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 Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer (NCT02096354), a randomized phase 2 study. The primary outcome is Overall Survival.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02096354 |
| Phase | Phase 2 |
| Condition | Colorectal Neoplasms |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 62 |
| Arms in the primary outcome | 2 |
| Lead sponsor | EpicentRx, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
People with advanced or metastatic colorectal cancer were eligible for the study. The registry describes a total enrollment of 62. The arm counts associated with the posted primary medians and the safety summaries are not the same as the total enrollment, and the registry record does not explain the differences between those populations.
Intervention
The experimental sequence was RRx-001 followed by irinotecan if a participant progressed and remained eligible. RRx-001 was given intravenously once weekly at a dose of 4 mg on Days 1, 8, 15, and 22 of a 4-week cycle. The registry’s general description says the later treatment was irinotecan plus bevacizumab when clinically appropriate; the arm description says irinotecan with or without bevacizumab.
Comparator
The comparator sequence was regorafenib followed by irinotecan if a participant progressed and remained eligible. Regorafenib was taken daily on Days 1- 21 of a 4-week cycle. The trial was randomized and open-label, so participants and study personnel were not masked to the assigned treatment. The registry describes a 66% chance of assignment to RRx-001 and a 33 % chance of assignment to regorafenib.
Primary question
The registry names overall survival as the primary outcome and posts median values for the two treatment sequences. However, the endpoint description refers to progression or death, while the timeframe refers to death or censoring. That inconsistency makes the intended endpoint definition unclear from the registry record alone. The posted medians describe each arm separately; a comparative estimate and sponsor-reported test for the primary outcome are not reported in the registry record.
3. Trial Design
This was a randomized, open-label, parallel-group phase 2 study sponsored by EpicentRx, Inc. The registry lists colorectal neoplasms as the condition and a total enrollment of 62. The study started in 2014-05, had primary completion on 2018-04-13, and is recorded as completed. Randomization assigned participants to RRx-001 followed by irinotecan or regorafenib followed by irinotecan. The record describes an allocation chance of 66% for RRx-001 and 33 % for regorafenib.
The planned treatment sequence had two stages. Participants first received their randomized treatment. On progression, participants could enter the second stage if their ECOG performance status was adequate and the investigator considered irinotecan-based therapy clinically appropriate. The general study description specifies irinotecan plus bevacizumab, whereas the arm descriptions allow irinotecan with or without bevacizumab. The registry does not explain how those descriptions relate to one another or how many participants entered the later treatment stage.
Both groups received best supportive care according to the study description. Because the trial was open-label, treatment assignment was known rather than concealed from participants and study personnel after randomization. This can matter when outcomes involve clinical judgments, reporting, or decisions about continued treatment; the registry record does not describe procedures intended to reduce those influences.
The record lists overall survival as the primary outcome, with progression-free survival, adverse events, objective response rate, and clinical benefit rate among the secondary outcomes. It does not report the protocol’s sample-size justification or a detailed statistical analysis plan. The posted primary arm counts are 24 for RRx-001 followed by irinotecan and 10 for regorafenib followed by irinotecan. Those counts do not match the safety populations, and the registry record does not explain the population definitions or the reasons for the differences.
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: 62 participants provided informed consent to participate in the study. Prior to arm assignment, 11 patients dropped out. Thus, 51 participants were eligible to be randomized to a study arm with all 51 receiving treatment on protocol. 34 participants were evaluable and included in the efficacy population within the mITT during the interim analysis. All 51 participants are included in the safety analysis.
Overall Study
| Stage | RRx-001 Followed by Irinotecan | Regorafenib Followed by Irinotecan | Not Randomized |
|---|---|---|---|
| STARTED | 38 | 13 | 11 |
| COMPLETED | 24 | 3 | 0 |
| NOT COMPLETED | 14 | 10 | 11 |
Reasons for not completing this period:
| Reason | RRx-001 Followed by Irinotecan | Regorafenib Followed by Irinotecan | Not Randomized |
|---|---|---|---|
| Physician Decision | 4 | 5 | 0 |
| Withdrawal by Subject | 3 | 1 | 0 |
| Adverse Event | 7 | 4 | 0 |
| Ineligible | 0 | 0 | 11 |
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 | RRx-001 Followed by Irinotecan | Regorafenib Followed by Irinotecan | Not Randomized | Total |
|---|---|---|---|---|---|
| Participants analysed | 38 | 13 | 11 | 62 | |
| Age, Continuous | years | 53.7 (SD 10.41) | 61.2 (SD 11.65) | 58.1 (SD 10.25) | 56.4 (SD 9.33) |
| Sex: Female, Male: Female | Participants | 21 | 9 | 6 | 36 |
| Sex: Female, Male: Male | Participants | 17 | 4 | 5 | 26 |
| Race/Ethnicity, Customized: White | Participants | 21 | 11 | 10 | 42 |
| Race/Ethnicity, Customized: Black or African American | Participants | 5 | 0 | 0 | 5 |
| Race/Ethnicity, Customized: Unknown | Participants | 1 | 0 | 1 | 2 |
| Race/Ethnicity, Customized: Asian | Participants | 11 | 1 | 0 | 12 |
| Race/Ethnicity, Customized: Native Hawaiian or Other Pacific Islander | Participants | 0 | 1 | 0 | 1 |
| Region of Enrollment: United States | participants | 24 | 10 | 11 | 45 |
6. Primary Endpoint
The registry lists the primary outcome as Overall Survival, measured over From date of enrollment until death or censorship..
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | months |
| Endpoint classification | Time-to-Event Analysis |
Overall survival is named as the primary outcome. In general, overall survival measures the time from a defined starting point until death from any cause; participants not known to have died by the analysis cutoff may be censored, meaning their eventual survival time is not yet observed. A median summarizes the time by which half of the population has experienced the event, subject to the endpoint definition and method used. It is a time-to-event summary, not a comparison of the full survival experience between treatment groups.
The registry’s endpoint wording needs particular care. Its timeframe says measurement runs from enrollment until death or censorship, but its description instead says measurement runs from randomization until documented progression or death, whichever came first. That latter event definition is not the same as overall survival. The record does not resolve the inconsistency, so the posted medians should be interpreted with uncertainty about which endpoint definition they represent.
The posted medians are 8.6 months for RRx-001 followed by irinotecan and 4.7 months for regorafenib followed by irinotecan. The associated 95% confidence interval information gives lower limits of 4.8 and 2.2 months, respectively; upper limits are not reported in the registry record. A confidence interval describes uncertainty around an estimate under the analysis method. With only a lower limit available, the interval cannot be fully assessed. The registry record does not include a comparative hazard ratio or sponsor-reported statistical test for this primary outcome.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary results give a median time of 8.6 months in the RRx-001-followed-by-irinotecan group and 4.7 months in the regorafenib-followed-by-irinotecan group. These are separate arm summaries, not a direct estimate of the treatment-group contrast. The registry record does not report a comparative hazard ratio, its confidence interval, or a sponsor-reported primary-outcome test. The difference between the two displayed medians should therefore not be treated as a calculated treatment effect or as evidence from a formal comparison.
Precision is also difficult to judge. The 95% confidence interval information includes a lower limit for each median, but no upper limit is reported. An interval with a missing bound does not communicate the full range of uncertainty. The record also gives arm counts of 24 and 10 alongside the primary outcome, but does not specify the analysis population or explain how those counts relate to the total enrollment of 62. For a time-to-event endpoint, the number and timing of events and the handling of censoring are important to interpretation; those details are not reported in the registry record.
There is a second interpretive issue: overall survival is the outcome title, while the endpoint description refers to progression or death. The timeframe instead refers to death or censoring. Since these definitions do not align, readers cannot confidently determine from the registry wording whether the displayed medians represent overall survival or another time-to-event outcome. The values can be described as posted, but their clinical meaning depends on resolving that endpoint definition.
The secondary clinical benefit result is based on counts of participants meeting that outcome. Its unadjusted comparison is imprecise: the confidence interval for the risk difference includes no difference, and the unadjusted p-value is 0.092. This does not establish equivalence, nor does it establish a treatment effect. The registry record does not report adjusted secondary analyses. Other secondary outcomes are listed, but detailed results for them are not included in the record.
Overall, the record contains descriptive arm-level primary medians and a secondary binary comparison, but does not provide a sponsor-reported comparative primary analysis. The endpoint-definition conflict, incomplete confidence interval information, and unreported analysis details limit what can be concluded from the posted numbers. They do not justify claims that one treatment sequence is superior, equivalent, or ineffective.
9. Statistical Methods Explained
The results involve two different statistical outcome types: a time-to-event summary for the primary outcome and a participant count for clinical benefit. These answer different questions, so their estimates and uncertainty should not be read as interchangeable. The registry does not report enough detail to establish the exact methods used for every posted result.
What does a median time-to-event value describe?
In general, a time-to-event outcome records how long it takes for a defined event to occur. The median is the time by which half of the population has had the event, as estimated under the analysis method. It does not describe the outcome for every participant, and two medians alone do not capture the full pattern of event times. A formal comparison commonly uses information across the observed event times and accounts for participants whose event time is not observed during follow-up. The registry record does not name the primary endpoint analysis method, so no particular estimator or test should be assumed.
Censoring occurs when a participant’s event is not observed before follow-up ends or the participant is otherwise no longer observed for that outcome. Censored participants can contribute information up to the point when their observation ends, but their eventual event time is unknown. The primary outcome timeframe mentions censoring, but the record does not describe the censoring rules, follow-up completeness, or numbers censored. Those details matter when evaluating how robustly the median represents the underlying time-to-event experience.
How should the confidence interval be read?
In general, a confidence interval expresses the uncertainty of an estimate under a specified statistical procedure. A narrower interval indicates greater precision than a wider one, all else being equal; it is not a guarantee that the true value lies inside that particular interval. The registry labels the primary dispersion as a 95% confidence interval, but posts only a lower bound for each median. Without the upper bounds, the intervals cannot be evaluated fully. No comparative interval for the primary outcome is reported in the registry record.
A median in each arm is also not itself a measure of the between-arm effect. A comparison needs an estimate that explicitly contrasts the assigned groups, together with uncertainty and a description of the analysis. A hazard ratio, for example, is a relative comparison of event rates over follow-up under model assumptions; it is not the ratio of the two medians. The registry record does not report a sponsor hazard ratio or another sponsor-reported comparative primary estimate. No missing comparative result should be reconstructed from the two medians.
What does the clinical benefit comparison measure?
Clinical benefit is posted as a binary outcome, represented by the number of participants meeting the outcome in each arm. A risk difference expresses the difference between the proportions in two groups. In general, a risk-difference confidence interval that includes zero is compatible with no difference under the interval procedure, as well as with differences in either direction. The posted unadjusted comparison has a confidence interval that includes zero and an unadjusted p-value of 0.092. This is not proof that the groups are the same; it indicates that the comparison, as reported, does not clearly distinguish a difference from no difference at conventional significance thresholds. No adjustment for multiple testing is reported.
Other measures, such as a risk ratio or odds ratio, express a binary contrast on a different scale. Their interpretation depends on the event definition and the populations used in each arm. Confidence intervals describe uncertainty on their respective scales. The presence of several effect measures for the same outcome does not create independent evidence: they are alternative ways of expressing one comparison based on the same participant counts.
What does the planning illustration mean?
The sample-size illustration is a planning exercise based on fractions of the observed clinical benefit effect, not the trial’s own design justification. It assumes a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. Its entries are participants per arm for 80% power and participants per arm for 90% power under the stated effect assumptions. Such figures describe hypothetical future planning under those assumptions. They are not the observed sample size, do not show the power of this completed trial, and should not be interpreted as evidence that the trial was adequately or inadequately powered. The registry record does not report the original protocol’s sample-size rationale.
Why do populations and analysis details matter?
The primary results are associated with arm counts of 24 and 10, while the adverse-event summaries use populations at risk of 38 and 13. A population at risk for safety reporting need not be identical to an outcome-specific analysis population. The registry does not define these populations or explain the differences, so they cannot be reconciled from the posted record alone. The method for handling missing outcome data, the analysis population for each endpoint, and any covariate adjustment are not reported in the registry record. These omissions limit assessment of bias, precision, and comparability between outcomes.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists several secondary outcomes in addition to the primary outcome. It does not report a multiplicity strategy, such as a prespecified hierarchy of outcomes or an adjustment to account for testing more than one hypothesis. In general, when many outcomes are tested, the chance of at least one apparently positive result arising by chance can increase. Unadjusted p-values should therefore be read as individual comparisons, not as if they automatically controlled the error rate across the complete set of outcomes. The record does not report adjusted secondary analyses.
Missing-data methods are not reported in the registry record. For time-to-event outcomes, relevant details include the rules for censoring and completeness of follow-up. For binary outcomes, the handling of participants without an assessable result can affect the denominator and the comparison. The record does not explain how missing observations, withdrawals, or participants who did not reach later treatment were handled. It would be inappropriate to assume a particular imputation method or that every randomized participant was included in every endpoint analysis.
Analysis populations are also not defined. The primary medians are associated with counts of 24 and 10, while the safety summaries use populations of 38 and 13 at risk. Total enrollment is 62. These figures describe different posted denominators, but the registry does not explain their relationship or specify whether analyses followed an intention-to-treat, per-protocol, or other population definition. Without those definitions, the effects of exclusions or outcome-specific availability cannot be assessed.
The primary endpoint itself is not consistently described: its title says overall survival, while its description refers to progression or death and its timeframe refers to death or censoring. This is not a missing-data detail, but it further limits interpretation of the analysis population and event definition. A protocol-level clarification, analysis plan, and complete endpoint results are not reported in the registry record.
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 |
|---|---|---|---|
| RRx-001 Followed by Irinotecan | 14 | 38 | 36.8% |
| Regorafenib Followed by Irinotecan | 7 | 13 | 53.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| RRx-001 Followed by Irinotecan | 3 of 38 |
| Regorafenib Followed by Irinotecan | 1 of 13 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| RRx-001 Followed by Irinotecan | 19 of 38 |
| Regorafenib Followed by Irinotecan | 10 of 13 |
Most frequent serious adverse event terms
| Event term | Organ system | RRx-001 Followed by Irinotecan | Regorafenib Followed by Irinotecan |
|---|---|---|---|
| Disease progression | General disorders | 3 of 38 | 0 of 13 |
| Abdominal pain | Gastrointestinal disorders | 1 of 38 | 1 of 13 |
| Rectal haemorrhage | Gastrointestinal disorders | 2 of 38 | 0 of 13 |
| Small intestinal obstruction | Gastrointestinal disorders | 2 of 38 | 0 of 13 |
| Infection | Infections and infestations | 2 of 38 | 0 of 13 |
| Pneumonia | Infections and infestations | 2 of 38 | 0 of 13 |
| Mental status changes | Psychiatric disorders | 1 of 38 | 1 of 13 |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | 2 of 38 | 0 of 13 |
| Anaemia | Blood and lymphatic system disorders | 1 of 38 | 0 of 13 |
| Iron deficiency anaemia | Blood and lymphatic system disorders | 1 of 38 | 0 of 13 |
Most frequent non-serious adverse event terms
| Event term | Organ system | RRx-001 Followed by Irinotecan | Regorafenib Followed by Irinotecan |
|---|---|---|---|
| Fatigue | General disorders | 16 of 38 | 7 of 13 |
| Abdominal pain | Gastrointestinal disorders | 9 of 38 | 6 of 13 |
| Infusion related reaction | Injury, poisoning and procedural complications | 13 of 38 | 0 of 13 |
| Diarrhea | Gastrointestinal disorders | 12 of 38 | 1 of 13 |
| Back Pain | Musculoskeletal and connective tissue disorders | 7 of 38 | 4 of 13 |
| Vomiting | Gastrointestinal disorders | 9 of 38 | 2 of 13 |
| Hypertension | Vascular disorders | 6 of 38 | 4 of 13 |
| Disease progression | General disorders | 7 of 38 | 2 of 13 |
| Anorexia | Metabolism and nutrition disorders | 0 of 38 | 9 of 13 |
| Urinary tract infection | Infections and infestations | 6 of 38 | 2 of 13 |
Serious events with the highest arm-level rate: disease progression (7.9%), av malformations (7.7%), abdominal pain (7.7%), abdominal pain lower (7.7%), constipation (7.7%).
The safety summaries report serious adverse events among 14 of 38 participants at risk in the RRx-001-followed-by-irinotecan group and 7 of 13 in the regorafenib-followed-by-irinotecan group. Other adverse events are reported for 19 of 38 and 10 of 13, respectively. The registry also lists 3 deaths in the first group and 1 in the second. These counts should be read alongside their stated populations at risk; they are not the same denominators as the posted primary outcome counts.
Counts alone do not establish that an event was caused by a study treatment, and the registry does not provide enough information to infer causation from the death counts. Nor do these summaries describe event timing, duration, recurrence, exposure-adjusted rates, or the clinical course of individual participants. The record lists disease progression at 7.9% and AV Malformations, abdominal pain, abdominal Pain lower, constipation, and lower Gastrointestinal haemorrhage at 7.7% each among its top serious terms. These listings identify reported terms but do not provide a complete context for comparing safety between groups. Differences in the populations at risk and the absence of a reported adjusted safety comparison warrant descriptive rather than causal interpretation.
12. What the Result Does, and Does Not, Mean
The posted results describe outcomes observed in a randomized, open-label phase 2 study of two treatment sequences. They include arm-specific primary medians, a secondary clinical benefit comparison, and adverse-event counts. These results can inform a reader about what the registry reports, but they do not by themselves establish which sequence is preferable or whether any observed difference is attributable to treatment.
The primary outcome is especially difficult to interpret because the registry uses inconsistent definitions: overall survival is the outcome title, but the description refers to progression or death. Only lower confidence limits for the medians are reported, and no sponsor-reported comparative primary analysis is included. Accordingly, the arm medians should not be treated as a complete treatment-effect estimate or as a definitive test of a difference. The missing definition and comparative analysis prevent a confident interpretation of the primary finding.
The clinical benefit comparison is a secondary result and is unadjusted. Its interval includes no difference, and no multiplicity adjustment is reported. It therefore does not establish either a treatment benefit or equivalence. The remaining listed secondary outcomes lack detailed results in the registry record, so the overall pattern across secondary endpoints cannot be assessed.
Safety counts provide a descriptive account of serious and other adverse events in the stated populations at risk. They do not prove that treatment caused an event or death, and differences in the denominators complicate direct comparison. The record does not supply the detailed event timing, exposure, or analysis information needed for stronger comparative safety conclusions.
These limits do not mean that the study has no informative content. They specify what the posted registry results can support: description of reported outcomes and their uncertainty, not a definitive causal or clinical judgment. Clarification of the primary endpoint, full confidence intervals, defined analysis populations, missing-data methods, and complete sponsor analyses would be needed for a more complete statistical interpretation.
13. Why This Trial Matters Statistically
This trial is statistically notable because several features of the registry record make the distinction between a descriptive result and a comparative result especially important. The study is randomized, but randomization alone does not make every posted arm summary a valid estimate of a treatment effect. The analysis must still define the outcome, use an appropriate population, account for follow-up and censoring, and report a direct comparison with its uncertainty.
The primary outcome illustrates this point. It is titled overall survival, yet the endpoint description refers to progression or death. Those events define different questions. The record posts arm-level medians but no comparative hazard ratio or sponsor-reported primary test, and the confidence interval bounds are incomplete. A reader cannot resolve those limitations by calculating a contrast from the two medians, because such a calculation would not replace the missing time-to-event analysis.
The secondary clinical benefit comparison is also a useful example of uncertainty. The unadjusted result is not conclusive, and its interpretation must account for the fact that multiple outcomes are listed without a reported multiplicity plan. This is a general statistical issue: examining several outcomes can make isolated nominal evidence less persuasive unless the testing strategy is specified in advance.
Finally, posted population counts differ across primary and safety outcomes, and the registry does not define analysis populations or explain the differences. This makes denominator awareness essential. The study therefore matters statistically not because the registry record settles the comparison, but because it shows why endpoint definitions, complete intervals, analysis populations, and prespecified inference plans are necessary for readers to judge the strength and limits of trial evidence.
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 trial-specific limitation is the inconsistent primary endpoint wording. Overall survival appears as the outcome title, the timeframe refers to death or censoring, and the description refers to progression or death. These definitions do not point to one unambiguous event, and the registry record does not resolve the issue. The resulting uncertainty affects interpretation of the posted medians and of what clinical question they answer.
The primary results also have incomplete precision information: lower confidence limits are listed, but upper limits are not reported. The record provides arm counts alongside the medians, but does not explain the analyzed populations, censoring, event counts, or follow-up completeness. No sponsor-reported comparative primary analysis is included. The counts for the primary outcome differ from the safety populations, and the registry does not reconcile them with total enrollment.
The study was open-label, so assignment was known. That can influence subjective assessments and decisions about treatment or follow-up, although the registry does not report whether any particular outcome was affected. The planned second-stage treatment was conditional on progression and eligibility, and the record does not describe how many participants entered it. The general description and arm descriptions also differ on whether bevacizumab was part of the later treatment, without an explanation.
Detailed results are not available in the registry record for several listed secondary outcomes, and no multiplicity strategy or missing-data method is reported. The safety summaries are counts with different populations at risk and do not establish causation. These limitations are specific to the available record; they do not establish that additional information does not exist elsewhere, only that it is not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer — NCT02096354.
- Registry record last updated 2024-10-15; status last verified 2024-09.
- Results first posted 2024-10-15.
- 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
NCT02096354 is a completed, randomized, open-label, parallel-group phase 2 study of RRx-001 followed by irinotecan versus regorafenib followed by irinotecan in metastatic colorectal cancer. The registry lists total enrollment of 62, a start in 2014-05, and primary completion on 2018-04-13.
Overall survival is named as the primary outcome, but the endpoint description and timeframe are inconsistent. The posted arm medians are 8.6 months and 4.7 months, with only lower confidence limits reported. A sponsor-reported comparative primary analysis is not included. Clinical benefit rate is the only secondary endpoint with a detailed comparison in the record described; other listed secondary outcomes lack detailed results. Serious and other adverse-event counts are reported for arm-specific populations at risk. The registry does not report the primary analysis plan, multiplicity strategy, missing-data methods, or analysis-population definitions.