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 Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome (NCT04496960), a randomized phase 1, phase 2 study. The primary outcome is Number of Adverse Events by Grade/Category.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04496960 |
| Phase | Phase 1, Phase 2 |
| Condition | Sjogren's Syndrome |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 23 |
| Arms in the primary outcome | n/a |
| Lead sponsor | National Institute of Dental and Craniofacial Research (NIDCR) |
| Results posted | Yes |
2. Clinical Question
The central question is whether the safety and tolerability of oral tofacitinib can be characterized in adults with Sjogren's syndrome during a controlled clinical trial. The registry describes a randomized, triple-masked, parallel-group study with tofacitinib and placebo arms. Participants were described as having mild to moderate disease activity and taking study capsules twice daily for 168 days.
Population
Adults ages 18-75 with Sjogren's syndrome. The primary endpoint population is identified as the intent-to-treat population.
Intervention
Tofacitinib 5 mg orally twice daily for 168 days.
Comparator
Placebo orally twice daily for 168 days.
Primary question
How many adverse events were recorded by grade or category through day 196, and what were their characteristics?
The primary outcome is a safety measure rather than a measure of disease improvement. The registry also lists changes in Physicians Global Assessment, ESSDAI, unstimulated and stimulated saliva flow, and ESSPRI as secondary outcomes. Their names indicate domains the study planned to assess, but outcome values for them are not reported in the registry record.
The study record lists enrollment of 23 and identifies the study as Phase Ib-IIa. The central statistical issue is how to read descriptive safety counts in a small, randomized study without turning them into a definitive estimate of comparative risk or a claim about treatment benefit.
3. Trial Design
The study is registered as a randomized, triple-masked, parallel-group trial, with tofacitinib and placebo as the two interventions. The registry describes adults with Sjogren's syndrome and mild to moderate disease activity. The tofacitinib regimen is 5 mg orally twice daily; placebo is also taken orally twice daily. Both regimens are described as lasting 168 days.
The registry lists the study phase as Phase Ib-IIa and enrollment as 23. Its status is active, not recruiting. The recorded study start is 2021-05-18 and primary completion is 2025-01-14. These registry entries describe the study record, not necessarily the timing or completeness of every analysis.
Participants were to be screened under a separate protocol. The listed assessments include medical and dental history, physical and disease assessments, heart and eye examinations, salivary gland ultrasound, laboratory testing, saliva collection, and a minor salivary gland biopsy. Some screening tests were to be repeated during the study. The brief summary also describes vascular assessments. The summary is truncated, so further visit details are not reported in the registry record.
Random allocation is intended to reduce systematic differences between treatment groups at the point of assignment. Masking is intended to limit the influence of treatment knowledge on participant experience, clinical assessment, and study conduct. The record identifies triple masking but does not specify in the information available which roles were masked or how masking was maintained.
The primary safety outcome covers adverse events up to day 196. This timeframe extends beyond the described 168-day dosing period, but the schedule of safety assessments after dosing is not reported in the registry record. The record identifies the intent-to-treat population for the primary outcome. Details of any additional analysis populations 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.
Before assignment: 23 Participants were consented * 12 participants started the study * 11 participants were screen failure
Overall Study
| Stage | Drug: Tofacitinib | Placebo |
|---|---|---|
| STARTED | 8 | 4 |
| COMPLETED | 8 | 3 |
| NOT COMPLETED | 0 | 1 |
Reasons for not completing this period:
| Reason | Drug: Tofacitinib | Placebo |
|---|---|---|
| Physician Decision | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Intent to treat population
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 | Drug: Tofacitinib | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 8 | 4 | 12 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 7 | 3 | 10 |
| Age, Categorical: >=65 years | Participants | 1 | 1 | 2 |
| Sex: Female, Male: Female | Participants | 8 | 4 | 12 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 2 | 0 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 6 | 4 | 10 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 6 | 4 | 10 |
| Race (NIH/OMB): More than one race | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Adverse Events by Grade/Category, measured over Up to day 196.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Count of adverse events |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the number of adverse events by grade or category, assessed through day 196. The registry says grading followed the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. This approach classifies events by severity, from mild symptoms or observations through life-threatening consequences and death related to an adverse event.
The registry defines a serious adverse event as any grade 3 or higher event. It separately defines toxicity as any study drug-related grade 3 or higher adverse event. Those definitions are not interchangeable: seriousness follows the stated grade threshold, while toxicity also requires the event to be related to study drug. The record's primary endpoint title concerns adverse-event counts by grade or category; interpretation should retain these distinctions.
Safety endpoints are used to describe the kinds and severity of harms observed during a study and to support monitoring of tolerability. Counts provide a direct description of recorded events, but their meaning depends on the number of participants observed, the follow-up period, event definitions, and completeness of reporting. Counts alone do not establish that an intervention caused an event or quantify a comparative risk with precision.
The posted results list serious-event counts and other adverse-event counts for both arms, along with zero deaths in each arm. They do not reduce the primary endpoint to one comparison across all event categories or grades. A single overall treatment contrast, confidence interval, or hypothesis test is therefore not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety figures are descriptive. For tofacitinib, the record lists 8 at risk and 1 affected for serious adverse events, and 8 at risk and 6 affected for other adverse events. For placebo, it lists 3 at risk and 1 affected for serious adverse events, and 3 at risk and 2 affected for other adverse events. Deaths are listed as 0 in each arm. The registry also identifies “Neutrophil count decreased” as a top serious term with 33.3%.
These counts should be read in the context of the recorded group sizes. The number at risk differs between the arms, with fewer participants listed for placebo. Counts are not rates adjusted for time under observation, and the posted information does not give person-time or a detailed account of exposure and follow-up by participant. It is therefore not possible to interpret the raw counts as a fully adjusted comparison of risk.
The serious-event definition is grade 3 or higher. The separately defined toxicity category requires a grade 3 or higher event to be study drug-related. The serious-event counts should not automatically be read as counts of drug-related toxicity: the registry does not give, in the posted summary, an arm-by-arm cross-tabulation that connects seriousness, grade, and attribution for each event. The listed top serious term is a reported term, but the registry information does not clarify its denominator or provide enough detail to infer the number of participants represented by the percentage.
The difference in the number at risk makes comparisons especially imprecise. With small groups, each observed event can have a substantial influence on a descriptive comparison, and an absence of a listed event does not establish that the underlying risk is zero. Conversely, observing an event does not by itself show that the intervention caused it. These are general statistical considerations; the posted record does not supply a precision estimate for the arm-level safety counts.
No p-value, confidence interval, adjusted effect estimate, or single comparison of the primary outcome is reported in the registry record. The registry lists no analyses. Accordingly, the counts support a description of what was recorded in this study, not a conclusion about the size or certainty of a difference between interventions.
The primary outcome is safety-focused. Although the registry lists several disease-activity, salivary-flow, and patient-reported secondary outcomes, their numerical results are not reported in the registry record. The safety findings should not be taken as evidence about those other outcomes, nor should the study's randomized design be mistaken for a guarantee that the available posted results answer every comparative question.
9. Statistical Methods Explained
The outcome is a count of adverse events classified by grade or category. Count outcomes differ from measurements such as a mean change in a score: they record the number of events or affected participants under a defined classification. Interpretation depends on what the registry counts, how repeated events are handled, and whether the count refers to events or people with events. Those details beyond the stated endpoint and posted group figures are not reported in the registry record.
What does grading contribute?
The registry uses CTCAE Version 5.0 to classify severity. Grade 1 is described as mild, with no intervention indicated. Grade 2 is moderate, with minimal, local, or noninvasive intervention indicated, or activity limitations. Grade 3 is severe or medically significant, potentially involving hospitalization, disability, or limitations in self-care. Grade 4 involves life-threatening consequences requiring urgent intervention. Grade 5 is death related to an adverse event. The registry defines serious as grade 3 or higher and toxicity as a study drug-related grade 3 or higher event. These labels organize clinical safety observations, but they do not substitute for the underlying event descriptions or establish causation.
Why do group sizes matter?
A count is easier to interpret when the number of people observed and the observation period are clear. The posted figures list participants at risk by arm, but the groups are not the same size. Raw counts do not adjust for differences in exposure duration, missed observation, or the possibility that one person experienced more than one event. The record does not report person-time or enough detail to determine whether the listed counts represent unique people or recurrent events across all categories. That uncertainty limits direct comparisons.
In general, a rate uses an event count in relation to an amount of observation or exposure. An incidence proportion instead describes the share of a defined population experiencing an event during a specified period. These are general concepts, not additional calculations for this study. The registry's posted counts should be interpreted according to their stated definitions rather than converted into a rate or proportion that the record does not report.
What would a confidence interval say?
General explanation: a confidence interval expresses the statistical uncertainty around an estimated quantity under the assumptions of the analysis. It helps readers distinguish a precise estimate from one compatible with a wide range of values. No confidence interval for the safety comparison is reported in the registry record. The small recorded groups mean that uncertainty is an important consideration, but no interval should be inferred from the event counts alone.
General explanation: a hypothesis test asks whether observed data are sufficiently inconsistent with a specified null hypothesis under a statistical model. A p-value, if reported, would not measure the probability that an intervention is safe or unsafe, and it would not convey the size or clinical importance of an effect. The registry does not report a p-value or a single hypothesis test for the primary endpoint.
How should multiple event categories be understood?
The primary outcome is described across grades or categories, rather than as one prespecified contrast in the posted results. In general, examining many categories creates multiple opportunities for an apparently notable pattern to arise by chance. Multiplicity methods can be used to control error rates or to distinguish a primary comparison from exploratory comparisons. Which methods were planned or applied is not reported in the registry record. The listed serious-event term should therefore be understood as a descriptive safety detail, not as a standalone statistical test.
General explanation: count data can show greater variability than a simple model assumes, a property often called over-dispersion. When that occurs, methods that explicitly allow extra variability may give more realistic uncertainty than a model that assumes the mean and variance are linked in a restrictive way. The registry record does not report a count-data model, an over-dispersion assessment, or a model-based estimate. This general issue cannot be used to infer which approach the investigators used.
What can randomization and masking establish?
Randomization is intended to make treatment assignment independent of participant characteristics, on average, and can support a fair comparison when allocation and follow-up are handled appropriately. In a small study, randomization does not ensure that groups are identical in every characteristic. Triple masking is intended to reduce bias related to knowledge of assigned treatment, although the specific masked roles and procedures are not reported in the registry record. Neither design feature removes uncertainty from sparse safety counts or missing observations.
The registry identifies the intent-to-treat population for the primary outcome, which generally refers to analyzing participants according to randomized assignment. The operational details of that population, handling of participants who discontinued, missing safety observations, and any alternative analysis populations are not reported in the registry record. No analysis results are listed. The record's sample-size assumptions describe a planning illustration based on a fraction of an observed effect, but the primary endpoint is not reduced to one comparison in the posted results. No comparison-specific planning result is reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary safety endpoint and secondary outcomes covering Physicians Global Assessment, ESSDAI, unstimulated and stimulated saliva flow, and ESSPRI. Considering several outcomes can raise multiplicity concerns: general statistical reasoning recognizes that repeated testing can increase the chance of at least one apparently notable result when all tests are treated as confirmatory. The registry record does not report whether an adjustment for multiplicity was planned or applied, nor does it identify a hierarchy among the secondary outcomes.
The posted results do not include numerical results for the listed secondary outcomes. They also do not report a single analysis of the primary endpoint, a p-value, or a confidence interval. The registry lists no analyses. Without a reported analysis plan and results, it is not possible to determine how outcome comparisons were specified or interpreted.
The primary endpoint identifies the intent-to-treat population. The record does not describe how missing safety observations, withdrawals, interruptions, or incomplete follow-up were handled. The extent and pattern of missing data are not reported in the registry record. A complete-case analysis, imputation, or any other missing-data method should not be assumed.
In general, missing data can affect interpretation when the chance of an observation being missing is related to treatment assignment, health status, or an adverse event. A transparent report would describe the amount and timing of missingness and the method used to address it. Those details are not reported in the registry record, so the posted counts cannot establish how complete the outcome ascertainment was.
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 |
|---|---|---|---|
| Drug: Tofacitinib | 1 | 8 | 12.5% |
| Placebo | 1 | 3 | 33.3% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Drug: Tofacitinib | 0 of 8 |
| Placebo | 0 of 3 |
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 |
|---|---|
| Drug: Tofacitinib | 6 of 8 |
| Placebo | 2 of 3 |
Most frequent serious adverse event terms
| Event term | Organ system | Drug: Tofacitinib | Placebo |
|---|---|---|---|
| Neutrophil count decreased | Investigations | 1 of 8 | 1 of 3 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Drug: Tofacitinib | Placebo |
|---|---|---|---|
| Upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | 5 of 8 | 1 of 3 |
| Oral candidiasis | Infections and infestations | 1 of 8 | 1 of 3 |
| Urinary tract infection | Infections and infestations | 2 of 8 | 0 of 3 |
| Abdominal pain | Gastrointestinal disorders | 1 of 8 | 0 of 3 |
| Diarrhoea | Gastrointestinal disorders | 1 of 8 | 0 of 3 |
| Nausea | Gastrointestinal disorders | 0 of 8 | 1 of 3 |
| Salivary gland calculus | Gastrointestinal disorders | 1 of 8 | 0 of 3 |
| Vomiting | Gastrointestinal disorders | 1 of 8 | 0 of 3 |
| Allergy to arthropod sting | Immune system disorders | 1 of 8 | 0 of 3 |
| Herpes simplex reactivation | Infections and infestations | 0 of 8 | 1 of 3 |
Serious events with the highest arm-level rate: neutrophil count decreased (33.3%).
The serious adverse-event figures list 1 affected out of 8 at risk for tofacitinib and 1 affected out of 3 at risk for placebo. Serious is defined in the registry as any grade 3 or higher adverse event. The other adverse-event figures list 6 affected out of 8 at risk for tofacitinib and 2 affected out of 3 at risk for placebo. Deaths are recorded as 0 in both arms.
These are counts from groups of different sizes, not a precision-adjusted comparison. They should not be read as proof that one intervention has more or fewer harms. The record does not provide a confidence interval, comparative test, person-time, or sufficient detail to determine the effect of differences in exposure and follow-up on the counts.
The registry separately defines toxicity as a study drug-related grade 3 or higher event. That attribution requirement is distinct from the serious-event definition. The posted group figures do not establish that every serious event was caused by study drug. “Neutrophil count decreased” is listed as a top serious term with 33.3%, but the denominator and additional context for that percentage are not reported in the registry record. The figures describe recorded safety observations, not a general prediction for other patients or settings.
12. What the Result Does, and Does Not, Mean
The registry describes a randomized, triple-masked study of tofacitinib and placebo in people with Sjogren's syndrome. Its primary outcome concerns adverse events by grade or category through day 196. The posted safety data list serious and other adverse-event counts for each arm, as well as zero deaths in each arm. These observations provide a limited description of events recorded in the study population.
They do not establish that tofacitinib caused or prevented any particular event. The registry's definition of serious events is based on grade, while its definition of toxicity also requires a relationship to study drug. The posted counts do not provide enough detail to equate serious events with drug-related toxicity. The “Neutrophil count decreased” term is listed as a top serious term, but the available record does not explain the percentage's denominator.
The data also do not establish a precise difference between the intervention groups. The groups have different numbers at risk, the counts are small, and no confidence interval or comparative test is reported. A zero recorded death count in both arms is an observation from this study record; it does not establish absence of risk. Likewise, the event counts should not be generalized beyond the trial population and observation period without supporting evidence.
The registry lists changes in disease activity, salivary flow, and patient-reported symptoms as secondary outcomes, but their numerical results are not reported in the registry record. The safety results therefore do not answer whether those measures changed or differed between groups. Nor does the study's early-phase designation alone establish efficacy, safety in broader populations, or long-term outcomes.
In general, randomized comparisons can help evaluate treatment effects, but their conclusions depend on complete outcome reporting, appropriate analyses, and sufficient precision. The posted record allows a description of selected safety counts, not a definitive judgment about comparative safety or treatment benefit.
13. Why This Trial Matters Statistically
This trial raises a useful statistical question: how much can be learned from adverse-event counts when a study has small groups and several event categories? The registry reports an enrollment of 23 and gives at-risk counts of 8 for tofacitinib and 3 for placebo in the posted safety figures. Such counts can identify events requiring attention, but they leave substantial uncertainty about the size of any underlying difference.
Safety reporting is not only about whether an event appears in a list. Readers need to know how events were defined and graded, how many people were observed, how long they were followed, whether events were recurrent, and whether investigators considered them related to study drug. The registry defines serious events and toxicity separately, which underscores why severity and attribution should not be treated as the same concept.
The randomized, masked design is relevant because it aims to limit bias in treatment assignment and outcome assessment. Yet good design does not remove the need for transparent analysis reporting. The registry does not report a single primary-endpoint comparison, a precision estimate, the handling of missing data, or the multiplicity approach. Those omissions restrict what can be concluded from the posted counts.
The listed secondary outcomes also illustrate why a trial's statistical interpretation depends on more than its primary endpoint. Disease activity, salivary function, and patient-reported measures may answer distinct questions, but their numerical results are not reported in the registry record. Keeping descriptive safety evidence separate from unreported secondary findings helps prevent a narrow set of observations from being interpreted as a broader claim about treatment effects.
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 interpretation is that the registry's primary endpoint spans adverse-event grades or categories but is not reduced to one comparative estimate in the posted results. No confidence interval, p-value, adjusted estimate, or full category-by-grade breakdown is reported. This prevents assessment of comparative precision and makes it difficult to distinguish a broad safety pattern from individual event details.
The safety groups are small and unequal in the posted figures: 8 are listed at risk for tofacitinib and 3 for placebo. The record does not provide person-time, detailed exposure duration by participant, or enough information to establish how repeat events were counted. The numerical summaries therefore cannot be interpreted as exposure-adjusted rates.
The registry's serious-event and toxicity definitions are distinct, but the posted results do not provide a complete account of attribution by arm and grade. The denominator for the 33.3% associated with “Neutrophil count decreased” is not reported in the registry record. Details about event onset, duration, resolution, and recurrence are also not reported in the registry record.
The record identifies the intent-to-treat population for the primary outcome but does not describe missing-data handling, withdrawals, or completeness of follow-up. The multiplicity strategy and detailed statistical analysis plan are not reported in the registry record. Numerical findings for the listed secondary outcomes are not reported either.
Finally, the study is described as Phase Ib-IIa, with an enrollment of 23 and a treatment period of 168 days. The available safety observations should be interpreted within that study context; the registry does not supply evidence for outcomes outside the reported population and follow-up.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome — NCT04496960.
- Registry record last updated 2025-12-18; status last verified 2025-12-03.
- Results first posted 2025-12-18.
- 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
The registry identifies NCT04496960 as a randomized, triple-masked, parallel-group Phase Ib-IIa trial of tofacitinib versus placebo in Sjogren's syndrome. Enrollment is listed as 23, and the status is active, not recruiting. The recorded study start is 2021-05-18 and primary completion is 2025-01-14.
The primary outcome is the number of adverse events by grade or category through day 196, assessed using CTCAE Version 5.0. The registry defines serious events as grade 3 or higher and toxicity as a study drug-related grade 3 or higher event. Posted safety counts include serious and other adverse events by arm and zero deaths in each arm. A single comparative analysis of the primary outcome is not reported in the registry record.
Secondary outcomes concern physician-assessed disease activity, salivary flow, and patient-reported symptoms. Their results, detailed missing-data methods, and multiplicity procedures are not reported in the registry record. The available record supports a descriptive reading of the posted safety observations, not a precise comparative conclusion.