Dimethyl Fumarate (DMF) in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dimethyl Fumarate (DMF) in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (NCT02981082), a randomized phase 1 study. The primary outcome is 6 Minute Walk Distance (6MWD).

2. Clinical Question

3. Trial Design

This was a randomized, placebo-controlled, quadruple-masked, parallel-group pilot study in phase 1. Its title identifies dimethyl fumarate in systemic sclerosis-associated pulmonary arterial hypertension, and the official title describes an investigation of clinical disease and biomarkers of oxidative stress. The registry status is terminated. The start is listed as 2016-12 and primary completion as 2020-02-10. The reason for termination is not reported in the registry record.

The interventions were DMF and an oral placebo tablet. The DMF arm description specifies twice-daily oral doses of 120mg for the first 7 days, then 240mg twice a day, for 24 weeks. The placebo description specifies twice-daily doses for 12 weeks. The primary outcome is measured from baseline to Week 24. This duration difference is present in the registry descriptions, but the record does not explain how placebo treatment related to the Week 24 assessment.

The primary outcome was mean percent change in 6MWD. The description says that the endpoint uses the last observation carried forward for withdrawn subjects. Clinical worsening, Borg Dyspnea Index, serum markers of oxidative stress, and proteomic biomarkers are listed as secondary outcomes. The record lists four secondary outcomes and five outcome measures, but it does not provide posted analyses for all of them; analyses are not reported in the registry record.

The enrollment field lists 6. The brief summary, however, describes a study in 34 patients. The outcome groups contain four DMF participants and two placebo participants, consistent with the enrollment field but not with the summary's description. The registry record does not reconcile these figures. The small posted groups make the reported descriptive results particularly limited in precision and scope.

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:

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 6 Minute Walk Distance (6MWD), measured over Baseline to Week 24.

The primary endpoint is percent change in six-minute walk distance from baseline to Week 24. The six-minute walk test records the distance a participant walks during a fixed-duration walking assessment. As a general statistical concept, this type of measure can represent functional capacity in a way that produces a continuous outcome, allowing changes to be described numerically. The registry frames improvement in 6MWD as the clinical-efficacy outcome for this pilot study.

The posted results report a mean percent change for each group. A negative mean indicates that the group’s measured distance, on average, decreased relative to baseline under the endpoint’s percent-change scale; it does not describe every participant’s change. Individual values can differ from the group mean, and the full range gives some indication of that variation. The registry lists the dispersion as full range, not as a confidence interval.

Using change from baseline focuses the outcome on within-participant change over the stated timeframe. Percent change expresses that change relative to the baseline distance, rather than in distance units. The registry record does not provide the formula used to calculate percent change or further details about endpoint measurement. It states that the Week 24 result uses last observation carried forward for withdrawn subjects. That approach carries a participant’s last recorded value forward to represent a later assessment; as a general statistical matter, this can make the estimate depend on assumptions about what would have happened after withdrawal. The record does not report how many participants withdrew or how their missing assessments were handled individually.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary result is a pair of group-level means for a continuous endpoint: mean percent change in 6MWD from baseline to Week 24. The group means are -7.07 for DMF and -14.97 for placebo. The registry also reports full ranges, with endpoints -24.69 and 8.2 for DMF, and -29.93 and 0.0 for placebo. The values are descriptive summaries. The registry record does not report a formal between-group test or a confidence interval for the difference in means.

What does a mean describe?

As a general statistical concept, a mean is the arithmetic average of the values in a group. It gives a compact description of the group’s central outcome, but it does not show the outcome for any particular participant. With very small groups, an individual value can have a strong influence on the mean. The reported group sizes are 4 for DMF and 2 for placebo, so these summaries should be read as descriptions of a small set of observed outcomes, not as precise estimates of what would be expected across a broader population.

The means are percent changes, not absolute changes in walking distance. A negative value represents a decrease on the stated percent-change scale. The mean does not establish that every participant experienced a decrease: the reported DMF range extends to 8.2, and the placebo range extends to 0.0. The record does not give the individual participant values, baseline distances, or a formula for calculating the percent change.

How should the ranges be read?

The dispersion is identified as full range. A full range reports the lowest and highest values in a group. It conveys the span of the observed values, but it does not describe how values are distributed between the endpoints. It is not a confidence interval and should not be interpreted as the plausible range for the population mean. A confidence interval is a general statistical tool for expressing uncertainty around an estimated quantity; no confidence interval for the primary comparison is reported in the registry record.

The ranges overlap. That observation does not itself determine whether groups differ statistically or clinically. In general, inference about a between-group effect requires an estimate of the contrast and an account of its uncertainty. The registry record reports neither a formal contrast nor its uncertainty for this endpoint. A reader should therefore distinguish the posted group means from a trial-level estimate of comparative effect.

What does randomization contribute?

Randomized allocation is intended, as a general design principle, to reduce systematic differences between groups at the point of assignment. It does not guarantee that groups will be similar in every characteristic, especially in a small study. The record states that allocation was randomized, masking was quadruple, and the design was parallel. It does not report the randomization method, allocation concealment procedures, or details about which roles were included in the masking description. Those details are not reported in the registry record.

Masking is generally used to limit the influence of treatment knowledge on participant experience, clinical care, outcome assessment, or analysis. The registry labels this study quadruple-masked but does not specify the masked parties. The record’s label therefore describes the design classification without supplying enough detail to assess how masking was implemented or maintained.

What is the role of missing-data handling?

The endpoint description says that the last observation carried forward was used for withdrawn subjects. As a general method, last observation carried forward substitutes a participant’s most recent observed value for a later value that is missing. It creates a value for the analysis, but that value is not a new measurement. The method implicitly treats the earlier measurement as an adequate representation of the later outcome. That assumption may be unrealistic if outcomes would have changed after the last observation.

Missing-data methods matter because participants with missing Week 24 outcomes may differ from those with observed outcomes, and their unobserved results cannot be known directly. General statistical practice considers why data are missing and how assumptions about the missing values affect conclusions. The record does not state how many observations were carried forward, why participants withdrew, whether all randomized participants were included in the primary analysis, or whether sensitivity analyses were conducted.

What can be inferred from the reported analysis?

The registry record presents group means and full ranges, but does not report a statistical model, standard error, confidence interval, p-value, or formal primary comparison. It does not describe covariate adjustment or specify an analysis population. These methods and results are not reported in the registry record. Without them, the reader can describe the observed summaries but cannot assess the precision of a comparative estimate using a reported inferential analysis.

The study is described as a pilot assessing safety and primary-outcome variability. As a general concept, variability describes how much individual outcomes differ within a group and helps inform the planning of later studies. The observed full ranges are one description of spread, but with these group sizes they provide limited information about the broader variability that might be expected. No sample-size justification or planned precision target is reported in the registry record. Any planning illustration based on an observed effect would be hypothetical; it would not be observed power or evidence that the study was adequately powered.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists four secondary outcomes: clinical worsening, Borg Dyspnea Index, serum markers of oxidative stress, and proteomic biomarkers. It also lists five outcome measures, while the posted record reports the primary endpoint results and no analyses for the secondary outcomes. The analyses are not reported in the registry record.

When a study examines multiple outcomes or multiple comparisons, the chance of finding an apparently notable result by chance can increase. As a general statistical concept, multiplicity refers to this issue and to methods that may be used to control or interpret it. The record does not report a multiplicity strategy, a hierarchy of secondary outcomes, or an analysis plan describing how multiple results would be handled. It is therefore not possible to determine from the registry record whether any adjustment was planned or performed.

The primary endpoint description says that last observation carried forward was used for withdrawn subjects. It does not state the number of withdrawals, the number of missing Week 24 measurements, or the reasons for missingness. It also does not describe alternative missing-data analyses. Consequently, the effect of missing-data assumptions on the posted means cannot be assessed from the record.

The registry does not identify the primary analysis population, such as whether results were analyzed according to randomized assignment or another population definition. It also does not report whether all randomized participants contributed to the endpoint analysis. The four DMF and two placebo participants listed with the outcomes establish the posted group sizes, but do not resolve the analysis-population definition or the handling of any unavailable assessments.

These omissions do not prove that no statistical plan or additional analyses existed; they indicate that those details are not reported in the registry record. The small outcome groups, the stated carry-forward approach, and the lack of posted secondary analyses all limit how fully the results can be evaluated.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: worsening of heart failure and shortness of breath secondary to anemia (50.0%).

The safety figures describe participants affected, not necessarily the total number of separate events. In the DMF group, 0 of 4 participants were reported with a serious adverse event; 4 of 4 were reported with other adverse events. In the placebo group, 1 of 2 participants was reported with a serious adverse event, and 2 of 2 were reported with other adverse events. No deaths were reported in either group.

The registry lists “Worsening of heart failure and shortness of breath secondary to anemia” as the top serious-event term, with 50.0%. The record does not provide further event-level detail or explicitly identify the group associated with that term in the listed top-term entry. The participant counts are very small, so these figures are descriptive and provide limited information about how frequently such events might occur in a larger population.

Serious adverse events and other adverse events are distinct reporting categories. The counts should not be combined into a single estimate, and the affected-participant counts do not establish whether events were caused by a study intervention. The registry record does not report an attribution assessment or provide additional details about event timing, duration, or severity beyond the serious-event classification and term listed.

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

The posted primary result describes mean percent change in 6MWD between baseline and Week 24 for the participants listed in each group. The means are -7.07 for DMF and -14.97 for placebo. The full ranges show that participant outcomes varied within both groups. These data document the observed summaries; they do not establish a precise comparative effect.

The registry record does not provide a formal comparison, a confidence interval, or a p-value for the primary endpoint. Without a reported estimate of the between-group contrast and its uncertainty, it is not possible to assess how compatible the results are with a range of possible effects. The small group sizes further limit precision. The means should not be interpreted as evidence that an intervention does or does not work.

The outcome was analyzed using last observation carried forward for withdrawn subjects, according to the endpoint description. The registry does not state how many participants had values carried forward or report sensitivity analyses using other missing-data assumptions. The estimates may therefore depend on the handling of unavailable Week 24 measurements in a way that cannot be evaluated from the posted record.

The trial’s pilot description and its stated interest in safety and outcome variability are relevant to interpretation. A pilot study can provide descriptive information about observed outcomes and may inform questions for subsequent research. However, the record does not report a sample-size justification, a precision target, or a formal analysis of the primary comparison. The record also does not report analyses for the listed secondary outcomes.

The enrollment field lists 6, whereas the brief summary describes 34 patients. The posted outcome groups include four DMF participants and two placebo participants. The record does not explain the differing enrollment descriptions. The study is marked terminated, but its reason for termination is not reported. These uncertainties, alongside the small groups and unreported analysis details, restrict the conclusions that can be drawn from the registry results.

13. Why This Trial Matters Statistically

This study is statistically notable as a randomized, masked pilot with a very small number of participants in the posted primary outcome groups. Its results illustrate why descriptive estimates, group sizes, and measures of spread need to be considered together. The means provide a concise description, while the full ranges indicate that individual results varied. Neither summary alone gives a precise estimate of a comparative effect.

The trial description says the study aimed to determine safety and primary-outcome variability. As a general statistical principle, pilot data can help characterize measurement and observed variation, but estimates from small groups are themselves uncertain. The registry does not report a sample-size justification or a precision goal. A planning calculation based on observed effects, if considered, should be treated as a hypothetical design illustration rather than observed power or evidence of a definitive treatment effect.

The record also makes missing-data assumptions important to consider: the endpoint description specifies last observation carried forward for withdrawn subjects, without reporting how many measurements were handled in this way. This is a reminder that a reported endpoint summary can depend on how unobserved outcomes are represented. Details on the analysis population and sensitivity analyses are not reported in the registry record.

Finally, internal consistency in registry descriptions affects interpretation. The enrollment field lists 6, the outcome groups list four and two participants, and the brief summary describes 34 patients. The registry does not resolve the difference. The placebo dosing duration is listed as 12 weeks, whereas the primary assessment timeframe reaches Week 24. These details do not permit conclusions about what occurred beyond the stated record, but they identify questions that would matter when evaluating the study’s design and results.

14. Limitations

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

The primary outcome is reported for only four DMF participants and two placebo participants. Such small groups leave the group means and ranges highly sensitive to individual observations and provide limited information about variability. The registry reports descriptive summaries but no formal comparison, confidence interval, or p-value, so the precision of a between-group estimate cannot be judged from the posted results.

There is an unresolved difference between the enrollment field, which lists 6, and the brief summary, which describes 34 patients. The posted outcome groups contain four and two participants, but the registry does not explain the discrepancy. The study is marked terminated, and the reason is not reported in the registry record.

The DMF arm description specifies treatment for 24 weeks, while the placebo arm description specifies 12 weeks. The primary outcome timeframe is baseline to Week 24. The record does not explain the relationship between placebo duration and the later endpoint assessment. The endpoint description also specifies last observation carried forward for withdrawn subjects, without reporting the number of withdrawals, missing assessments, or sensitivity analyses.

The registry does not report the primary analysis population, detailed statistical methods, a sample-size justification, or an analysis plan for multiple outcomes. Although four secondary outcomes are listed, their analyses are not reported in the registry record. The record also does not provide individual outcome values or the method used to calculate percent change. These limits prevent a detailed assessment of the analysis and of how robust the posted summaries are to alternative assumptions.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dimethyl Fumarate (DMF) in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension — NCT02981082.
• Registry record last updated 2022-03-17; status last verified 2022-03.
• Results first posted 2022-03-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT02981082 is a phase 1, randomized, quadruple-masked, parallel-group, placebo-controlled pilot study of DMF in systemic sclerosis-associated pulmonary arterial hypertension. The registry status is terminated. The enrollment field lists 6, while the brief summary describes 34 patients; the posted primary outcome groups contain 4 DMF participants and 2 placebo participants.

The primary endpoint is mean percent change in 6MWD from baseline to Week 24. The posted means are -7.07 for DMF and -14.97 for placebo, with full ranges of -24.69 to 8.2 and -29.93 to 0.0, respectively. The endpoint description states that last observation carried forward was used for withdrawn subjects. A formal comparison and its uncertainty are not reported in the registry record.

The record lists clinical worsening, Borg Dyspnea Index, serum markers of oxidative stress, and proteomic biomarkers as secondary outcomes, but their analyses are not reported. It reports no deaths, and lists serious adverse events affecting 0 of 4 DMF participants and 1 of 2 placebo participants. The reason for termination is not reported in the registry record.