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 Vision Restoration With a Collagen Crosslinked Boston Keratoprosthesis Unit (NCT02863809), a randomized phase 1, phase 2 study. The primary outcome is Time From Surgery to Device Loss or Replacement.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02863809 |
| Phase | Phase 1, Phase 2 |
| Condition | Keratolysis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 76 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Joseph B. Ciolino, MD |
| Results posted | Yes |
2. Clinical Question
Population
The trial enrolled people considered candidates for high-risk keratoprosthesis implantation who were not candidates for a traditional corneal transplant because of a history of corneal melts or autoimmune diseases. The condition listed in the registry record is keratolysis. The record does not provide further eligibility detail or describe the characteristics of the enrolled participants.
Intervention
The active treatment involved de-epithelialized corneas treated with riboflavin 0.1% and dextran 20% solution, followed by ultraviolet A light. The clinical question concerns whether adding ultraviolet A exposure as part of corneal collagen cross-linking is associated with a different time to device loss or replacement than the vehicle procedure.
Comparator
The control procedure used de-epithelialized corneas exposed to riboflavin 0.1% and dextran 20% solution without ultraviolet A light. This comparison is designed to distinguish the active cross-linking procedure from exposure to the solution alone. The record describes the study as vehicle-controlled, randomized, and double-masked, but does not report how masking was implemented.
Primary question
The primary outcome is time from surgery to device loss or replacement, summarized as median weeks from surgery to removal over a timeframe of 2 years. The posted medians are 95.0 weeks in the active treatment arm and 34.0 weeks in the control treatment arm. The inter-quartile ranges are 60.0 to 117.0 weeks and 11.0 to 66.0 weeks, respectively. These summaries describe the recorded outcome; the registry record does not include an inferential comparison for this endpoint, such as a hazard ratio or confidence interval.
3. Trial Design
The registry describes a Phase I/II, prospective, randomized, multicenter, double-masked, vehicle-controlled, parallel-group trial. The study is listed as completed. Its enrollment is 76, and the registry record lists a start date of 2017-03-15 and a primary completion date of 2021-06-30. These record-level details describe the planned and registered study, but do not by themselves establish how many participants contributed data to each outcome.
The two groups differed in whether the corneal carrier tissue received ultraviolet A exposure. In the active treatment arm, de-epithelialized corneas were treated with riboflavin 0.1% and dextran 20% solution and ultraviolet A light. In the control treatment arm, the same solution was used without ultraviolet A light. The registry lists riboflavin, dextran, and a UVA light source as interventions. It does not report further procedural detail, such as treatment duration or the method used to conceal allocation.
The primary endpoint was time from surgery to device loss or replacement, with median weeks from surgery to removal as the stated summary measure and a 2-year timeframe. The active arm lists 33.0 participants and the control arm lists 34.0 for this endpoint. The posted median and inter-quartile range are descriptive summaries. No statistical analysis of the primary endpoint is listed in the registry record. The record also lists four secondary outcomes, including Kpro retention at 12 months and delayed epithelial healing events at day 30. Results are posted for two secondary outcomes; reported analyses are not listed.
The record does not report the sample-size justification, the intended analysis population, details of follow-up or censoring, or whether any interim analyses were planned. It also does not describe the masking procedures or the specific statistical plan. Those omissions limit interpretation of how the study was intended to handle incomplete follow-up and compare the randomized groups.
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: 76 subjects enrolled - signed consent form * 5 screen fails (did not meet eligibility criteria); * 1 withdrawal (signed consent form but declined to participate before randomization occurred) * 2 other (signed consent forms but were not able to receive surgery due to COVID-19 restrictions)
Overall Study
| Stage | Active Treatment Arm | Control Treatment Arm |
|---|---|---|
| STARTED | 34 | 34 |
| Screen Fail (Post Randomization) | 1 | 0 |
| COMPLETED | 24 | 24 |
| NOT COMPLETED | 10 | 10 |
Reasons for not completing this period:
| Reason | Active Treatment Arm | Control Treatment Arm |
|---|---|---|
| Adverse Event | 8 | 8 |
| Withdrawal by Subject | 0 | 1 |
| Lost to Follow-up | 1 | 1 |
| Death | 1 | 0 |
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: Participants receiving cross-linked (CXL) versus non-cross-linked (non-CXL) donor corneas (One subject who was randomized in the active arm (CXL corneal carrier) was excluded from efficacy analysis due to not meeting the inclusion criteria)
| Characteristic | Unit | Active Treatment Arm | Control Treatment Arm | Total |
|---|---|---|---|---|
| Participants analysed | 33 | 34 | 67 | |
| Age, Continuous | years | 61.8 (SD 15.3) | 62.8 (SD 16.9) | 62.3 (SD 15.89) |
| Sex: Female, Male: Female | Participants | 20 | 21 | 41 |
| Sex: Female, Male: Male | Participants | 13 | 13 | 26 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 4 | 5 | 9 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 29 | 29 | 58 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): Asian | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 4 | 6 | 10 |
| Race (NIH/OMB): White | Participants | 20 | 23 | 43 |
| Race (NIH/OMB): More than one race | Participants | 5 | 5 | 10 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Previous sterile keratolysis | Participants | 28 | 28 | 56 |
| Autoimmune disease: Steven Johnson Syndrome | Participants | 3 | 4 | 7 |
| Autoimmune disease: Rheumatoid Arthritis | Participants | 1 | 3 | 4 |
| Autoimmune disease: Graft Versus Host Disease | Participants | 1 | 1 | 2 |
| Autoimmune disease: Mucus Membrane Pemphigoid | Participants | 1 | 0 | 1 |
| Autoimmune disease: Vogt-Koyangi-Harada Syndrome | Participants | 1 | 0 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Time From Surgery to Device Loss or Replacement, measured over 2 years.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | median weeks from surgery to removal |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint measures the time from surgery until device loss or replacement. The registry describes recording the time and reason when a device fails after surgery, and states that device losses in the control group would be compared with those in the investigational group. The outcome is summarized as median weeks from surgery to removal, with an inter-quartile range, over a timeframe of 2 years.
Time-to-event outcomes can retain information about when an event occurs, not only whether it occurred. In general, this can be useful when participants have different lengths of follow-up or when some have not experienced the event by the end of observation. Proper interpretation then depends on how follow-up and censoring are defined and analyzed. The registry record does not report those details for this endpoint.
The posted medians are 95.0 weeks for the active treatment arm and 34.0 weeks for the control treatment arm. Their inter-quartile ranges are 60.0 to 117.0 weeks and 11.0 to 66.0 weeks, respectively. These summaries give the middle of each observed distribution and its central spread; they do not, by themselves, establish a treatment effect. No hazard ratio, confidence interval, or sponsor-reported inferential comparison for the primary endpoint is listed in the registry record. The endpoint description also refers to comparing numbers of device losses, while the posted result is a median time. The record does not explain the relationship between those formulations.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The primary result is descriptive. The median time from surgery to device loss or replacement is 95.0 weeks in the active treatment arm, with an inter-quartile range of 60.0 to 117.0 weeks. In the control treatment arm, the median is 34.0 weeks, with an inter-quartile range of 11.0 to 66.0 weeks. These values describe the observed summaries in the registry record. They do not establish the size or precision of a between-group treatment effect.
No sponsor-reported hazard ratio, confidence interval, or p-value for the primary endpoint appears in the registry record. The record lists no analyses. A median in each group is not a substitute for a formal time-to-event comparison: it does not show how the full event-time distributions compare, account for censoring, or quantify uncertainty in the contrast. The registry's primary endpoint description refers to comparing device losses, but the posted result is expressed as median weeks from surgery to removal. No additional details clarify the endpoint analysis or explain that distinction.
The posted secondary outcomes include counts for Kpro retention at 12 months and delayed epithelial healing events at day 30. The accompanying unadjusted calculations are explicitly recalculations from posted summary statistics, not analyses reported by the sponsor. For retention, the recalculated risk difference is 0.085, with a confidence interval from -0.091 to 0.260 and p = 0.35. For delayed epithelial healing, the recalculated risk difference is 0.009, with a confidence interval from -0.210 to 0.228 and p = 0.936. Both intervals include zero, so these data do not provide a precise unadjusted difference between groups. The interval widths also indicate substantial uncertainty.
These secondary comparisons should not be treated as confirmation or refutation of the primary endpoint. They concern different outcomes and timeframes, and the registry record does not report a prespecified multiplicity strategy or sponsor analyses for them. Their p-values are unadjusted recalculations. The primary outcome itself lacks a posted inferential comparison, so the registry results do not support a formal conclusion about the relative time to device loss or replacement. Interpretation should remain limited to the recorded summaries and the uncertainty evident in the secondary calculations.
9. Statistical Methods Explained
What does a median describe?
A median is the midpoint of an observed distribution: half of the observations lie at or below it and half at or above it, subject to the way the data are recorded. It is often useful when outcomes are skewed or when a typical time is more informative than an arithmetic average. The inter-quartile range describes the central half of the distribution, from the 25th percentile to the 75th percentile. It conveys spread but is not a confidence interval for the median and does not quantify the uncertainty in a comparison between groups.
For the primary endpoint, the posted median is 95.0 weeks in the active treatment arm and 34.0 weeks in the control treatment arm. The corresponding inter-quartile ranges are 60.0 to 117.0 weeks and 11.0 to 66.0 weeks. These summaries do not show how many devices were lost, whether follow-up differed between participants, or how participants without a recorded event were handled. Such information is important in time-to-event analyses and is not reported in the registry record.
Why can a time-to-event comparison need more than medians?
In general, a time-to-event method uses the timing of events and can account for participants whose event has not been observed by the end of follow-up, provided the censoring information and analysis are handled appropriately. A hazard ratio is one common summary of a relative event rate over follow-up, while a confidence interval expresses uncertainty around an estimate. Neither a hazard ratio nor a confidence interval for the primary endpoint is reported in the registry record. The record also does not identify an analysis method, give event counts, describe censoring, or report whether the assumptions of any time-to-event model were assessed. Consequently, a formal comparative interpretation cannot be reconstructed from the posted medians alone.
How should the secondary risk differences be read?
The secondary calculations compare the observed proportions of participants with each outcome. A risk difference is the active-arm proportion minus the control-arm proportion in the stated comparison. A value above zero means the observed proportion was higher in the active arm; a value below zero means it was lower. A confidence interval gives a range of values compatible with the data under the calculation's assumptions. When an interval includes zero, the results are compatible with no difference as well as with differences in either direction. This is not proof that the groups are identical.
For Kpro retention at 12 months, the recalculated risk difference is 0.085, with a confidence interval from -0.091 to 0.260 and an unadjusted p-value of 0.35. The posted proportions are 0.794 in the control arm and 0.879 in the active arm. For delayed epithelial healing events at day 30, the recalculated risk difference is 0.009, with a confidence interval from -0.210 to 0.228 and an unadjusted p-value of 0.936. The posted proportions are 0.294 in the control arm and 0.303 in the active arm. These calculations are unadjusted re-calculations from the posted summary statistics; they are not listed as sponsor-reported analyses in the registry record.
A p-value measures how unusual data at least as incompatible with a specified null model would be, if that model and the calculation assumptions were correct. It does not give the probability that the null hypothesis is true, and it does not measure clinical importance. Because the secondary results are unadjusted and the record does not report a multiplicity plan, their p-values should be interpreted cautiously rather than as stand-alone confirmatory evidence.
What do the sample-size illustrations mean?
The sample-size illustrations are based on the observed secondary effects, not on the trial's own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation. The displayed scenarios plan for 100%, 75%, or 50% of the observed effect and give participants per arm for 80% power and participants per arm for 90% power. These are planning illustrations. They are not observed power, do not show the power achieved by this trial, and do not establish that the study was planned using those assumptions.
In general, planning estimates can become very large when the effect assumed for a future study is small relative to the variability and event frequency in the available data. Observed effects are uncertain, especially when based on limited samples, so using them directly as the target for a future study can produce unstable planning estimates. The registry record does not report the original sample-size justification, the planned detectable effect, or whether a different design calculation was used.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report a multiplicity strategy for the primary and secondary outcomes. This matters because separate tests across multiple outcomes can increase the chance of observing a small p-value even when there is no underlying effect. The two posted secondary p-values are unadjusted recalculations, and no sponsor-reported analysis is listed. They should therefore be read as exploratory descriptions of the posted summaries, not as a controlled set of confirmatory tests.
The record lists four secondary outcomes, but results are posted for two. It does not report why results for the other listed secondary outcomes are absent, whether they were measured, or whether their analyses were omitted for another reason. The record also does not report a hierarchy for interpreting outcomes or specify whether the primary endpoint was intended to be tested before the secondary endpoints.
Information on missing data is not reported in the registry record. There is no description of the amount or pattern of missing outcome data, how incomplete follow-up was handled, or whether any imputation or sensitivity analysis was planned. This is particularly relevant to the primary time-to-event endpoint, for which censoring and follow-up details affect interpretation. The record does not identify the analysis population, such as an intention-to-treat population or a population defined by treatment received, and does not explain how deviations from assigned treatment would be handled.
These omissions do not establish that the trial used an inappropriate method; they mean that the registry record does not allow readers to assess those choices. The reported arm summaries can be described as posted, while the intended analysis plan, missing-data handling, and multiplicity control remain unknown. This limits the strength of inferences that can be drawn from the registry results.
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 |
|---|---|---|---|
| Active Treatment Arm | 6 | 34 | 17.6% |
| Control Treatment Arm | 10 | 34 | 29.4% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Active Treatment Arm | 1 of 34 |
| Control Treatment Arm | 0 of 34 |
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 |
|---|---|
| Active Treatment Arm | 17 of 34 |
| Control Treatment Arm | 16 of 34 |
Most frequent serious adverse event terms
| Event term | Organ system | Active Treatment Arm | Control Treatment Arm |
|---|---|---|---|
| Corneal Melt | Eye disorders | 2 of 34 | 3 of 34 |
| Infection | Eye disorders | 2 of 34 | 1 of 34 |
| High Intraocular Pressure | Eye disorders | 0 of 34 | 1 of 34 |
| Choroidal Detachment | Eye disorders | 1 of 34 | 0 of 34 |
| Endophthalmitis | Eye disorders | 1 of 34 | 0 of 34 |
| Retinal Detachment | Eye disorders | 0 of 34 | 1 of 34 |
| Complication of corneal transplant | Eye disorders | 0 of 34 | 1 of 34 |
| Persistent Epithelial Defect | Eye disorders | 0 of 34 | 1 of 34 |
| Epiretinal membrane | Eye disorders | 0 of 34 | 1 of 34 |
| Wound Dehiscence | Eye disorders | 0 of 34 | 1 of 34 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Active Treatment Arm | Control Treatment Arm |
|---|---|---|---|
| Retroprosthetic Membrane | Eye disorders | 4 of 34 | 3 of 34 |
| Vitreous | Eye disorders | 2 of 34 | 5 of 34 |
| EPI Defect | Eye disorders | 3 of 34 | 3 of 34 |
| Eye Pain (discomfort) | Eye disorders | 2 of 34 | 3 of 34 |
| High Intraocular Pressure | Eye disorders | 2 of 34 | 2 of 34 |
| Corneal Thinning | Eye disorders | 1 of 34 | 2 of 34 |
| Loose suture | Eye disorders | 2 of 34 | 1 of 34 |
| Hemmorrge | Eye disorders | 3 of 34 | 0 of 34 |
Serious events with the highest arm-level rate: corneal melt (8.8%), infection (5.9%), high intraocular pressure (2.9%), choroidal detachment (2.9%), endophthalmitis (2.9%).
For serious adverse events, the registry lists 6 affected participants among 34 at risk in the active treatment arm and 10 among 34 at risk in the control treatment arm. For other adverse events, it lists 17 among 34 at risk in the active arm and 16 among 34 at risk in the control arm. The record lists 1 death in the active treatment arm and 0 in the control treatment arm. These are descriptive counts; they do not establish that an event was caused by the intervention or that the groups differ in risk.
The registry's listed serious adverse event terms include Corneal Melt at 8.8%, Infection at 5.9%, and High Intraocular Pressure, Choroidal Detachment, Endophthalmitis, and Retinal Detachment at 2.9% each. These percentages describe the registry's listed terms. The record does not provide enough detail to determine whether participants could contribute to more than one term or how the term percentages were calculated.
The primary endpoint arm counts are 33.0 and 34.0, while the adverse event records list 34 participants at risk in each arm. The registry does not explain the difference in denominators across these results. Adverse event counts should be interpreted in the context of that reporting and the limited detail on event timing, severity, attribution, and follow-up.
12. What the Result Does, and Does Not, Mean
The posted primary endpoint summaries show different medians in the two arms: 95.0 weeks in the active treatment arm and 34.0 weeks in the control treatment arm. The inter-quartile ranges also describe the spread of recorded times in each group. These are observations from the registry record, not a formal estimate of the comparative treatment effect. Without an inferential analysis, event counts, and information about follow-up and censoring, the difference between the medians cannot be interpreted as a precise causal effect.
The secondary recalculations likewise do not establish a definitive difference. Their confidence intervals include zero and are broad, leaving uncertainty about the direction and size of any group contrast. The unadjusted p-values do not account for testing multiple outcomes, and the registry does not list sponsor-reported analyses for these secondary results. The outcomes also measure different events and timepoints, so they cannot be combined into a single conclusion about the primary endpoint.
These findings do not show that the intervention works or does not work. A descriptive contrast is not equivalent to evidence of efficacy, and a non-significant p-value is not evidence that two treatments are equivalent. Equivalence or non-inferiority conclusions require specific design choices and analyses that are not reported in the registry record.
In general, trial results are best interpreted alongside the planned analysis, completeness of follow-up, participant characteristics, and the full outcome data. The registry record does not report several of these details, including the primary endpoint's comparative analysis, missing-data handling, analysis population, and multiplicity plan. The appropriate conclusion is therefore limited: the record reports arm-level medians for the primary endpoint and selected secondary summaries, but does not provide enough statistical detail to quantify a reliable primary between-group effect or its uncertainty.
13. Why This Trial Matters Statistically
This trial raises a central statistical issue in clinical research: a clinically important time-to-event question is summarized in the registry by group medians, but the record does not include a comparative time-to-event analysis. Medians and inter-quartile ranges are useful descriptions, yet they do not show how uncertainty in the group contrast was assessed or how participants without an observed event contributed to the analysis. For a time-to-event endpoint, those details can substantially shape interpretation.
The registry also illustrates why outcome definitions and analysis summaries need to align clearly. The primary endpoint title concerns time from surgery to device loss or replacement, and the description refers to comparing numbers of device losses. The posted measure is median weeks from surgery to removal. The record does not explain how these formulations connect, nor does it give an event count or a hazard ratio. Clear reporting would allow readers to understand what event was analyzed, what time origin was used, and how incomplete follow-up was treated.
The secondary outcomes emphasize another statistical concern: several outcomes can be registered, but only some may have results or inferential analyses reported. Without a stated multiplicity plan, unadjusted results deserve cautious interpretation. The sample-size illustrations also show why planning should be based on prespecified assumptions rather than automatically treating an observed effect as a reliable target. The registry explicitly describes the illustrations as based on observed effects, not as the trial's design justification.
For clinicians and researchers, the record is useful for identifying the randomized comparison and the outcomes registered, but it also demonstrates the importance of complete statistical reporting. A transparent analysis plan, event and follow-up information, and clear reporting of missing data and analysis populations would make the results easier to assess. Their absence in the registry record limits inference; it does not, by itself, establish a flaw in the conduct of the trial.
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.
Several limitations specific to this record constrain interpretation. First, the primary result is presented as arm-level medians and inter-quartile ranges without a reported hazard ratio, confidence interval, p-value, or other inferential comparison. Event counts, censoring information, and details of follow-up are also not reported in the registry record. As a result, the time-to-event contrast cannot be evaluated for precision or reconstructed from the summaries.
Second, the registry lists an enrollment of 76, while the primary outcome arms list 33.0 and 34.0 participants. The adverse event records list 34 participants at risk in each arm. The record does not explain these different denominators or indicate how many participants were randomized, treated, followed, or included in each analysis. No assumption should be made about the reasons for the differences.
Third, the registry record does not report the statistical analysis plan, sample-size justification, analysis population, missing-data approach, or multiplicity strategy. It does not explain why results for two of the four listed secondary outcomes are absent. These gaps prevent assessment of whether outcome selection, analysis decisions, or incomplete follow-up may have influenced the posted results.
Finally, the trial description identifies a high-risk population with a history of corneal melts or autoimmune diseases that made participants unsuitable for a traditional corneal transplant, but detailed participant characteristics are not reported. The record does not give further information about the settings or participants that would help assess how broadly the results apply. These limitations describe what cannot be established from the registry record; they do not demonstrate that the study methods were deficient.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Vision Restoration With a Collagen Crosslinked Boston Keratoprosthesis Unit — NCT02863809.
- Registry record last updated 2023-05-10; status last verified 2023-04.
- Results first posted 2023-05-10.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT02863809 is a completed Phase I/II randomized, multicenter, double-masked, vehicle-controlled, parallel-group trial of corneal collagen cross-linking of keratoprosthesis carrier tissue in high-risk implantation. The registry lists enrollment of 76 and a primary completion date of 2021-06-30. The active procedure used riboflavin 0.1% and dextran 20% solution with ultraviolet A light; the control used the solution without ultraviolet A light.
The primary endpoint was time from surgery to device loss or replacement, summarized by median weeks from surgery to removal over 2 years. The posted median is 95.0 weeks for the active arm and 34.0 weeks for the control arm. No inferential primary analysis is listed. Two secondary outcomes have posted results and unadjusted recalculations, but sponsor-reported analyses are not listed. Details of the statistical plan, missing data, analysis populations, and multiplicity handling are not reported in the registry record.