroup analyses rather than the registered primary endpoint. Smaller subgroups generally provide less precise estimates, and the ClinicalTrials.gov record does not provide subgroup sample sizes or an interaction test. Therefore, the numerical differences among these estimates should not be interpreted as establishing a dose-strength interaction.
11. Post-Hoc Analyses by Background PAH Therapy
Three additional post-hoc analyses evaluated change in 6MWD according to background pulmonary arterial hypertension therapy. The registry defines the background-therapy subgroups according to treatment received for 90 days or greater at randomization.
| Background therapy subgroup | Definition in registry | Estimate | 95% CI | P-value |
|---|---|---|---|---|
| ERA | Receiving treatment with an ERA for 90 days or greater at randomization | 5 | -12 to 24 | 0.615 |
| PDE5-I | Receiving treatment with a PDE5-I for 90 days or greater at randomization | 17 | -6 to 40 | 0.230 |
| ERA and PDE5-I | Receiving treatment with an ERA and PDE5-I for 90 days or greater at randomization | 10 | -6 to 28 | 0.209 |
All three comparisons used ANCOVA and a Hodges-Lehmann effect estimate. The confidence intervals for all three background-therapy analyses include 0.
These analyses ask a narrower question than the primary randomized comparison. They describe the reported treatment comparison within selected background-therapy groups. Because the analyses are post-hoc and the ClinicalTrials.gov record does not include interaction tests or subgroup sample sizes, they cannot independently establish that the treatment effect differs according to background therapy.
12. All Post-Hoc Analyses at a Glance
| Post-hoc analysis | Estimate | 95% CI | P-value |
|---|---|---|---|
| Baseline 6MWD Quartile 1: 126-302 Meters | 24 | 0 to 45 | 0.121 |
| Baseline 6MWD Quartile 2: 303-362 Meters | 15 | -7 to 41 | 0.069 |
| Baseline 6MWD Quartile 3: 363-397 Meters | 4 | -15 to 24 | 0.889 |
| Baseline 6MWD Quartile 4: 398-450 Meters | 0 | -23 to 24 | 0.966 |
| Lowest dose strength: 1 mg | 5 | -16 to 28 | 0.853 |
| Lowest dose strength: 0.5 mg | 7 | -7 to 21 | 0.327 |
| Lowest dose strength: 0.25 mg | 29.5 | 1 to 73 | 0.085 |
| Background PAH therapy: ERA | 5 | -12 to 24 | 0.615 |
| Background PAH therapy: PDE5-I | 17 | -6 to 40 | 0.230 |
| Background PAH therapy: ERA and PDE5-I | 10 | -6 to 28 | 0.209 |
13. Statistical Methods Explained
Why was ANCOVA used for 6MWD?
6MWD is a continuous outcome, and the registered primary endpoint concerns change from Baseline. ANCOVA provides a linear-model framework for comparing treatment groups while incorporating baseline information. This can improve precision when baseline functional capacity varies among participants. The trial data identify ANCOVA as the reported method but do not provide the complete model specification.
What is a Hodges-Lehmann estimate?
The Hodges-Lehmann approach provides an estimate of a treatment-group difference that is closely associated with rank-based inference. In this trial it appears as the reported effect measure for the ANCOVA analyses as well as for the Wilcoxon analyses. The important distinction is that the effect estimate communicates the magnitude of the group comparison, while the P-value communicates evidence against a null hypothesis under the specified test.
Why use the Wilcoxon rank-sum test for the Borg and Dyspnea-Fatigue endpoints?
The Wilcoxon rank-sum test is a nonparametric method for comparing two independent groups. It is useful when an outcome is ordinal, non-normally distributed, or otherwise better handled through ranks rather than a conventional normal-theory comparison. The registry reports this method for the Borg Dyspnea Score and Dyspnea-Fatigue Index.
Why is Fisher's exact test used for Clinical Worsening Assessment?
Clinical Worsening Assessment is reported as a binary endpoint. Fisher's exact test evaluates the association between treatment group and a binary outcome using an exact calculation rather than relying on a large-sample approximation. The registry specifically identifies Fisher Exact as the method for this endpoint.
What does a 95% confidence interval tell us here?
A two-sided 95% confidence interval describes the uncertainty around the reported effect estimate under the relevant statistical framework. For the primary 6MWD result, the interval is 0 to 22 meters around an estimate of 11.0 meters. It does not describe the range of individual patient responses and does not mean that there is a 95% probability that the true effect lies inside this particular interval.
Why should the P-value not be treated as the effect size?
A P-value depends on the observed data and the statistical model or test, including the amount of information available. It does not directly measure the size of a treatment effect. For FREEDOM-C, the primary analysis illustrates this distinction clearly: the estimated effect is 11.0 meters, its 95% confidence interval is 0 to 22 meters, and the P-value is 0.072. These three quantities answer different statistical questions.
Why are the post-hoc subgroup results not equivalent to primary results?
The registry labels these analyses as post-hoc. Dividing participants into baseline 6MWD quartiles, dose-strength groups, or background-therapy groups creates smaller analysis populations and increases the number of comparisons. Without a reported interaction test and a reported multiplicity-control strategy, a difference in one subgroup's P-value from another's does not establish treatment-effect heterogeneity.
14. Missing Baseline Measurements
The statistical analyses posted on ClinicalTrials.gov explicitly identify missing Baseline values for two secondary endpoints.
| Endpoint | Missing Baseline information |
|---|---|
| Borg Dyspnea Score | One subject in the placebo arm did not have a Baseline Borg score value. |
| Dyspnea-Fatigue Index | Five subjects in the placebo arm and three subjects in the active arm did not have a Baseline dypsnea-fatigue index score. |
15. Safety
The ClinicalTrials.gov record reports serious adverse events by treatment arm. The affected counts are presented against the corresponding numbers at risk.
| Safety measure | Placebo arm | Active arm |
|---|---|---|
| Serious adverse events | 33/176 | 32/174 |
These counts should be kept separate from the efficacy analysis. A serious-adverse-event count is a safety outcome, whereas the primary 6MWD analysis evaluates a continuous functional endpoint. The ClinicalTrials.gov record does not provide a formal statistical comparison or confidence interval for serious adverse events, so no such comparison is added here.
16. Confidence Intervals Across the Trial
The FREEDOM-C results provide a useful illustration of how confidence intervals help distinguish an estimated effect from its uncertainty.
| Analysis | Estimate | 95% CI | What the interval indicates |
|---|---|---|---|
| Primary 6MWD, Week 16 | 11.0 | 0 to 22 | Includes the null difference at 0 |
| Borg Dyspnea, Week 16 | 0.0 | -1.0 to 0.0 | Includes the null difference at 0 |
| Dyspnea-Fatigue Index, Week 16 | 0.0 | 0.0 to 1.0 | Begins at the null value |
| 6MWD, Week 12 | 13.0 | 3.0 to 23.0 | Entire interval is above 0 |
| 6MWD, Week 8 | 9.0 | 0.0 to 18.0 | Includes the null difference at 0 |
| 6MWD, Week 4 | 4 | -2.4 to 12.0 | Includes both negative and positive differences |
Confidence intervals are particularly useful when several time points are reported. The Week 4 estimate is 4 meters with an interval extending from -2.4 to 12.0, while the Week 12 estimate is 13.0 meters with an interval from 3.0 to 23.0. These are not interchangeable summaries: they correspond to different time frames and different statistical estimates.
17. Interpreting the Primary Result Without Overreading It
What the estimate says
The reported primary Hodges-Lehmann estimate is 11.0 meters for the active-versus-placebo comparison in change in 6MWD from Baseline to Week 16.
What it does not say
It does not mean that every participant improved by 11.0 meters, nor does it describe an individual patient's expected response.
What the CI says
The two-sided 95% confidence interval is 0 to 22 meters, showing uncertainty around the estimated group difference.
What the P-value says
P = 0.072 summarizes evidence against the reported null hypothesis; it is not a probability that the treatment works or a measure of effect size.
The primary result should therefore be read as a complete statistical object: estimate + confidence interval + P-value + endpoint definition + analysis method. Removing any one of these elements makes the result easier to misinterpret.
18. Comparing the Time Course of 6MWD Results
The posted analyses allow the 6MWD treatment comparison to be examined at four time points. These are distinct estimates rather than a reconstructed longitudinal curve.
The point estimates are 4 meters at Week 4, 9.0 meters at Week 8, 13.0 meters at Week 12, and 11.0 meters at Week 16. These values should not be interpreted as a fitted trajectory because the ClinicalTrials.gov record provides separate summary estimates rather than participant-level longitudinal measurements.
19. Why This Trial Matters Statistically
FREEDOM-C is a useful teaching example because it combines randomized treatment allocation, masking, a continuous functional endpoint, covariate-adjusted analysis, nonparametric testing, exact categorical testing, multiple assessment times, and post-hoc subgroup analyses.
| Concept | How it appears in FREEDOM-C |
|---|---|
| Randomization | The trial is registered as randomized with two parallel arms. |
| Blinding | Masking is registered as quadruple. |
| Continuous outcome | 6MWD is measured in meters and analyzed as a continuous endpoint. |
| ANCOVA | Used for the primary 6MWD analysis and several secondary/post-hoc 6MWD analyses. |
| Hodges-Lehmann estimation | Reported as the effect measure for the 6MWD and nonparametric analyses. |
| Wilcoxon test | Used for Borg Dyspnea Score and Dyspnea-Fatigue Index. |
| Fisher exact test | Used for the binary Clinical Worsening Assessment. |
| Confidence intervals | Two-sided 95% intervals are reported for the primary and several secondary/post-hoc continuous analyses. |
| Multiple time points | 6MWD was analyzed at Weeks 4, 8, 12, and 16. |
| Post-hoc subgroup analysis | 6MWD was examined by baseline-distance quartile, dose strength, and background PAH therapy. |
| Missing baseline values | The registry identifies missing Baseline measurements for Borg Dyspnea Score and Dyspnea-Fatigue Index. |
| Safety analysis | Serious adverse events are reported by randomized treatment arm. |
20. Limitations
- Primary confidence interval reaches the null: the primary 95% CI is 0 to 22 meters, so the reported interval includes a zero between-group difference.
- Multiple analyses: the registry contains 17 posted statistical analyses, including secondary and post-hoc comparisons. The ClinicalTrials.gov record does not report a multiplicity-control strategy for these analyses.
- Post-hoc subgroup analyses: the 10 subgroup analyses were conducted within smaller populations and are therefore less precise than the primary randomized comparison. No interaction test is reported.
- Multiple time points: 6MWD was analyzed at four different follow-up times. The ClinicalTrials.gov record does not report a formal repeated-measures or treatment-by-time analysis.
- Missing baseline measurements: one placebo participant lacked a Baseline Borg score, while five placebo participants and three active participants lacked a Baseline dyspnea-fatigue index score. The ClinicalTrials.gov record does not state the imputation method, if any.
- Incomplete model specification: the registry identifies ANCOVA but does not provide the complete covariate specification in the ClinicalTrials.gov record.
- Safety comparison: serious adverse-event counts are reported, but no formal statistical comparison is reported in the ClinicalTrials.gov record.
- Effect-measure terminology: the registry reports Hodges-Lehmann as the effect measure for analyses identified as ANCOVA. This page preserves that reported terminology rather than replacing it with an inferred alternative measure.
21. Statistical Interpretation vs Clinical Interpretation
Statistical interpretation
The primary analysis estimated an 11.0-meter active-versus-placebo difference in change in 6MWD at Week 16, with a two-sided 95% CI of 0 to 22 meters and P = 0.072.
Clinical interpretation
Clinical significance cannot be assigned from the P-value alone. The ClinicalTrials.gov record does not specify a minimally important difference for 6MWD, so no threshold-based clinical conclusion is added.
This distinction is important. Statistical evidence concerns the uncertainty and compatibility of the observed data with a specified hypothesis. Clinical importance requires a separate judgment about the magnitude of the outcome, the patient population, the endpoint's meaning, and an appropriate clinical threshold. The registry-reported FREEDOM-C data do not provide such a threshold.
22. What the P-values Across Endpoints Illustrate
| Analysis | Estimate | P-value | Statistical lesson |
|---|---|---|---|
| Primary 6MWD, Week 16 | 11.0 | 0.072 | Effect estimates and CIs should accompany the P-value. |
| Borg Dyspnea Score | 0.0 | 0.062 | A P-value near a conventional threshold does not quantify effect magnitude. |
| Dyspnea-Fatigue Index | 0.0 | 0.011 | Statistical evidence does not by itself describe clinical magnitude. |
| 6MWD, Week 12 | 13.0 | 0.015 | Estimate and CI provide information beyond the P-value. |
| 6MWD, Week 8 | 9.0 | 0.051 | A small change in P-value does not imply a categorical change in effect. |
| 6MWD, Week 4 | 4 | 0.238 | A nonsignificant P-value does not prove absence of an effect. |
| Clinical Worsening Assessment | Not reported | 0.491 | Without an effect estimate, the P-value does not communicate the size of the group difference. |
23. A Practical Reading of the FREEDOM-C Statistical Record
A disciplined reading starts with the registered endpoint rather than the most favorable secondary or subgroup result. The primary endpoint was change in 6MWD from Baseline to Week 16. Its reported estimate was 11.0 meters, the two-sided 95% confidence interval was 0 to 22 meters, and the P-value was 0.072.
The next layer is the secondary evidence. At Week 12, the 6MWD estimate was 13.0 meters with a 95% confidence interval of 3.0 to 23.0 meters and P = 0.015. At Week 8, the estimate was 9.0 meters with a confidence interval of 0.0 to 18.0 meters and P = 0.051. At Week 4, the estimate was 4 meters with a confidence interval of -2.4 to 12.0 meters and P = 0.238.
Finally, the post-hoc analyses should be kept in their proper statistical category. They explore whether the 16-week 6MWD comparison differs according to baseline 6MWD, minimum dose strength, or background therapy. They are informative as exploratory analyses, but the ClinicalTrials.gov record does not provide the interaction tests or multiplicity framework needed to turn these subgroup comparisons into definitive claims about heterogeneity.
24. Related Tutorials
Learn more about the methods used in this trial:
25. Related Calculators
26. Sources
- ClinicalTrials.gov: FREEDOM-C, NCT00325442. Trial profile, registered endpoint, posted outcome measures, statistical analyses, and safety information.
- PubMed: PubMed record for PMID 41627369.
- PubMed: PubMed record for PMID 22628490.
Continue through the Clinical Biostats statistical pathway
Use the methods in FREEDOM-C as a starting point for deeper study of ANCOVA, nonparametric tests, confidence intervals, randomization, blinding, and categorical-data analysis.
27. Record Summary
FREEDOM-C provides a compact but statistically rich example of randomized clinical-trial analysis. The study used randomized parallel allocation and quadruple masking to compare oral treprostinil with placebo in a phase 3 treatment setting. Its registered primary endpoint was change in 6MWD from Baseline to Week 16, analyzed using ANCOVA with a reported Hodges-Lehmann estimate of 11.0 meters, a two-sided 95% confidence interval of 0 to 22 meters, and P = 0.072.
The broader statistical record includes nonparametric analyses of Borg Dyspnea Score and Dyspnea-Fatigue Index, earlier 6MWD assessments at Weeks 4, 8, and 12, and Fisher exact testing of Clinical Worsening Assessment. Ten additional post-hoc 6MWD analyses examine baseline-distance quartiles, lowest dose strength, and background PAH therapy.
The most important interpretive discipline is to distinguish the registered primary analysis from the secondary and post-hoc analyses. Estimates, confidence intervals, and P-values should be read together, while subgroup findings require particular caution because the ClinicalTrials.gov record does not report interaction testing or a multiplicity-control strategy. The same principle applies to safety: serious adverse events are reported as 33/176 in the placebo arm and 32/174 in the active arm, but the ClinicalTrials.gov record does not provide a formal statistical comparison.