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 Prospective Effectiveness and Safety Study of Cladribine in Participants Who Change First-line DMD Treatments for Multiple Sclerosis (CLAD CROSS) (NCT04934800), a registered phase not stated study. The primary outcome is Change in Annualized Relapse Rate (ARR) Between the Pre-Baseline 12-Month Period (Baseline) and Over the 12 Months Period Before the End of Study Follow-Up (2 Years).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04934800 |
| Phase | Phase not stated |
| Condition | Multiple Sclerosis |
| Allocation | Not Stated |
| Design model | Not Stated |
| Masking | Not Stated |
| Enrollment | 256 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
| Results posted | Yes |
2. Clinical Question
The clinical question concerns participants with multiple sclerosis who changed from a first-line disease-modifying drug to cladribine tablets in routine clinical practice. The study was intended to describe relapse activity and disability outcomes after that treatment change, alongside safety and quality-of-life measures. Its primary outcome focuses on annualized relapse rate before treatment and during a later period near the end of follow-up.
Population
Participants with multiple sclerosis who changed from first-line treatment. The listed first-line drugs were interferons, glatiramer acetate, teriflunomide, and dimethyl fumarate. Registry enrollment is 256.
Intervention
Cladribine tablets, used after the change from a first-line disease-modifying drug in routine clinical practice.
Comparator
The primary outcome compares relapse rate across two time periods within the treatment course. A separate control treatment arm is not described, and allocation is not stated.
Primary question
How did annualized relapse rate in the 12 months before baseline compare with the rate in the 12 months before the end of study follow-up, labeled 2 years?
This is a before-and-after question, not a randomized comparison of cladribine with another treatment. The registry identifies other outcomes, including disability progression and improvement, adverse events, and quality of life. Numerical results for the primary comparison and those secondary outcomes are not reported in the registry record. Consequently, the clinical question can be described, but the magnitude and precision of any observed change cannot be assessed from the registry information.
3. Trial Design
CLAD CROSS is listed as a prospective effectiveness and safety study in participants who changed first-line disease-modifying treatment for multiple sclerosis. Its stated setting is routine clinical practice, and its stated aim was to study cladribine tablets in a real-world setting. The registry lists cladribine as the intervention and enrollment of 256. It does not identify a separate comparator treatment arm or state how treatment allocation occurred.
The registry gives a start date of 2019-12-10, a primary completion date of 2024-05-20, and a status of COMPLETED. These registry dates describe the study record; they do not provide individual participants’ follow-up duration or outcome ascertainment patterns. The primary outcome is framed as a change in annualized relapse rate between the 12 months before baseline and the 12 months before the end of study follow-up, labeled 2 years.
Several secondary outcomes are listed: change in annualized relapse rate during the 12 months after cladribine initiation; disability progression and improvement assessed with the Expanded Disability Status Scale, with broader measures also involving the Timed 25 Foot Walk and 9 Hole Peg Test; treatment-emergent adverse events and serious adverse events; and quality of life assessed using MSIS-29 and EQ-5D-3L. The registry lists 11 outcome measures. Numerical results for these outcomes are not reported in the registry record.
The primary outcome’s analysis population is described as the Full Analysis Set: participants who provided informed consent and received at least one dose of cladribine. For that outcome, the number analyzed means participants evaluable for the measure. The actual evaluable number is not reported in the registry record. A detailed protocol, a sample-size justification, interim analyses, and a statistical analysis plan are not reported in the registry record.
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
| Stage | Cladribine |
|---|---|
| STARTED | 256 |
| COMPLETED | 234 |
| NOT COMPLETED | 22 |
Reasons for not completing this period:
| Reason | Cladribine |
|---|---|
| Other | 1 |
| Withdrawal by Subject | 5 |
| Lack of Efficacy | 1 |
| Adverse Event | 9 |
| Lost to Follow-up | 5 |
| Enrolled but not treated | 1 |
Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) included all the participants who provided informed consent and who received at least one dose of Cladribine. Here "Number Analyzed" signifies those participants who were evaluable for this outcome measure.
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 | Cladribine |
|---|---|---|
| Participants analysed | 256 | |
| Age, Continuous | years | 38.3 (SD 10.90) |
| Sex: Female, Male: Female | Participants | 174 |
| Sex: Female, Male: Male | Participants | 82 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 0 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 256 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 2 |
| Race (NIH/OMB): White | Participants | 253 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Annualized Relapse Rate (ARR) Between the Pre-Baseline 12-Month Period (Baseline) and Over the 12 Months Period Before the End of Study Follow-Up (2 Years), measured over 12-months pre-baseline (Baseline) and 12 Months Prior to End of Study follow up (2 years).
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | relapses per year |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change in annualized relapse rate, measured in relapses per year. The registry defines a relapse as new symptoms or worsening of existing symptoms attributed to multiple sclerosis, lasting at least 24 hours and separated from a previous attack by at least 30 days, without fever or infection. Baseline annualized relapse rate is defined using relapses reported in the 12 months before cladribine treatment.
For the later period, the registry describes annualizing relapses reported at visits by accounting for the time between specified visit dates. The comparison is between the pre-baseline 12-month period and the 12 months before the end of study follow-up, labeled 2 years. The registry says that a 95% confidence interval for the difference was to be presented with summary statistics and included as a descriptive measure of effect.
Annualized relapse rate expresses relapse frequency relative to time, which makes periods of differing lengths more interpretable on a common time scale. As a general statistical point, a rate is a summary of event frequency over observed time; it does not show how relapses were distributed among individual participants. The endpoint’s definition therefore helps clarify what is counted and which time windows are compared, but it cannot by itself establish why any change occurred.
The numerical primary outcome, including the estimated change and its confidence interval, is not reported in the registry record. The registry description supports explaining the endpoint and its intended comparison, but not quantifying the result.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a completed prospective study, an enrollment of 256, and a primary question about annualized relapse rate before and after the change to cladribine. However, it does not report the numerical primary outcome, the number evaluable for that outcome, or its 95% confidence interval. Without those results, the direction, size, and precision of the recorded change cannot be characterized. The completed status does not substitute for a reported estimate.
The design matters when interpreting the question. The primary comparison uses two periods from participants’ treatment course rather than a stated randomized comparison with another treatment. A before-and-after contrast can describe how the measured rate differed between those periods, but it cannot by itself separate a treatment-related effect from other changes over time or differences in who contributed data to each period. No separate control treatment arm is described, and allocation is not stated.
The registry specifies a descriptive role for the 95% confidence interval around the difference. In general, a confidence interval conveys the uncertainty associated with an estimate under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, but it does not resolve design limitations or demonstrate that a difference is caused by treatment. In this record, neither the estimate nor its interval is reported, so precision cannot be judged.
The study also lists outcomes for disability, safety, and quality of life. The outcome descriptions establish what was intended for assessment, not what was observed. Numerical findings for these outcomes are not reported in the registry record. The listed safety counts can be described separately, but they do not provide a comparison with an untreated group or another therapy, and they cannot establish that an event was caused by cladribine.
The registry lists 11 outcome measures and 0 analyses. The relationship between that outcome listing and any complete results reporting is not explained in the registry record. There is no reported multiplicity strategy, missing-data approach, or detailed analysis plan. These omissions limit assessment of how the results were selected, how incomplete observations were handled, and whether the reported outcomes were analyzed as intended. They also mean that no conclusion about statistical significance or robustness can be drawn from the record.
Overall, the available information describes the study question, outcome definitions, and some safety counts, but not an effect estimate for the primary endpoint. The scientifically appropriate reading is therefore descriptive: the registry records a planned before-and-after rate assessment and supplies no numerical result with which to judge the observed change or its uncertainty.
9. Statistical Methods Explained
The primary measure is a continuous rate, expressed as relapses per year. The registry specifies the mean as the summary parameter and a 95% confidence interval as the dispersion measure. It describes the interval for the difference as a descriptive measure of effect. The actual mean values, difference, and interval are not reported in the registry record, so the statistical method can be explained but not evaluated against an observed result.
What does annualized relapse rate represent?
In general, an annualized rate relates the number of events to time at risk or time observed. This can make event frequency comparable across periods that do not have identical observation time. The registry defines the primary baseline rate from relapses in the 12 months before cladribine treatment. For the later rate, it describes using relapse reports at visits and the elapsed time between specified visits to annualize the count. The endpoint definition is important because changing the event definition or time window could change the resulting rate.
A rate summarizes event frequency, not the full pattern of events. Two groups of participants could have the same average rate while differing in how relapses are distributed across individuals. In a before-and-after assessment, the mean rate also does not reveal whether every participant had a change in the same direction. Participant-level distributions and evaluable counts are not reported in the registry record.
How should a confidence interval be read?
In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and its assumptions. It conveys precision: an interval that spans a broad range leaves more uncertainty about the size of the underlying effect than a narrow interval. It is not a guarantee that the true value lies in the interval, nor does it account automatically for bias, confounding, or missing observations.
The registry states that a 95% confidence interval for the difference was presented as descriptive. That stated convention does not reveal whether the interval excludes no change, because the numerical interval is not reported. Nor does an interval alone establish a causal effect. The record’s observational, before-and-after framing must be considered separately from statistical precision.
Why is the design relevant to the estimate?
A within-participant time comparison can be useful for describing change across treatment periods, but time itself can influence observed outcomes. In general, other changes during follow-up, changes in measurement, and the selection of participants with available data can affect a before-and-after estimate. A concurrent comparator can help distinguish changes associated with the intervention from broader changes over the same period, but a separate control arm is not described in this registry record. No causal adjustment strategy is reported.
Randomization, when used, assigns treatment by a stated process intended to make comparison groups more alike on average. Allocation is not stated in the registry record. The record therefore does not support describing this study as randomized or attributing a difference to treatment assignment. This does not invalidate a descriptive real-world study; it defines what conclusions its design can support.
What can be learned from the analysis population description?
The primary outcome description defines the Full Analysis Set as participants who gave informed consent and received at least one cladribine dose. It also clarifies that the number analyzed for the outcome means those evaluable for that measure. This distinction matters because enrollment and analysis denominators can differ when outcomes are unavailable or participants do not meet an outcome-specific evaluability requirement. The number evaluable for the primary outcome is not reported in the registry record.
In general, missing observations can affect both the precision and the direction of an estimate, depending on why data are missing and how missingness relates to outcomes. Statistical methods may use complete observations, imputation, or other approaches, but the method used for this study is not reported in the registry record. No missing-data assumptions should be inferred from the outcome description alone.
How should the listed outcome set be considered?
The registry lists multiple secondary measures covering relapse rate, disability, adverse events, and quality of life. When studies assess multiple outcomes, general statistical practice considers whether a multiplicity strategy was prespecified, because repeated testing can increase the chance of apparently notable findings. The multiplicity approach is not reported in the registry record. The listing of outcomes alone does not show which were analyzed, how they were prioritized, or whether any adjustment was used.
The registry lists 0 analyses, and it does not report numerical primary outcome results. A detailed statistical analysis plan, interim analyses, and sample-size justification are also not reported in the registry record. As a general principle, a sample-size calculation depends on design assumptions and a target effect; without the study’s stated assumptions and observed primary result, a planning illustration cannot validate the original design or describe the certainty of the result. The estimates needed to assess the primary analysis are absent from the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 11 outcome measures, including relapse rate, disability progression and improvement, treatment-emergent adverse events, serious adverse events, and quality-of-life measures. It does not report a multiplicity strategy, such as a hierarchy among outcomes or an adjustment for multiple testing. In general, evaluating multiple outcomes raises questions about which findings were prespecified as primary and how the possibility of chance findings was managed. The outcome list alone does not answer those questions.
The primary outcome description identifies a Full Analysis Set comprising participants who provided informed consent and received at least one dose of cladribine. It also says that the number analyzed is the number evaluable for that outcome. The count of participants evaluable for the primary outcome is not reported in the registry record. Enrollment of 256 should therefore not be read as the number contributing data to every analysis.
The approach to missing observations, exclusions, and incomplete follow-up is not reported in the registry record. In general, missing data can influence estimates if the likelihood of having an observed outcome is related to participants’ characteristics or outcomes. Different analytical approaches rely on different assumptions; without the study’s stated approach, readers cannot assess those assumptions or their influence.
The registry lists 0 analyses and does not include a detailed statistical analysis plan or interim-analysis information. These omissions leave the intended handling of multiple outcomes, missing data, and analysis populations unclear. They also prevent assessment of whether the posted outcome descriptions correspond to the analyses conducted.
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 |
|---|---|---|---|
| Cladribine | 10 | 256 | 3.9% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cladribine | 0 of 256 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cladribine | 90 of 256 |
Most frequent serious adverse event terms
| Event term | Organ system | Cladribine |
|---|---|---|
| Multiple sclerosis relapse | Nervous system disorders | 3 of 256 |
| Appendicitis | Infections and infestations | 1 of 256 |
| COVID-19 | Infections and infestations | 1 of 256 |
| Pneumonia | Infections and infestations | 1 of 256 |
| Urinary tract infection | Infections and infestations | 1 of 256 |
| Drug-induced liver injury | Hepatobiliary disorders | 1 of 256 |
| Hepatitis acute | Hepatobiliary disorders | 1 of 256 |
| Lymphopenia | Blood and lymphatic system disorders | 1 of 256 |
| Humerus fracture | Injury, poisoning and procedural complications | 1 of 256 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cladribine |
|---|---|---|
| COVID-19 | Infections and infestations | 24 of 256 |
| Lymphopenia | Blood and lymphatic system disorders | 24 of 256 |
| Headache | Nervous system disorders | 10 of 256 |
| Multiple sclerosis relapse | Nervous system disorders | 9 of 256 |
| Fatigue | General disorders | 5 of 256 |
| Upper respiratory tract infection | Infections and infestations | 4 of 256 |
| Urinary tract infection | Infections and infestations | 4 of 256 |
| Pregnancy | Pregnancy, puerperium and perinatal conditions | 4 of 256 |
| Gastroenteritis | Infections and infestations | 3 of 256 |
| Influenza | Infections and infestations | 3 of 256 |
Serious events with the highest arm-level rate: multiple sclerosis relapse (1.2%), appendicitis (0.4%), covid-19 (0.4%), pneumonia (0.4%), urinary tract infection (0.4%).
For the cladribine group, the registry lists 256 participants at risk for serious adverse events and 10 participants affected. It lists 256 at risk for other adverse events and 90 affected. Deaths are listed as 0. These are descriptive counts in the registry record; they are not a comparison against another treatment group.
The serious adverse event terms listed include multiple sclerosis relapse at 1.2%, and appendicitis, COVID-19, pneumonia, urinary tract infection, and drug-induced liver injury at 0.4% each. These percentages describe the registry’s listed terms. The record does not provide enough detail to determine whether participants could contribute to more than one term, or to reconstruct the full event-level distribution.
In general, an adverse event is an event recorded during a study, while a serious adverse event is classified by seriousness criteria. A recorded event does not, by itself, show that treatment caused it. The counts also do not establish comparative risk, because a separate comparator group is not described. The registry does not report further information needed to assess timing, duration, severity beyond the serious classification, or individual attribution. These figures should therefore be read as descriptive safety reporting, not as a treatment-effect estimate.
12. What the Result Does, and Does Not, Mean
The registry record gives a clear description of the intended primary question: compare annualized relapse rate in the 12 months before baseline with the 12 months before the end of follow-up, labeled 2 years. It also defines relapse and describes the intended use of a 95% confidence interval for the difference. However, the numerical primary result and interval are not reported in the registry record. The direction, size, and precision of the change therefore cannot be stated.
The record also documents that the study was prospective, conducted in routine clinical practice, and focused on participants who changed from first-line disease-modifying treatment to cladribine tablets. It lists an enrollment of 256 and several secondary outcomes. Those descriptions establish the study’s scope, not the results for those outcomes. Numerical results for the listed disability and quality-of-life outcomes are not reported in the registry record.
The safety information includes counts of participants affected and listed serious-event terms. Such data can describe what was recorded in the treated group, but they do not establish causation or comparative safety. The record does not describe a separate control treatment arm, and allocation is not stated.
In general, an observed before-and-after difference would describe change over time in the analyzed data. Without a suitable comparison and supporting assumptions, it would not by itself show that treatment caused that change. Precision would also depend on the estimate, its interval, the number evaluable, and the analysis approach; these details are not available for the primary result.
Thus, the registry supports understanding the study design and outcome definitions, but not judging the primary treatment-associated effect. The absence of a reported estimate is not evidence that no change occurred. It means that the registry record does not provide the numerical result needed to characterize the change.
13. Why This Trial Matters Statistically
This study addresses a real-world treatment-transition question: outcomes after participants with multiple sclerosis changed from a listed first-line disease-modifying treatment to cladribine tablets in routine clinical practice. Prospective follow-up and explicit outcome definitions can make a clinical question easier to interpret, particularly when the endpoint depends on identifying events and defining observation periods.
Statistically, the central feature is a before-and-after comparison of annualized relapse rate. That framing highlights both the value and the limits of descriptive effectiveness research. It can document how outcomes differ across periods in the participants studied, while leaving open whether a change is attributable to treatment, other time-related factors, or differences in available observations. The registry does not describe a separate control treatment arm or state allocation.
The record also distinguishes an enrollment figure from the outcome-specific number analyzed: the analysis population includes participants who consented and received at least one dose, while the analyzed number is defined as those evaluable for the endpoint. This distinction is important for reading any clinical study because the number enrolled does not necessarily equal the number contributing to each measure. The actual evaluable count is not reported in the registry record.
The registry’s descriptions of confidence intervals, secondary outcomes, and safety reporting offer a framework for interpreting what the study was intended to measure. Yet the numerical primary estimate and its confidence interval are not reported. This makes the record useful for understanding the question and intended methods, but insufficient for assessing the size or precision of the primary finding. That distinction—between a well-described question and an available result—is central to sound statistical interpretation.
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 most direct limitation of the registry record for interpretation is that it does not report the numerical result for the primary annualized relapse rate comparison or its 95% confidence interval. Without those values, the estimated change and its precision cannot be assessed. The outcome-specific number analyzed is also not reported, despite the definition that this number refers to participants evaluable for the outcome.
The study is described as a real-world prospective study of people changing from first-line treatment, but a separate control treatment arm is not described and allocation is not stated. The primary question compares periods before and after the treatment change. As a general limitation of such comparisons, time-related influences and changes in the composition of observed participants can complicate interpretation. The registry record does not report methods to address these issues.
Although the registry lists secondary outcomes and 11 outcome measures, it lists 0 analyses. Numerical results for the secondary outcomes are not reported in the registry record. A multiplicity strategy, detailed statistical analysis plan, missing-data method, interim-analysis information, and sample-size justification are also not reported. These omissions limit assessment of analysis choices and the handling of incomplete data.
The safety information lists affected participants and serious adverse event terms, but does not provide a comparator group for evaluating relative safety. The listed counts and percentages do not establish causality. The registry record also does not provide enough information in these entries to reconstruct all participant-level event patterns or assess the context of each event. These limitations apply to interpretation of the registry record, not necessarily to information that may exist outside it.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Prospective Effectiveness and Safety Study of Cladribine in Participants Who Change First-line DMD Treatments for Multiple Sclerosis (CLAD CROSS) — NCT04934800.
- Registry record last updated 2025-06-24; status last verified 2025-06.
- Results first posted 2025-06-24.
- 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
CLAD CROSS, registered as NCT04934800, is a prospective effectiveness and safety study of cladribine tablets in participants with multiple sclerosis who changed from first-line disease-modifying treatment. The registry describes routine clinical practice as the setting and lists enrollment of 256. The study status is COMPLETED; its start date is 2019-12-10, and its primary completion date is 2024-05-20.
The primary outcome is change in annualized relapse rate between the 12 months before baseline and the 12 months before the end of study follow-up, labeled 2 years. The registry describes the Full Analysis Set and says the outcome-specific analyzed number is the number evaluable. Numerical primary results and the confidence interval are not reported in the registry record.
Secondary measures cover relapse rate, disability, adverse events, and quality of life. The record lists 0 analyses. Safety entries report 10 participants affected by serious adverse events and 90 affected by other adverse events, with 0 deaths listed. These are descriptive entries and do not provide a treatment comparison.