This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effect of Physical ACtivity in Fingolimod Treated patiEnts (PACE) With Relapsing-remitting Multiple Sclerosis (NCT01490840), a registered phase 4 study. The primary outcome is Change From Baseline in Fatigue as Measured by the Modified Fatigue Impact Scale (mFIS )..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01490840 |
| Phase | Phase 4 |
| Condition | Fatigue in Multiple Sclerosis |
| Allocation | Not Stated |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 178 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned patients with relapsing-remitting multiple sclerosis treated with fingolimod. The primary outcome population was the Modified Full Analysis Set, defined in the record as participants with sufficient e-training compliance. The registry does not give further detail about eligibility criteria or how compliance was defined.
Intervention
The intervention was individualized web-based physical training. The E-training arm description says participants had an introductory group session hosted by a sports therapist, alongside fingolimod prescribed as per clinical practice. The available arm description is incomplete, so further details of the training schedule are not available in the registry record.
Comparator
The Waiting arm did not receive e-training during phase 1 and continued fingolimod as prescribed in clinical practice. The description says participants were offered training after a six-month waiting period. The registry record flags the arms as not a like-for-like control comparison and says allocation was not stated in the comparison information.
Primary question
The primary endpoint was change from baseline to six months in fatigue measured by the Modified Fatigue Impact Scale (mFIS). The mFIS covers physical, cognitive, and psychosocial functioning. A negative change indicates improvement. The registry lists the endpoint and its measurement scale, but does not report the arm estimates or confidence intervals needed to describe the observed result.
3. Trial Design
PACE is described in its official title as a six-month, multicenter, randomized, controlled, parallel-group study, followed by an optional six-month extension. It is listed as a phase 4 study. Its stated focus was physical training and fatigue among patients with relapsing-remitting multiple sclerosis treated with fingolimod. The study status is terminated. The registry lists a start date of 2011-11 and a primary completion date of 2014-07.
The intervention was physical exercise, described in the summary as individualized web-based training. Both arm descriptions specify fingolimod as baseline treatment prescribed according to clinical practice. During phase 1, the E-training group received an introductory session hosted by a sports therapist. The Waiting group did not receive e-training during that phase; its description says training was offered after a six-month waiting period. The arm descriptions in the registry record are truncated, so details beyond those statements cannot be established.
There is an important qualification when reading the comparison. Although the study title describes a randomized controlled design, the registry comparison information flags the allocation as not stated and says the arms are not a like-for-like control comparison. That warning should be kept in view rather than assuming that the posted arm contrast is a straightforward randomized comparison. The record does not explain the reason for this qualification.
The primary outcome was change in mFIS score from baseline to six months. Secondary outcomes listed in the record include muscle strength and endurance, quality of life, fatigue assessed by another instrument, depression, aerobic capacity, and peak expiratory flow. Listing an outcome does not establish that a result for it is posted. The registry does not give the primary endpoint estimates in the information.
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: At the end of the 6 month core phase (phase 1), participants in the waiting group had the option to receive e-training for 6 months in the phase 2 optional extension. Participants in the e-training group had the option to continue their e-training for another 6 months in the phase 2 extension.
Phase 1
| Stage | E-training | Waiting |
|---|---|---|
| STARTED | 94 | 84 |
| Modified Full Analysis Set | 56 | 83 |
| COMPLETED | 84 | 78 |
| NOT COMPLETED | 10 | 6 |
Reasons for not completing this period:
| Reason | E-training | Waiting |
|---|---|---|
| Lost to Follow-up | 1 | 0 |
| Adverse Event | 2 | 1 |
| Withdrawal by Subject | 6 | 5 |
| Visit 6a omitted | 1 | 0 |
Phase 2
| Stage | E-training | Waiting |
|---|---|---|
| STARTED | 81 | 74 |
| COMPLETED | 75 | 68 |
| NOT COMPLETED | 6 | 6 |
Reasons for not completing this period:
| Reason | E-training | Waiting |
|---|---|---|
| Withdrawal by Subject | 4 | 3 |
| Permanent interruption of fingolimod | 0 | 1 |
| Lost to Follow-up | 1 | 1 |
| Adverse Event | 1 | 1 |
Analysis population for the primary outcome, as defined in the registry: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.
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.
| Characteristic | Unit | E-training | Waiting | Total |
|---|---|---|---|---|
| Participants analysed | 94 | 84 | 178 | |
| Age, Continuous | Years | 40.9 (SD 10.4) | 39.4 (SD 8.7) | 40.2 (SD 9.6) |
| Sex: Female, Male: Female | Participants | 65 | 57 | 122 |
| Sex: Female, Male: Male | Participants | 29 | 27 | 56 |
6. Primary Endpoint
The registry lists the primary outcome as Change From Baseline in Fatigue as Measured by the Modified Fatigue Impact Scale (mFIS )., measured over Baseline, 6 months.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | score on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change from baseline in the Modified Fatigue Impact Scale (mFIS) at six months. The mFIS is a structured, self-report questionnaire with 21 items. Its questions assess the effects of fatigue on physical, cognitive, and psychosocial functioning, and the registry describes it as generally completable with little or no interviewer intervention. The score ranges from 0, described as not tired, to 84, described as tired. The recorded direction is important: a negative change from baseline indicates improvement.
A change score expresses how an individual's or group's measurement differs from baseline at the stated follow-up. Here, it is intended to summarize change in fatigue over the initial six-month period. Using a defined instrument makes the outcome more reproducible than an unspecified judgment of fatigue, while the multiple domains reflect that fatigue can affect different aspects of functioning. These are general measurement considerations, not claims about the performance of the mFIS in this particular trial.
The registry specifies least-squares means and 95% confidence intervals as the endpoint summary. A least-squares mean is a model-based group mean; its interpretation depends on the model and the data included. The model details and numerical estimates are not reported in the registry record. Without the arm estimates and their intervals, the posted information does not establish the direction or precision of the observed between-arm result.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a clinically relevant statistical question: whether fatigue scores changed over six months in the study arms, using mFIS change from baseline as the primary endpoint. It also defines the score direction, so a negative within-group change is described as improvement. But the endpoint entry contains no numerical least-squares means, confidence intervals, or between-arm estimate. The result itself therefore cannot be summarized as favoring either arm, nor can its magnitude or precision be assessed from this record.
This distinction matters because an endpoint description is not an endpoint result. Knowing the scale, follow-up, and planned summary does not reveal what participants scored. The record's 95% confidence-interval label indicates the type of uncertainty summary intended for the estimates, but the interval limits are not available. In general, a confidence interval describes the range of values compatible with the data and analysis under the interval's assumptions. Its width helps convey precision; without its limits, precision cannot be evaluated.
The comparison also requires caution for a separate reason. The study title describes randomization, but the registry comparison information says allocation is not stated and labels the arms as not a like-for-like control comparison. A causal interpretation of a difference between arms normally depends on how treatment assignment and analysis were handled. The record does not provide enough information to resolve the qualification or assess comparability. Accordingly, any contrast should not be treated as an unqualified randomized treatment effect.
The primary analysis population is described as the Modified Full Analysis Set, which included participants with sufficient e-training compliance. This definition makes compliance part of the stated population. It does not tell us how many participants met the criterion, how the criterion was set, or how those included differed from those not included. These details affect the interpretation of the estimated result, particularly if inclusion depends on events after training begins.
The posted record also lists safety counts, but those counts do not fill the gap in the primary efficacy results. Nor do the listed secondary measures establish a result for fatigue on the primary scale. The calculated tables, plots, and planning section on the page should be read according to what they display; the registry text itself does not give a primary estimate to interpret. In particular, no conclusion about the size or statistical uncertainty of the primary contrast can be drawn from the outcome definition alone.
The appropriate reading is therefore limited: PACE registered a six-month fatigue outcome and specified how its score was oriented and summarized, but the primary numerical results are not reported in the registry record. This is an information limitation, not evidence that the arms had identical outcomes or that there was no effect. The absence of an estimate prevents a positive or negative conclusion about the observed between-arm contrast.
9. Statistical Methods Explained
The registry describes the primary outcome as a continuous measure: mFIS score change from baseline to six months. A continuous outcome can take values across a scale rather than being limited to categories such as event or no event. A group summary can therefore describe an average score or average change. In this record, the stated summary is the least-squares mean, with a 95% confidence interval. The numerical summaries themselves are not reported in the registry record.
What does a least-squares mean represent?
In general, a least-squares mean is an average estimated from a statistical model, rather than necessarily the simple arithmetic average of observed values. A model can account for specified terms or covariates, depending on its construction. That can make the estimate useful for a planned comparison, but it also means the model specification matters for interpretation. The registry information does not state the model terms, covariates, assumptions, or estimation details. It would therefore be inappropriate to attribute a particular adjustment or model structure to this study.
How should the confidence interval be read?
A confidence interval expresses uncertainty around an estimate under the statistical procedure used. Narrower intervals indicate greater precision in the estimate, while wider intervals indicate less precision. For a contrast between arms, the interval can help assess which values of the contrast are compatible with the data and model. These are general explanations. The endpoint lists 95% confidence intervals, but their limits are absent, so neither precision nor the range of compatible effects can be assessed from the registry record.
The outcome description gives the scale direction: a negative change from baseline indicates improvement. That direction applies to change in mFIS score; it should not be confused with the direction of a between-arm contrast unless the contrast's subtraction order is known. The registry entries do not state that order or provide an estimated contrast. This prevents a numerical interpretation of the comparison even if the scale direction is clear.
What does the analysis population imply?
The primary outcome is specified for the Modified Full Analysis Set. The record defines this set as participants with sufficient e-training compliance. In general, an analysis population determines which participants contribute to an estimate and therefore forms part of the estimand: the quantity the analysis is intended to describe. Restricting an analysis to participants who meet a compliance criterion can answer a different question from an analysis of all participants assigned to groups. The registry does not state the compliance threshold, the numbers included, or the rationale for this population definition, so those aspects cannot be assessed.
Missing outcome data can also affect continuous-outcome estimates. In general, the consequences depend on how much information is missing, why it is missing, and the method used to handle it. A model-based analysis may use assumptions about missingness; other approaches may make different assumptions. The record does not report the amount or pattern of missing mFIS data, the method used for missing values, or sensitivity analyses. Thus, the robustness of any estimate to missing data cannot be evaluated from the registry record.
What can be said about multiplicity?
The record lists a primary endpoint and multiple secondary outcomes. When many outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase if each is interpreted without adjustment. This is the general multiplicity concern. A study may prespecify one primary outcome, use an adjustment, or treat secondary outcomes as exploratory; which approach was used needs to be documented. The registry information does not report a multiplicity strategy, a testing hierarchy, or how secondary outcomes were to be interpreted. No particular adjustment should be assumed.
The record's sample-size assumptions describe a planning illustration based on an observed effect: a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and effects defined as stated fractions of the observed effect. Such illustrations are planning scenarios, not observed power and not evidence about the actual precision of the trial result. The registry information does not give a numerical primary effect estimate with which to evaluate the illustration. The trial's own sample-size justification is not reported in the registry record.
Finally, the comparison warning is relevant to statistical interpretation. In general, a randomized comparison can support causal interpretation when allocation and conduct preserve the intended comparison and analysis aligns with the design. Here, although the official title uses randomized controlled language, the comparison note says allocation is not stated and the arms are not a like-for-like control comparison. The registry does not explain the discrepancy. The statistical methods and analysis details needed to judge the comparison are therefore incomplete.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists the mFIS change as the primary outcome and also lists secondary measures covering strength, endurance, quality of life, fatigue assessed with WEIMuS, depression, aerobic capacity, and peak expiratory flow. Multiple outcomes can create a multiplicity issue: if many hypotheses are examined, the chance of at least one apparently notable finding can rise. As a general matter, investigators may address this with a prespecified hierarchy, adjustment, or an explicitly exploratory interpretation. The strategy used is not reported in the registry record.
The primary analysis population is the Modified Full Analysis Set, defined as participants with sufficient e-training compliance. The record does not report the compliance threshold, the number meeting it, or the number included in the primary outcome analysis. It also does not report missing mFIS data, reasons for missingness, or the method used to handle missing values. Without these details, readers cannot determine how much the analysis population differed from the enrolled group or assess sensitivity to missing data.
These omissions are distinct from the absence of endpoint estimates. Even if estimates were available, missingness and population definitions would affect how broadly to interpret them. The registry also does not report a sensitivity analysis or a statistical analysis plan that could clarify these decisions. Consequently, neither multiplicity control nor the handling of incomplete outcome data can be evaluated from the information.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| E-training | 5 | 94 | 5.3% |
| Waiting | 9 | 84 | 10.7% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| E-training | 58 of 94 |
| Waiting | 59 of 84 |
Most frequent serious adverse event terms
| Event term | Organ system | E-training | Waiting |
|---|---|---|---|
| SPINAL FRACTURE | Injury, poisoning and procedural complications | 1 of 94 | 1 of 84 |
| ARRHYTHMIA | Cardiac disorders | 0 of 94 | 1 of 84 |
| EXTRASYSTOLES | Cardiac disorders | 0 of 94 | 1 of 84 |
| PALPITATIONS | Cardiac disorders | 0 of 94 | 1 of 84 |
| APPENDICITIS PERFORATED | Infections and infestations | 0 of 94 | 1 of 84 |
| CONJUNCTIVITIS | Infections and infestations | 0 of 94 | 1 of 84 |
| BONE CONTUSION | Injury, poisoning and procedural complications | 0 of 94 | 1 of 84 |
| CONCUSSION | Injury, poisoning and procedural complications | 0 of 94 | 1 of 84 |
| DISLOCATION OF VERTEBRA | Injury, poisoning and procedural complications | 1 of 94 | 0 of 84 |
| RADIUS FRACTURE | Injury, poisoning and procedural complications | 1 of 94 | 0 of 84 |
Most frequent non-serious adverse event terms
| Event term | Organ system | E-training | Waiting |
|---|---|---|---|
| NASOPHARYNGITIS | Infections and infestations | 34 of 94 | 33 of 84 |
| MULTIPLE SCLEROSIS RELAPSE | Nervous system disorders | 22 of 94 | 15 of 84 |
| SLEEP DISORDER | Psychiatric disorders | 10 of 94 | 4 of 84 |
| HYPERTENSION | Vascular disorders | 4 of 94 | 9 of 84 |
| DEPRESSION | Psychiatric disorders | 4 of 94 | 8 of 84 |
| BRONCHITIS | Infections and infestations | 3 of 94 | 8 of 84 |
| COUGH | Respiratory, thoracic and mediastinal disorders | 3 of 94 | 8 of 84 |
| BACK PAIN | Musculoskeletal and connective tissue disorders | 5 of 94 | 5 of 84 |
| HEADACHE | Nervous system disorders | 4 of 94 | 6 of 84 |
| ORAL HERPES | Infections and infestations | 6 of 94 | 2 of 84 |
Serious events with the highest arm-level rate: arrhythmia (1.2%), extrasystoles (1.2%), palpitations (1.2%), appendicitis perforated (1.2%), conjunctivitis (1.2%).
The registry lists serious adverse event counts for E-training and Waiting. For E-training, 94 participants were listed at risk and 5 were listed as affected by serious events. For Waiting, 84 were listed at risk and 9 were listed as affected. These are participant counts as recorded; they should be read alongside the stated denominators and not as an estimate of the primary fatigue outcome. The record separately lists other adverse events affecting 58 participants in E-training and 59 in Waiting, with 94 and 84 respectively listed at risk.
The serious-event terms listed include ARRHYTHMIA, EXTRASYSTOLES, PALPITATIONS, APPENDICITIS PERFORATED, CONJUNCTIVITIS, and BONE CONTUSION, each shown as 1.2%. The registry excerpt does not establish whether terms overlap within participants or provide enough context to infer comparative risk. The death entries are null; null should not be interpreted as a recorded count of zero. These figures are descriptive registry entries, and the comparison warning about the arms also applies when reading them.
12. What the Result Does, and Does Not, Mean
This record establishes that PACE addressed physical training and fatigue in patients with relapsing-remitting multiple sclerosis treated with fingolimod. It identifies mFIS change from baseline to six months as the primary endpoint and explains that a negative change indicates improvement. It also describes the primary outcome population as participants meeting a sufficient e-training compliance criterion. These details allow readers to understand the intended measurement and population, but they do not reveal the trial's numerical primary outcome.
The primary arm estimates, confidence intervals, and a numerical between-arm contrast are not reported in the registry record. Therefore, this page cannot say how much fatigue changed, how different the arms were, or how precise an estimated contrast would be. Missing numerical results do not demonstrate that there was no difference; they simply leave the result unknown from this record. The design description also carries a qualification: the title calls the study randomized and controlled, while the comparison note says allocation was not stated and the arms are not a like-for-like control comparison.
The listed secondary outcomes and adverse-event counts provide additional descriptive context, but they do not substitute for the primary endpoint estimate or resolve the comparison caveat. Nor can the study's termination status alone explain why it ended; the reason is not reported in the registry record. The optional extension described in the title should not be confused with the six-month primary endpoint timeframe.
In statistical terms, the record documents an outcome definition and some design features, but not the central effect estimate needed to assess magnitude or uncertainty. The sample-size section is a planning illustration, not observed power. Any interpretation should preserve these limits and avoid turning an absent result into a claim of benefit, harm, or equivalence.
13. Why This Trial Matters Statistically
This study is statistically informative as an example of why a clearly described endpoint is only one part of evidence interpretation. The registry specifies a recognizable fatigue instrument, its score range and direction, the six-month time point, and a least-squares mean with a 95% confidence interval. Those details help readers understand what was intended to be measured. Without the numerical estimates and interval limits, however, they cannot show the size or precision of the observed result.
The record also highlights that labels about design need to be read alongside comparison-specific information. The official title describes a randomized controlled study, while the comparison note says allocation is not stated and the arms are not a like-for-like control comparison. This creates an interpretive caveat that should not be erased by the title alone. Statistical conclusions depend not just on the name of a design, but on how allocation, analysis populations, and outcome data are handled.
Another important issue is the stated Modified Full Analysis Set, which requires sufficient e-training compliance. Population definitions can change the question an estimate answers, especially when inclusion depends on participant behavior after the intervention starts. Since the registry does not define the threshold or report the analysis numbers, readers cannot assess that choice fully.
Finally, the record includes several secondary outcomes and safety summaries, but does not report the multiplicity strategy or missing-data approach. These omissions show why a results page must distinguish between listed outcomes, observed estimates, and planned statistical summaries. Here, the available record supports a careful account of the trial question and its reporting limits, rather than a numerical conclusion about the primary comparison.
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 main limitation for interpreting this trial from the registry record is that the primary mFIS estimates and 95% confidence intervals are not reported. As a result, the magnitude and precision of the primary result cannot be assessed. The record does not provide a numerical between-arm contrast, and the direction of the between-arm contrast cannot be inferred from the definition of a negative within-group change alone.
The comparison has an additional caveat. The official title describes a randomized controlled study, but the comparison information states that allocation is not stated and that the arms are not a like-for-like control comparison. The registry does not explain this qualification. It also does not provide enough analysis detail to determine how the comparison was constructed or what interpretation was intended.
The primary population depends on sufficient e-training compliance, but the registry does not specify the threshold, count the participants meeting it, or describe how this population relates to all enrolled participants. The missing-data method, amount of missing primary outcome data, and sensitivity analyses are also not reported. The statistical model behind the least-squares means and the approach to multiplicity are not reported in the registry record.
The arm descriptions are truncated, limiting what can be said about the training schedule and the later phase. The reason for termination is not reported. The null death entries do not establish a zero death count. Finally, the safety figures are descriptive and should not be treated as a complete comparative safety analysis, particularly given the stated comparison caveat.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effect of Physical ACtivity in Fingolimod Treated patiEnts (PACE) With Relapsing-remitting Multiple Sclerosis — NCT01490840.
- Registry record last updated 2016-05-12; status last verified 2016-04.
- Results first posted 2016-05-12.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
PACE is a phase 4, multicenter, parallel-group study concerning individualized web-based physical training for patients with relapsing-remitting multiple sclerosis treated with fingolimod. Its official title describes a six-month randomized, controlled study followed by an optional six-month extension. The registry lists the study as terminated, with a start date of 2011-11 and primary completion date of 2014-07.
The primary outcome was change from baseline to six months in mFIS score, summarized as a least-squares mean with a 95% confidence interval. Negative change indicates improvement. The primary analysis population was the Modified Full Analysis Set, described as participants with sufficient e-training compliance. Numerical primary outcome estimates are not reported in the registry record.
Interpretation is further limited by the registry note that allocation was not stated and the arms were not a like-for-like control comparison. The record also does not report the multiplicity strategy, missing-data approach, or reason for termination.