This page separates reported trial results from statistical interpretation. Trial-specific numerical results and design facts on this page are restricted to the ClinicalTrials.gov record. The registry provides the official trial record.
1. Trial at a Glance
CLARITY was a randomized, parallel, triple-masked phase 3 treatment trial in relapsing-remitting multiple sclerosis. The study enrolled 1326 participants and compared two cladribine dose groups with placebo, with the primary endpoint being the annualized qualifying relapse rate at Week 96.
| Feature | CLARITY |
|---|---|
| Trial name | CLARITY |
| Phase | Phase 3 |
| Condition | Multiple Sclerosis, Relapsing-Remitting |
| Design | Randomized, parallel |
| Masking | Triple |
| Primary purpose | Treatment |
| Enrollment | 1326 |
| Interventions | Cladribine 5.25 mg/kg; Cladribine 3.5 mg/kg; Placebo |
| Primary endpoint | Annualized Qualifying Relapse Rate at Week 96 |
| Primary endpoint type | Count / rate |
| Primary hypothesis | Superiority |
| Lead sponsor | EMD Serono |
| Sponsor type | Industry |
| Study status | Completed |
| Start | 2005-04 |
| Primary completion | 2008-11 |
| ClinicalTrials.gov | NCT00213135 |
2. Clinical Question
The statistical question was whether treatment with oral cladribine was associated with a different annualized qualifying relapse rate than placebo over the registered Week 96 assessment period.
Population
Subjects with relapsing-remitting multiple sclerosis.
Intervention
Cladribine 5.25 mg/kg or cladribine 3.5 mg/kg.
Comparator
Placebo.
Primary question
Does either cladribine dose reduce the annualized qualifying relapse rate relative to placebo at Week 96?
3. Trial Design
Cladribine 5.25 mg/kg
- Drug intervention
- Cladribine dose: 5.25 mg/kg
Cladribine 3.5 mg/kg
- Drug intervention
- Cladribine dose: 3.5 mg/kg
Placebo
- Other intervention
- Placebo comparator
The parallel design means participants were assigned to one of the three study arms rather than moving between randomized treatment groups as part of the registered design. The ClinicalTrials.gov record identifies randomization, triple masking, and parallel allocation, but do not provide additional allocation-ratio or stratification details.
4. Endpoints
| Endpoint | Time frame | Registry definition / type |
|---|---|---|
| Annualized Qualifying Relapse Rate | Week 96 | A qualifying relapse was defined as an increase of 2 points in at least one functional system of the expanded disability status scale (EDSS) or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. The annualized relapse rate for each treatment group was calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25. |
The registry classifies the primary endpoint as a count / rate endpoint, specifically an annualized rate expressed as relapses per year. The formal analyses posted for this endpoint compare each cladribine dose group with placebo.
5. Statistical Methodology
Primary analysis population: intention-to-treat
The posted primary analyses used the intention-to-treat (ITT) population, defined in the registry analysis as including all participants who were randomized in the study. This is an important design-to-analysis connection: the efficacy comparison follows randomized assignment rather than restricting the analysis to participants who completed treatment or adhered perfectly to the assigned intervention.
Wald chi-squared test
The registry reports a Wald Chi-square test for each primary comparison. The statistical method is a chi-squared test, classified in the ClinicalTrials.gov record as a categorical-data method.
The Wald framework evaluates whether an estimated treatment effect is sufficiently far from the null value relative to its estimated uncertainty. The reported p-value then addresses evidence against the null hypothesis; it does not itself describe the magnitude of the treatment effect.
Relative risk as the effect measure
The effect measure reported for both primary analyses was Relative Risk, normalized as risk ratio / relative risk. The two comparisons were cladribine 5.25 mg/kg versus placebo and cladribine 3.5 mg/kg versus placebo.
An RR below 1 indicates that the estimated quantity in the treatment group is lower relative to the comparator under the analysis framework. It is a relative measure and should not be confused with an absolute difference in relapse rates.
Superiority framework
The registered hypothesis type was superiority. Accordingly, the comparisons were framed around whether the cladribine groups differed favorably from placebo rather than whether cladribine merely met a prespecified non-inferiority margin.
Confidence intervals
Both posted primary analyses include two-sided 95% confidence intervals. The interval describes statistical uncertainty around the estimated relative risk under the analysis model and sampling framework. It does not describe the range of individual patient outcomes.
6. Results: Annualized Qualifying Relapse Rate
The primary endpoint was analyzed at Week 96 in the ITT population. The registry posts two formal primary analyses, one for each cladribine dose versus placebo.
Cladribine 5.25 mg/kg vs Placebo
Relative Risk
95% CI: 0.35–0.54 · P < 0.001
Outcome: Annualized Qualifying Relapse Rate at Week 96
| Feature | Reported result |
|---|---|
| Analysis population | Intention-to-treat population: all participants randomized in the study |
| Comparison | Cladribine 5.25 mg/kg vs Placebo |
| Method | Wald Chi-square test |
| Effect measure | Relative Risk |
| Estimate | 0.43 |
| 95% CI | 0.35–0.54 |
| P-value | <0.001 |
| Hypothesis | Superiority |
The reported relative risk of 0.43 means that the estimated annualized qualifying relapse rate in the cladribine 5.25 mg/kg group was 0.43 times the corresponding rate in the placebo group under the posted analysis.
This can also be expressed as an estimated 57% lower relative rate, because 1 − 0.43 = 0.57. This is a relative interpretation; it does not mean that 57% of participants avoided relapse, nor does it establish a 57% absolute reduction in relapse probability.
The 95% confidence interval of 0.35–0.54 describes the statistical precision of the relative-risk estimate. It does not mean that individual patients have a 95% probability of experiencing a relative risk somewhere inside that interval.
The P < 0.001 result addresses the evidence against the null hypothesis in the reported test. A p-value is not a measure of effect size and should not be read as the probability that the treatment works or as the magnitude of benefit.
Because the endpoint is an annualized relapse rate rather than a time-to-event endpoint, the interpretation is different from a hazard ratio. There is no Cox proportional-hazards assumption to interpret for this posted primary analysis.
Cladribine 3.5 mg/kg vs Placebo
Relative Risk
95% CI: 0.34–0.54 · P < 0.001
Outcome: Annualized Qualifying Relapse Rate at Week 96
| Feature | Reported result |
|---|---|
| Analysis population | Intention-to-treat population: all participants randomized in the study |
| Comparison | Cladribine 3.5 mg/kg vs Placebo |
| Method | Wald Chi-square test |
| Effect measure | Relative Risk |
| Estimate | 0.43 |
| 95% CI | 0.34–0.54 |
| P-value | <0.001 |
| Hypothesis | Superiority |
The reported relative risk of 0.43 means that the estimated annualized qualifying relapse rate in the cladribine 3.5 mg/kg group was 0.43 times the corresponding rate in the placebo group under the posted analysis.
Equivalently, the relative-rate interpretation is approximately a 57% lower estimated rate because 1 − 0.43 = 0.57. This does not mean that 57% of patients were protected from relapse, and it does not provide an absolute reduction without the underlying group-specific rates.
The 95% confidence interval of 0.34–0.54 quantifies uncertainty around the estimated relative risk. Its width provides information about precision, while its position relative to the null value of 1 is relevant to the hypothesis test.
The reported P < 0.001 indicates strong statistical evidence against the null hypothesis under the posted Wald chi-squared analysis. It does not quantify the clinical importance of the effect and should not be interpreted as a probability that the null hypothesis is true or false.
As with the other primary comparison, this is a relative rate measure. The analysis does not by itself establish an absolute risk difference or describe how the treatment effect varies across individual patients.
7. Comparing the Two Primary Effect Estimates
The two posted point estimates are identical at 0.43, while their confidence intervals differ slightly: 0.35–0.54 for 5.25 mg/kg and 0.34–0.54 for 3.5 mg/kg. Both analyses have a reported two-sided 95% confidence interval and a p-value of <0.001.
8. Statistical Methods Explained
Why was an ITT population used?
The posted efficacy analyses define the ITT population as all participants randomized in the study. This preserves the randomized comparison by keeping participants associated with their original treatment assignment. ITT is particularly important when the goal is to estimate the effect of assigning a treatment strategy rather than the effect among only those who fully adhere to treatment.
What does a relative risk of 0.43 mean?
A relative risk of 0.43 means the estimated rate in the treatment group is 43% of the comparator rate under the analysis. The complementary interpretation is a 57% lower relative rate. Neither expression gives the absolute difference between groups without the underlying rates.
Why is the null value 1 rather than 0?
For a ratio measure, no relative difference corresponds to a ratio of 1. A value below 1 indicates a lower treatment-group rate, while a value above 1 indicates a higher treatment-group rate. This differs from an absolute difference, for which the null value is 0.
What does the 95% confidence interval tell us?
The interval gives a range of values reflecting statistical uncertainty around the estimated relative risk. For the 5.25 mg/kg comparison, the interval is 0.35–0.54; for the 3.5 mg/kg comparison, it is 0.34–0.54. Narrower intervals generally indicate greater precision than wider intervals, although precision must always be considered in context.
What does P < 0.001 mean?
It indicates that, under the statistical test and null hypothesis used for the comparison, the observed evidence is inconsistent with the null at conventional significance thresholds. It does not measure the size of the treatment effect, the probability that treatment is effective, or the probability that the null hypothesis is true.
Why use a chi-squared test?
The registry reports the Wald Chi-square test and normalizes the method to a chi-squared test within the categorical-data family. In this analysis, the test is used to evaluate the estimated relative treatment effect relative to its null value. The associated confidence interval and relative-risk estimate provide information that the p-value alone cannot provide.
Why is the endpoint called an annualized relapse rate?
The registry classifies the primary endpoint as a count / rate endpoint and gives the outcome unit as relapses per year. Annualization places relapse occurrence on a common rate scale, allowing the randomized groups to be compared through a relative rate measure.
9. Multiplicity and the Three-Arm Design
The ClinicalTrials.gov record shows three randomized arms and two posted primary endpoint analyses. Each formal analysis compares one cladribine dose with placebo. The ClinicalTrials.gov record does not specify an alpha-allocation strategy, multiplicity adjustment procedure, or hierarchical testing sequence for the two active-versus-placebo comparisons.
| Comparison | Primary endpoint | Formal analysis | Reported p-value |
|---|---|---|---|
| Cladribine 5.25 mg/kg vs Placebo | Annualized Qualifying Relapse Rate, Week 96 | Wald Chi-square; Relative Risk | <0.001 |
| Cladribine 3.5 mg/kg vs Placebo | Annualized Qualifying Relapse Rate, Week 96 | Wald Chi-square; Relative Risk | <0.001 |
Because two active treatment groups are each compared with the same placebo group, multiplicity is a design consideration whenever both comparisons contribute to a single confirmatory decision framework. The ClinicalTrials.gov record does not provide enough information to state whether or how the familywise type I error was controlled.
10. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized arm using affected participants over participants at risk.
| Arm | Serious adverse events | Affected / at risk |
|---|---|---|
| Cladribine 5.25 mg/kg | Serious adverse events | 41/454 |
| Cladribine 3.5 mg/kg | Serious adverse events | 36/430 |
| Placebo | Serious adverse events | 28/435 |
5.25 mg/kg
41 affected participants among 454 at risk.
3.5 mg/kg
36 affected participants among 430 at risk.
Placebo
28 affected participants among 435 at risk.
Interpretive role
Safety outcomes are separate from the primary relapse-rate efficacy analysis.
The serious-adverse-event figures should not be conflated with the primary efficacy endpoint. They describe a safety outcome using the affected/at-risk counts reported in the ClinicalTrials.gov record, whereas the primary statistical analysis concerns annualized qualifying relapse rate at Week 96.
11. What the Relative Risk Does — and Does Not — Mean
For both active-dose comparisons, the reported relative risk is 0.43. This means the estimated annualized qualifying relapse rate was 43% of the placebo rate under each posted comparison.
The corresponding relative-rate interpretation is a 57% lower estimated rate. This is not the same as saying that 57% of patients benefited, that 57% of relapses were prevented, or that the absolute relapse probability fell by 57%.
The confidence intervals provide the precision component of the result. The interval is 0.35–0.54 for cladribine 5.25 mg/kg versus placebo and 0.34–0.54 for cladribine 3.5 mg/kg versus placebo.
These intervals describe uncertainty around the estimated relative effect; they do not describe the distribution of individual treatment responses.
Both comparisons have P < 0.001. This quantifies the evidence against the null hypothesis under the reported Wald chi-squared framework. It does not quantify effect magnitude, clinical importance, or the probability that the treatment hypothesis is correct.
The endpoint is an annualized qualifying relapse rate, and the registry labels the effect measure Relative Risk. Because the endpoint is a rate, the reported relative-risk interpretation should be kept tied to the annualized rate rather than silently converting it into an individual patient's probability of relapse.
12. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The two posted primary analyses report relative-risk estimates of 0.43, two-sided 95% confidence intervals below 1, and P < 0.001 under Wald chi-squared testing in the ITT population.
Clinical interpretation
The statistical results describe the relative annualized qualifying relapse rate associated with each cladribine dose compared with placebo. Clinical interpretation should keep that relative measure distinct from absolute relapse rates and from safety outcomes.
13. Missing Data and Analysis Boundaries
The statistical analyses posted on ClinicalTrials.gov identify the ITT population but do not provide a missing-data or imputation procedure. They also do not provide enough information to reconstruct the individual relapse observations or determine how incomplete follow-up contributed to the annualized rate calculation.
| Topic | What the ClinicalTrials.gov record supports |
|---|---|
| Analysis population | ITT; all participants randomized in the study |
| Missing-data method | Not specified in the ClinicalTrials.gov record |
| Imputation | Not specified in the ClinicalTrials.gov record |
| Stratification | Not specified in the ClinicalTrials.gov record |
| Interim analysis | Not specified in the ClinicalTrials.gov record |
| Bayesian methods | Not reported in the ClinicalTrials.gov record |
| Crossover | Not reported in the ClinicalTrials.gov record |
| Non-inferiority margin | Not applicable to the reported superiority hypothesis |
This distinction is important when interpreting a registry-based statistical analysis. A method that is not included in the ClinicalTrials.gov record should not be assumed merely because it is common in similar trials.
14. Limitations
- Registry-level detail: the ClinicalTrials.gov record provides the primary endpoint, formal statistical methods, effect estimates, confidence intervals, p-values, analysis population, and serious-adverse-event counts, but not a complete statistical analysis plan.
- Multiplicity: two active-dose comparisons are reported, but the ClinicalTrials.gov record does not specify an alpha-allocation or multiplicity-adjustment procedure.
- Missing-data methods: the ClinicalTrials.gov record does not specify imputation or other missing-data handling procedures.
- No subgroup estimates: the ClinicalTrials.gov record does not provide subgroup-specific efficacy estimates or interaction tests.
- No absolute relapse rates: the posted primary analyses provide relative-risk estimates but do not supply the underlying group-specific annualized rates in the ClinicalTrials.gov record.
- Relative-risk interpretation: a relative rate of 0.43 does not provide an absolute treatment effect without the corresponding baseline rate.
- Safety interpretation: serious-adverse-event counts should be considered separately from the efficacy endpoint rather than combined into a single numerical benefit-risk statistic.
15. Why This Trial Matters Statistically
CLARITY is a useful teaching case because the ClinicalTrials.gov record connect a randomized three-arm design to an ITT efficacy analysis, a rate-based clinical endpoint, relative-risk estimation, Wald chi-squared testing, confidence intervals, p-values, and a separate safety analysis.
| Concept | How it appears in CLARITY |
|---|---|
| Randomization | The trial is registered as randomized. |
| Parallel design | The three study arms are registered as a parallel design. |
| Blinding | The registry identifies triple masking. |
| ITT analysis | The primary analyses include all participants randomized in the study. |
| Count / rate endpoint | Annualized Qualifying Relapse Rate at Week 96. |
| Relative risk | The primary effect measure is Relative Risk. |
| Chi-squared testing | The reported method is Wald Chi-square. |
| Confidence interval | Both primary analyses report two-sided 95% CIs. |
| P-value | Both primary comparisons report P < 0.001. |
| Superiority | The registered hypothesis type is superiority. |
| Multiple active comparisons | Both cladribine doses are formally compared with placebo. |
| Safety analysis | Serious adverse events are reported by arm as affected / at risk. |
16. A Statistical Reading of the Primary Results
The point estimate indicates a substantially lower estimated annualized qualifying relapse rate in the cladribine group relative to placebo under the posted analysis.
The second active-dose comparison produces the same reported point estimate, with a slightly different lower confidence limit.
Several statistical ideas are visible simultaneously. First, the estimate describes relative effect, not absolute effect. Second, the confidence interval communicates precision. Third, the p-value communicates evidence against the null under the specified test, not effect size. Fourth, the ITT population ties the analysis to the randomized design. Finally, the existence of two active-dose comparisons makes multiplicity an important design question even though the ClinicalTrials.gov record does not state the adjustment procedure.
17. Longitudinal Trial Record
Study start
The registered study start is April 2005.
Primary completion
The registered primary completion date is November 2008.
Final registry status
The ClinicalTrials.gov record identifies the study as completed and reports results for the primary endpoint.
18. Trial Results in Context
The most important numerical feature of the posted CLARITY efficacy analyses is the consistency of the point estimate across the two active-dose comparisons: both report a relative risk of 0.43. The confidence intervals are also similar, although not identical.
| Statistical component | 5.25 mg/kg vs placebo | 3.5 mg/kg vs placebo |
|---|---|---|
| Endpoint | Annualized Qualifying Relapse Rate, Week 96 | Annualized Qualifying Relapse Rate, Week 96 |
| Population | ITT | ITT |
| Method | Wald Chi-square | Wald Chi-square |
| Effect measure | Relative Risk | Relative Risk |
| Estimate | 0.43 | 0.43 |
| 95% CI | 0.35–0.54 | 0.34–0.54 |
| P-value | <0.001 | <0.001 |
The appropriate conclusion from the ClinicalTrials.gov record is therefore specific: both active-dose comparisons produced the posted relative-risk estimates and statistical test results against placebo. The data do not support extending that conclusion to an unreported direct comparison between the two cladribine doses.
19. Related Tutorials
Learn more about the statistical methods and trial-design concepts used in this analysis:
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: NCT00213135 — CLARITY.
- PubMed: PMID 20089960.
- PubMed: PMID 36017797.
- PubMed: PMID 36017780.
- PubMed: PMID 35920065.
- PubMed: PMID 35019731.
Continue through the Clinical Biostats statistical pathway
Use the related tutorials and calculators to explore the statistical concepts represented in the CLARITY analysis.
22. Record Summary
CLARITY is a randomized, parallel, triple-masked phase 3 trial of cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, and placebo in subjects with relapsing-remitting multiple sclerosis. The registered primary endpoint was the annualized qualifying relapse rate at Week 96. Both posted primary analyses used the intention-to-treat population and a Wald chi-squared test, with Relative Risk as the effect measure and superiority as the hypothesis type.
The reported relative risk was 0.43 for both cladribine dose comparisons. The 95% confidence interval was 0.35–0.54 for 5.25 mg/kg versus placebo and 0.34–0.54 for 3.5 mg/kg versus placebo; both comparisons reported P < 0.001. These results indicate lower estimated annualized qualifying relapse rates relative to placebo under the posted analyses, while the relative-risk scale should not be confused with an absolute risk difference or individual treatment benefit.