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 A Study of Suboptimally Controlled Participants Previously Taking Injectable DMDs for RMS (CLICK-MS) (NCT03933215), a registered phase not stated study. The primary outcome is Annualized Relapse Rate (ARR).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03933215 |
| Phase | Phase not stated |
| Condition | Multiple Sclerosis |
| Allocation | Not Stated |
| Design model | Not Stated |
| Masking | Not Stated |
| Enrollment | 100 |
| Arms in the primary outcome | n/a |
| Lead sponsor | EMD Serono Research & Development Institute, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Participants had relapsing forms of multiple sclerosis, including relapsing-remitting multiple sclerosis or active secondary progressive multiple sclerosis. They had previously taken an injectable disease-modifying drug approved in the United States for relapsing forms of multiple sclerosis and had a suboptimal response. The registry describes the analysis population as participants enrolled who received at least one dose of cladribine tablets; for the primary outcome, only participants evaluable for that outcome count as analyzed. The number evaluable for the annualized relapse rate is not reported in the registry record.
Intervention
Participants transitioned to cladribine tablets. The study evaluated effectiveness, patient-reported outcomes and safety in a real-world setting. The registry lists cladribine as the intervention, but the arm description is blank. Details of individual treatment decisions, dosing in practice, and adherence are not reported in the registry record.
Comparator
No like-for-like control comparison is described. The study is observational, and allocation is not stated. The registry does not identify a concurrent comparator arm or describe a randomized assignment. Therefore, the central question is not framed as a controlled estimate of the difference between cladribine tablets and another treatment.
Primary question
The primary outcome is the mean annualized relapse rate from baseline through up to 24 months. In plain terms, it is intended to describe the rate of qualifying relapses over follow-up, expressed as relapses per year. A qualifying relapse is defined as new or worsening neurological symptoms attributable to multiple sclerosis, lasting more than 24 hours, without fever, infection, injury or adverse events, after a stable or improving neurological state for at least 30 days. The primary numerical estimate and its confidence interval are not reported in the registry record.
Thus, the registry describes a real-world follow-up study of participants who moved to cladribine tablets after suboptimal control on injectable disease-modifying drugs. Its stated purpose is to evaluate outcomes in that clinical context. Without a reported comparator group and without the primary relapse-rate estimate, the registry record does not establish a comparative treatment effect.
3. Trial Design
CLICK-MS is registered as an observational study of cladribine tablets in participants with relapsing forms of multiple sclerosis who had previously taken injectable disease-modifying drugs and had a suboptimal response. The listed conditions include multiple sclerosis. The study’s stated aim encompasses effectiveness, patient-reported outcomes and safety in a real-world setting. Its intervention listing names cladribine; no arm description is provided.
The registry lists enrollment as 100 and gives the study status as completed. The listed study start date is 2019-05-21, and the primary completion date is 2024-03-30. Enrollment is a registry characteristic; it does not by itself establish how many participants contributed data to a particular outcome. For the primary outcome, the record defines the Full Analysis Set as enrolled participants who received at least one dose of cladribine tablets, while the phrase “overall number of participants analyzed” refers to those evaluable for that outcome. That evaluable count is not reported in the registry record.
The primary assessment covers baseline, identified as Month 0, through up to 24 months. The secondary outcomes concern changes from baseline at Month 6, Month 12 and Month 24 in treatment satisfaction, health-related quality of life, fatigue, depression and work-related measures. These include the TSQM-14, SF-36, MFIS-5, BDI-FS and WPAI-MS. The registry lists 24 outcome measures, but does not provide numerical results for those measures in the record.
This is not a randomized comparison: allocation is not stated, and the listed arms are not a like-for-like control comparison. The record does not report a separate untreated or active comparator group. It also does not report a detailed statistical analysis plan, recruitment procedures, treatment adherence, or the handling of treatment changes during follow-up. Those omissions limit what can be concluded about study conduct and the meaning of any observed change.
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 | 100 |
| Treated | 62 |
| COMPLETED | 34 |
| NOT COMPLETED | 66 |
Reasons for not completing this period:
| Reason | Cladribine |
|---|---|
| Other | 6 |
| Sponsor decision | 5 |
| Protocol Violation | 5 |
| Withdrawal by Subject | 6 |
| Lost to Follow-up | 6 |
| Enrolled but not treated | 38 |
Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) included all participants enrolled in the study who received at least 1 dose of cladribine tablets. Here, "overall number of participants 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.
Population: The Full Analysis Set (FAS) included all participants enrolled in the study who received at least 1 dose of cladribine tablets.
| Characteristic | Unit | Cladribine |
|---|---|---|
| Participants analysed | 62 | |
| Age, Continuous | years | 49 (SD 12.4) |
| Sex: Female, Male: Female | Participants | 49 |
| Sex: Female, Male: Male | Participants | 13 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 51 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 9 |
| 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 | 7 |
| Race (NIH/OMB): White | Participants | 52 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 3 |
6. Primary Endpoint
The registry lists the primary outcome as Annualized Relapse Rate (ARR), measured over Baseline (Month 0) up to 24 Months.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | relapses per year |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the mean annualized relapse rate, measured from baseline (Month 0) through up to 24 months and expressed as relapses per year. An annualized rate places relapse experience on a yearly scale, which is useful when participants may contribute different amounts of follow-up time. It can describe relapse frequency over a follow-up period without treating the raw count alone as the full outcome.
The registry defines a qualifying relapse as new or worsening neurological symptoms attributed to multiple sclerosis, lasting more than 24 hours, without fever, infection, injury or adverse events. The symptoms must follow a stable or improving neurological state for at least 30 days. These criteria distinguish a qualifying relapse from temporary symptoms or changes attributed to other causes, according to the registry definition.
The endpoint is reported as a mean, with a 95% confidence interval specified as its dispersion measure. A confidence interval communicates the statistical uncertainty around an estimate; its width depends on the data and analysis. The registry record does not report the mean annualized relapse rate, its confidence limits, or the number of participants evaluable for this outcome. Therefore, the endpoint’s definition is available, but its observed result and precision cannot be assessed from the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clinically specific question: what effectiveness, patient-reported outcome and safety experience is observed after participants with relapsing forms of multiple sclerosis and a suboptimal response to injectable disease-modifying drugs transition to cladribine tablets in routine practice? The primary outcome is defined as mean annualized relapse rate from baseline through up to 24 months. However, the posted results do not report that rate or its 95% confidence interval. There is consequently no primary effect estimate in the registry record to interpret for magnitude or precision.
The absence of a reported estimate is not evidence that the relapse rate was zero, unchanged, or improved. It means that the registry record does not provide a numerical primary outcome result. Nor does the listed enrollment establish the outcome analysis denominator: the record distinguishes participants who enrolled and received at least one dose from those evaluable for the particular outcome, and the evaluable number is not reported.
The study is observational, and allocation is not stated. There is no described like-for-like control comparison. Any outcome observed after transition to cladribine would therefore describe the experience of the enrolled participants, rather than isolate a causal effect of cladribine against a concurrent comparison group. Participants enter the study in a specific treatment context—after a suboptimal response to injectable drugs—and the registry does not report methods for accounting for differences in baseline disease status, prior treatment histories, or other factors that might influence subsequent outcomes.
The record does list safety counts. In the cladribine group, 3 participants are reported as affected by serious adverse events, with 62 at risk; 34 are reported as affected by other adverse events, also with 62 at risk. Deaths are listed as 0. These counts describe what the registry reports, but do not establish that an event was caused by treatment. The serious event terms listed each have a reported frequency of 1.6%. The record does not give further detail about timing, severity beyond the serious classification, relatedness, duration, or overlap among event categories.
Patient-reported secondary outcomes are specified at Month 6, Month 12 and Month 24, including satisfaction, health status, fatigue, depressive symptoms and work impairment. The registry lists the outcome measures but does not report numerical results for them. No conclusions about the direction or size of changes in those measures can be drawn from their names or planned time points alone.
Overall, the registry record communicates the study question, endpoint definitions and selected safety counts, but not the primary relapse-rate result or secondary outcome estimates. Its observational design also means that any reported before-and-after patterns would need to be interpreted as associations in this enrolled group, not as proof of a comparative treatment effect.
9. Statistical Methods Explained
The statistical methods that can be described are limited to the information stated in the registry record. It identifies a continuous outcome summarized as a mean and specifies a 95% confidence interval for the annualized relapse rate. It does not report the analysis model, covariate adjustments, missing-data procedures, multiplicity strategy or detailed statistical plan. These methods should not be inferred from the endpoint definition or from the study’s observational status.
What does an annualized rate represent?
In general, a rate expresses events in relation to time at risk. Annualization places the rate on a yearly scale, allowing follow-up experience to be described in a common unit even when observation time differs. This is distinct from simply reporting a count of relapses. The specific calculation used in this study, including how follow-up time and incomplete observation were handled, is not reported in the registry record.
The endpoint is a mean of a continuous measure, as specified in the registry. In general, a mean gives an average level across the observations included in an analysis. The value can be influenced by the distribution of the data, particularly if a small number of participants have notably different values. The record does not report the distribution of relapse rates, participant-level data, or alternative summaries, so it is not possible to assess whether the mean alone adequately describes the outcome.
How should a confidence interval be read?
In general, a confidence interval expresses uncertainty around an estimate under the assumptions of the statistical method used. A narrower interval indicates greater precision than a wider interval, while the interval’s location conveys which values are compatible with the analysis. The registry specifies a 95% confidence interval for the primary endpoint, but does not report its limits. Without the estimate and interval, neither the observed rate nor its statistical precision can be evaluated.
A confidence interval is not a guarantee that the true value lies inside the reported limits, and it does not by itself resolve bias or confounding. It summarizes uncertainty as represented by the analysis. In an observational study, the interval would not account for every possible systematic difference between participants or for unmeasured factors unless those were addressed through design or analysis. The registry record does not state whether adjustments were made.
What does the observational design imply?
In general, observational studies record treatment and outcomes as they occur rather than assigning participants to treatments through randomization. This can support a description of real-world experience, but treatment selection may be related to participants’ characteristics and clinical histories. A comparison between groups, if groups exist, may therefore reflect both treatment and baseline differences. In this registry record, allocation is not stated, and the arms are explicitly not described as a like-for-like control comparison. The record does not report a randomized assignment or a comparator suitable for a controlled treatment-effect estimate.
For an outcome measured from baseline through follow-up, a change after treatment transition can be described, but change alone does not identify what would have happened to the same participants over the same period without that transition. The registry record does not describe a causal inference approach or an adjustment strategy that would address this issue. Accordingly, even if numerical changes were reported, they would need to be interpreted in light of the observational design.
What are the analysis population and denominator?
The registry defines the Full Analysis Set as all enrolled participants who received at least one dose of cladribine tablets. It separately clarifies that the “overall number of participants analyzed” for an outcome refers to participants evaluable for that outcome. This distinction matters because eligibility for an outcome analysis may depend on having the information needed for that measure. The number evaluable for the primary annualized relapse rate is not reported. The registry’s enrollment figure should not be substituted for an outcome-specific denominator.
The record does not state how participants with no follow-up information, incomplete observation, or missing relapse assessments were treated. It does not report whether missing information was imputed, whether analyses used available observations, or whether participants were excluded for particular reasons. Any of these decisions can affect the analyzed population and the estimate, so the reported analysis approach would be needed to evaluate them.
What can safety counts establish?
Adverse-event counts are descriptive. The registry reports participants at risk and participants affected for serious and other adverse events, alongside a death count and selected serious event terms. In general, a count indicates how many participants were recorded in a category; it does not establish causation or describe the full clinical course. A participant may have more than one event, and categories may overlap, but whether that occurred in this study is not reported in the registry record. The counts should not be converted into totals across categories or treated as event rates without the relevant definitions and analysis details.
The registry also lists patient-reported secondary outcomes at specified follow-up visits, but numerical analyses are not reported. A change score generally compares a follow-up measure with its baseline value. Its interpretation depends on the scale, the direction in which scores indicate better or worse status, the available observations and the method used to handle missing data. Those result values and analytic details are not reported in the registry record. The listed outcome names alone do not reveal whether scores changed or how precisely any change was estimated.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 24 outcome measures. The primary outcome is the annualized relapse rate, while the secondary outcomes include measures of treatment satisfaction, health status, fatigue, depression and work productivity or activity impairment. Several patient-reported outcomes are specified for assessment at Month 6, Month 12 and Month 24. Considering many outcomes or time points creates a multiplicity question: when many statistical tests are performed, the chance of at least one apparently notable result can increase. In general, statistical plans may address this through prespecified primary outcomes, adjusted testing procedures, or careful emphasis on estimation rather than isolated significance tests.
The registry record does not report whether a multiplicity adjustment was planned or used, how outcomes were prioritized beyond identifying the primary endpoint, or whether analyses at different visits were treated as separate tests. It reports 0 analyses, and does not provide numerical results for the primary or listed secondary outcomes. No claims about statistical significance, hypothesis testing, or correction for multiple comparisons can therefore be drawn from the record.
Missing-data handling is also not reported in the registry record. The record defines the Full Analysis Set as participants enrolled who received at least one dose, and says the analyzed count for an outcome means those evaluable for that outcome. It does not give the outcome-specific evaluable count or explain why data might be unavailable. The approach to incomplete follow-up, missing questionnaires, or unobserved relapses is not reported. In general, missingness can affect both the number of observations contributing to an estimate and how representative those observations are of the intended population.
The registry’s enrollment figure is not a substitute for the number analyzed for each outcome. Without the outcome-specific denominators and missing-data methods, the completeness of the analyses and the potential impact of missing information cannot be judged.
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 | 3 | 62 | 4.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cladribine | 0 of 62 |
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 | 34 of 62 |
Most frequent serious adverse event terms
| Event term | Organ system | Cladribine |
|---|---|---|
| Gastritis | Gastrointestinal disorders | 1 of 62 |
| Anal squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 62 |
| Low absolute lymphocyte count | Investigations | 1 of 62 |
| Suspected infection of the kidney | Infections and infestations | 1 of 62 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cladribine |
|---|---|---|
| Lymphopenia | Blood and lymphatic system disorders | 9 of 62 |
| COVID-19 | Infections and infestations | 5 of 62 |
| Herpes zoster | Infections and infestations | 4 of 62 |
| Urinary tract infection | Infections and infestations | 3 of 62 |
| Abdominal discomfort | Gastrointestinal disorders | 2 of 62 |
| Nausea | Gastrointestinal disorders | 2 of 62 |
| Pyrexia | General disorders | 2 of 62 |
| Hypersensitivity | Immune system disorders | 2 of 62 |
| Bronchitis | Infections and infestations | 2 of 62 |
| Upper respiratory tract infection | Infections and infestations | 2 of 62 |
Serious events with the highest arm-level rate: gastritis (1.6%), anal squamous cell carcinoma (1.6%), low absolute lymphocyte count (1.6%), suspected infection of the kidney (1.6%).
The registry reports safety information for the cladribine group. For serious adverse events, 62 participants are listed as at risk and 3 as affected. For other adverse events, 62 are listed as at risk and 34 as affected. The number of deaths is listed as 0. These are reported counts, not estimates of a causal treatment effect. The record does not report the event observation period or provide detailed definitions for the at-risk denominators beyond the registry’s displayed safety data.
The serious adverse event terms listed are gastritis, anal squamous cell carcinoma, low absolute lymphocyte count and suspected infection of the kidney. Each term is reported as 1.6%. These term-level figures should be read as registry-reported frequencies; they do not establish that the events were caused by cladribine. The record does not report further details such as onset, duration, outcome, investigator assessment of relatedness, or whether participants had more than one event.
Serious and other adverse events are separate reporting categories, and the registry does not explain their overlap. The participant counts should not be added together to infer a total affected, since the same person could potentially appear in more than one category. The record also does not provide a comparison group, so the safety counts cannot show whether these experiences were more or less common than under another treatment.
12. What the Result Does, and Does Not, Mean
The study addresses outcomes among participants with relapsing forms of multiple sclerosis who had a suboptimal response to injectable disease-modifying drugs and transitioned to cladribine tablets. That focus gives the registry record a defined real-world context. It is not a randomized comparison, and allocation is not stated, so the study does not provide a like-for-like controlled estimate of the effect of cladribine versus another treatment.
The primary endpoint is clearly defined as mean annualized relapse rate from baseline through up to 24 months, with a 95% confidence interval specified. But the registry record does not report the numerical estimate, its confidence limits, or the number evaluable for the outcome. Therefore, the posted information does not show the observed relapse rate or how precisely it was estimated. It does not establish that relapse rates increased, decreased or remained unchanged.
The registry lists outcomes for treatment satisfaction, health status, fatigue, depressive symptoms and work-related impairment. It specifies assessment at Month 6, Month 12 and Month 24, but does not provide numerical results for those outcomes. Their inclusion indicates what the study intended to evaluate; it is not evidence that a particular outcome improved or worsened.
The safety information consists of reported serious and other adverse-event counts and selected serious event terms. These data describe recorded events in the cladribine group, but the registry record does not establish causation, provide a like-for-like safety comparison, or give the detailed context needed to assess individual events. The listed death count is 0; this is a registry count, not a broad conclusion about safety.
In general, observed outcomes after a treatment transition can be useful for describing the experience of a defined group. However, without a suitable comparator and methods that address differences between treatment groups, observed outcomes do not isolate the effect attributable to treatment. The registry record also does not report key details about missing data, outcome-specific analysis populations or statistical adjustment. These limitations mean that conclusions should remain descriptive and tied to the information actually reported.
13. Why This Trial Matters Statistically
CLICK-MS is statistically relevant because it focuses on a treatment transition in a specific real-world setting: participants with relapsing forms of multiple sclerosis who had a suboptimal response to injectable disease-modifying drugs. The registry includes both a clinical outcome—annualized relapse rate—and patient-reported measures covering treatment satisfaction, health status, fatigue, depressive symptoms and work-related impairment. Looking across these domains can characterize more than relapse experience alone, provided the results and analysis methods are reported.
The registry’s primary outcome definition makes clear what counts as a qualifying relapse and identifies the follow-up window. Its stated use of a mean and 95% confidence interval also signals that the intended presentation includes an estimate and an expression of precision. Those details help readers understand the outcome being assessed, but they cannot replace the missing numerical result. The record does not report the primary estimate or interval, so the intended statistical summary cannot be evaluated.
The observational design is important to interpretation. Real-world evidence can describe outcomes among people treated in practice, but an uncontrolled before-and-after description does not by itself establish what would have occurred without the treatment transition. Allocation is not stated, and the record does not describe a like-for-like comparison. This distinguishes descriptive effectiveness evidence from a randomized comparative treatment estimate.
The record also highlights why analysis denominators and missing-data methods matter. It defines an analysis population based on enrollment and receipt of at least one dose, while specifying that the analyzed count for an outcome refers to participants evaluable for that measure. Since the evaluable count and handling of missing observations are not reported, readers cannot assess how complete the outcome data are. Together, these features make the registry useful for understanding the question and design, while emphasizing that a complete statistical interpretation requires outcome estimates, precision measures and transparent analysis details.
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 important limitation for interpreting effectiveness is that the registry record does not report the primary annualized relapse rate estimate or its 95% confidence interval. It also does not report the number evaluable for that endpoint. Without these, the observed result and its precision cannot be assessed.
The design is observational, allocation is not stated, and the arms are not a like-for-like control comparison. The record does not describe a comparator group suitable for estimating a relative treatment effect. It also does not report adjustment for baseline differences, prior treatment history, or other factors that might influence outcomes. These omissions limit causal interpretation of any outcome after treatment transition.
The record lists 24 outcome measures but does not give their numerical results. It does not report a multiplicity strategy, so it is not possible to determine how the analysis addressed the range of outcomes and follow-up assessments. Missing-data methods and outcome-specific denominators are also not reported. The number enrolled cannot be assumed to equal the number contributing to every outcome.
For safety, the record provides selected counts and serious event terms but not event timing, duration, relatedness, overlap among categories, or a comparison group. These details would be needed for a fuller assessment of the safety experience. The registry also does not report details such as adherence or treatment changes during follow-up, which could help contextualize real-world outcomes. These are limitations of the information in the registry record, rather than evidence that a particular result is absent from all other sources.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Suboptimally Controlled Participants Previously Taking Injectable DMDs for RMS (CLICK-MS) — NCT03933215.
- Registry record last updated 2025-04-29; status last verified 2025-04.
- Results first posted 2025-04-29.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
CLICK-MS (NCT03933215) is listed as a completed observational study sponsored by EMD Serono Research & Development Institute, Inc. The registry lists enrollment as 100 and describes an evaluation of cladribine tablets among participants with relapsing forms of multiple sclerosis who had a suboptimal response to injectable disease-modifying drugs.
The primary outcome is mean annualized relapse rate from baseline through up to 24 months, with a 95% confidence interval specified. The record also lists patient-reported secondary outcomes at Month 6, Month 12 and Month 24. It does not report numerical results for the primary endpoint or those secondary outcomes. Safety entries include serious and other adverse-event counts, selected serious event terms, and a death count of 0.
The record describes no like-for-like control comparison, does not state allocation, and does not report the primary outcome’s evaluable count, missing-data methods or multiplicity approach. These omissions limit statistical interpretation of the posted information.