Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2) (NCT03738618), a randomized phase 3 study. The primary outcome is Cumulative Ongoing Pregnancy Rate After the Fresh Cycle and Cryopreserved Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation (COS).

2. Clinical Question

The primary result is a comparison of the percentage of participants meeting that pregnancy definition across the specified fresh and cryopreserved cycles. The registry reports 43.3% in the FE 999049 group and 0.0% in the placebo group. These figures describe the posted outcome in the trial’s stated analysis population; they are not a guarantee of what would occur in another study or for an individual.

The timing matters to interpretation. The endpoint combines the fresh cycle with eligible cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation, while pregnancy status is assessed 8-9 weeks after transfer. The registry gives the timeframe as up to approximately 16 months after stimulation began. The result therefore concerns cumulative outcomes across those specified cycles, rather than only an outcome from the initial fresh cycle.

3. Trial Design

The registry describes RITA-2 as a phase 3, randomized, double-blind, placebo-controlled, parallel-groups, multicenter trial. It records quadruple masking. The study compared FE 999049 (follitropin delta) with placebo among women aged 35-42 years undergoing assisted reproductive technology. The registry lists an enrollment of 588 and marks the trial completed. The recorded start date is 2018-10-29, and the primary completion date is 2020-12-21.

For the primary outcome, the mITT analysis set comprised all randomized and exposed participants. Participants were analyzed according to planned treatment. The posted arm summaries list 533 participants for FE 999049 and 54 for placebo. The outcome values are percentages of participants: 43.3% for FE 999049 and 0.0% for placebo. The posted event counts used in the unadjusted recalculation are 231 and 0, respectively. These counts and arm summaries are reported as recorded; no further assumptions about treatment exposure, follow-up, or participant flow should be inferred from them.

The primary endpoint was cumulative ongoing pregnancy after the fresh cycle and cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. The record defines ongoing pregnancy as at least one intrauterine viable fetus 8-9 weeks after transfer. The stated timeframe is 8-9 weeks after transfer, up to approximately 16 months after stimulation began.

The registry also lists 69 outcome measures and 12 analyses. It lists secondary outcomes spanning pregnancy, implantation, treatment timing, and laboratory outcomes. The record does not report the rationale for the enrollment target, a sample-size justification, interim analyses, or further details about the allocation procedure. Those aspects should not be inferred from the trial’s phase or design labels.

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: In total, 666 participants were screened of which 588 participants were randomized. Of the randomized participants, 587 participants were exposed to the investigational medicinal product (IMP): 533 to FE 999049 (Follitropin Delta) and 54 to Placebo. One participant was randomization failure and did not receive the IMP.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The mITT analysis set comprised all randomized and exposed participants. Participants were analyzed according to planned treatment.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The mITT analysis set comprised all randomized and exposed participants. Participants were analyzed according to planned treatment.

6. Primary Endpoint

The registry lists the primary outcome as Cumulative Ongoing Pregnancy Rate After the Fresh Cycle and Cryopreserved Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation (COS), measured over 8-9 weeks after transfer (up to approximately 16 months after start of stimulation).

The primary endpoint is the cumulative ongoing pregnancy rate after the fresh cycle and cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. It is expressed as the percentage of participants meeting the outcome definition. A participant met that definition if there was at least one intrauterine viable fetus 8-9 weeks after transfer.

This endpoint captures ongoing pregnancy across the specified fresh and cryopreserved cycles, rather than restricting the outcome to the fresh cycle alone. That makes the cycle window central to interpretation: the record includes cryopreserved cycles initiated within 12 months from the start of stimulation. The stated assessment time is 8-9 weeks after transfer, with follow-up described as extending up to approximately 16 months after stimulation began.

In general, a defined endpoint helps make the outcome being counted explicit. Here, the registry’s definition distinguishes ongoing pregnancy from earlier pregnancy measures also listed among the secondary outcomes, such as positive beta human chorionic gonadotropin, clinical pregnancy, and implantation. The primary result should therefore be read as the proportion meeting this particular ongoing-pregnancy definition, not as a measure of every stage of treatment or every pregnancy-related outcome.

The registry does not report further details about how participants with unavailable outcome information were handled. That missing-data procedure is not reported in the registry record.

7. Results Posted in the Registry

• FE 999049 (Follitropin Delta): 43.3% (231/533) versus 0.0% (0/54) on control; risk difference 43.3 percentage points (95% CI 39.1 to 47.5); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Oocytes Retrieved

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • FE 999049 (Follitropin Delta): mean 11.30 versus 0.00 on control; difference 11.30 (95% CI 10.54 to 12.06), standardized effect d = 1.33; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FE 999049 (Follitropin Delta) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Fertilized Oocytes

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • FE 999049 (Follitropin Delta): mean 6.40 versus 0.00 on control; difference 6.40 (95% CI 5.92 to 6.88), standardized effect d = 1.18; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FE 999049 (Follitropin Delta) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Endometrial Thickness on Stimulation Day 5

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • FE 999049 (Follitropin Delta): mean 8.00 versus 6.20 on control; difference 1.80 (95% CI 1.26 to 2.34), standardized effect d = 0.86; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FE 999049 (Follitropin Delta) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists secondary outcomes covering pregnancy and implantation across fresh and cryopreserved cycles, timing to ongoing pregnancy, and laboratory or treatment measures. The posted secondary results include continuous measures such as oocytes retrieved, fertilized oocytes, and endometrial thickness on stimulation day 5. This range of outcomes provides context around different stages and aspects of assisted reproductive treatment, but it does not change the definition of the primary endpoint.

At a broad level, the secondary outcome families concern processes and outcomes that are related to the clinical pathway addressed by the primary comparison. They can help describe whether patterns across pregnancy-related and laboratory measures are coherent with the primary result. However, each outcome has its own definition, timing, scale, and analysis population, and the registry record does not provide a single combined secondary estimate that can be treated as an overall confirmation.

Unadjusted secondary results carry less weight when many outcomes are examined. In general, testing multiple outcomes increases the chance that at least one result will appear notable even if there is no underlying effect for that outcome. A prespecified multiplicity strategy can address that issue, but such a strategy is not reported in the registry record. Secondary p-values should therefore be interpreted as exploratory unless the trial’s analysis plan establishes otherwise.

The record lists 69 outcome measures and 12 analyses, and lists 68 secondary outcomes as posted. It does not report a hierarchy for interpreting these outcomes or whether statistical testing was adjusted across them. The primary result should remain distinct from the broader secondary outcome set; the latter can add context but cannot independently establish or overturn the primary finding.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Ongoing Pregnancy Rate in the Fresh Cycle and in the Cryopreserved Cycles
• Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Including Duration
• Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Measured in Number of Cycles Before Achieving Ongoing Pregnancy
• Ongoing Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
• Clinical Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
• Vital Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
• Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
• Positive Beta Human Chorionic Gonadotropin (βhCG) Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary comparison estimate?

The endpoint is binary at the participant level: each participant either met the ongoing-pregnancy definition or did not. The posted arm results are percentages of participants, and the comparison is a treatment difference. In general, a risk difference subtracts the event proportion in one group from the event proportion in the other. The unadjusted recalculation reports that contrast as 0.433, with a 95% confidence interval from 0.391 to 0.475. No adjustment for other variables is described in this recalculation.

The registry’s reported analysis is identified as a Fisher Exact analysis of the treatment difference. In general, Fisher’s exact test is a method for comparing categorical outcomes using the observed group counts, and it can be useful when event counts are sparse or one group has no observed events. The registry reports a treatment difference of 43.3, a 95% confidence interval from 36.5 to 47.6, and p < 0.001. The exact procedure used to form that interval is not further described in the registry record.

How should the p-value be understood?

In general, a p-value measures how incompatible the observed data are with a specified null model, assuming that model and the analysis assumptions hold. It is not the probability that the null hypothesis is true, the probability that a result arose by chance, or a measure of clinical importance. The registry reports p < 0.001 for the sponsor’s analysis; the unadjusted recalculation also reports p < 0.001. These values are evidence against a no-difference null under the respective methods, but they do not describe the size or practical importance of the effect by themselves.

What does the confidence interval contribute?

In general, a confidence interval conveys uncertainty about an estimated contrast. It gives a range of values compatible with the data under the method’s assumptions and indicates how precisely the contrast has been estimated. The recalculated interval is on the proportion-difference scale; the registry’s reported treatment-difference interval is stated as 36.5 to 47.6. The methods and scales should be kept distinct when reading these estimates. Confidence intervals do not include uncertainty from every possible source, such as selection of the endpoint or choices made in the analysis plan.

What does the mITT population mean in this record?

The registry defines the mITT analysis set as all randomized and exposed participants and says participants were analyzed according to planned treatment. This describes which participants are included and how the treatment groups are assigned for the primary analysis. The record does not provide a detailed participant-flow account or explain how any participants without an observed primary outcome were handled. Those procedures are not reported in the registry record.

How should planning illustrations be read?

In general, a power-based sample-size calculation estimates the number of participants needed under specified assumptions to have a chosen probability of detecting a specified effect at a chosen significance level. The planning illustrations associated with the continuous secondary outcomes use the observed effect or a stated fraction of that effect, two-sided significance level 0.05, equal allocation, and a normal approximation. They are planning illustrations, not observed power and not the trial’s own design justification. The registry does not report that these assumptions were used to choose the trial enrollment.

The illustrations apply to the listed continuous secondary outcomes, not to the primary binary pregnancy endpoint. For example, the registry lists planning rows for the number of oocytes retrieved, number of fertilized oocytes, and endometrial thickness on stimulation day 5. These are not evidence that a future study with the illustrated group size would reproduce the observed result. Planning depends on the assumed effect, variability, analysis method, and study conduct; the registry’s illustrations do not resolve those uncertainties.

Why can methods matter even when results point in the same direction?

Different procedures can produce different interval estimates while using the same observed data. General statistical methods may differ in how they estimate uncertainty, particularly when an outcome is uncommon or a group has no observed events. The registry’s Fisher Exact analysis and the simple unadjusted recalculation should therefore be reported with their own methods and estimates. The record marks no discrepancy, so the sponsor’s own analysis is not displaced by the recalculation.

More broadly, the analysis plan can specify the endpoint, population, treatment contrast, handling of missing data, and approach to multiple outcomes. Those choices affect what a result means and how confidently it can be interpreted. The full statistical plan, missing-data procedure, and multiplicity strategy are not reported in the registry record, so no specific methods should be attributed to the trial beyond those explicitly recorded.

11. Confidence Intervals and Precision

For the unadjusted recalculation, the estimated risk difference is 0.433, with a 95% confidence interval from 0.391 to 0.475. The interval expresses uncertainty in the estimated contrast under the recalculation’s method. Its endpoints are both above zero, indicating that the estimated contrast remains positive across that interval. This does not mean every plausible source of uncertainty is captured by the interval.

The registry’s reported Fisher Exact analysis gives a treatment difference of 43.3, with a 95% confidence interval from 36.5 to 47.6. This is the sponsor’s reported analysis and should be kept distinct from the simple recalculation. The registry record does not provide further detail about how the interval was constructed. As the record marks no discrepancy, the recalculated interval is supplementary and does not replace the sponsor’s analysis.

In general, a confidence interval is more informative than a point estimate alone because it shows a range of values compatible with the data under the method used. A narrower interval indicates greater precision under that method; a wider interval indicates more uncertainty. The interval does not measure the probability that the true value lies within it after the data have been observed, and it does not establish clinical importance.

The placebo arm had 0.0% with the primary outcome, and the posted count used in the recalculation was 0. A zero observed count does not prove that the event is impossible in the broader population. It can also make inference sensitive to the method used, which is one reason to distinguish the registry’s reported analysis from the unadjusted recalculation. No additional confidence interval for either arm-specific percentage is reported in the registry record.

12. Analyses Reported by the Sponsor

The registry’s own primary analysis is reported as a Fisher Exact analysis of the treatment difference. It gives a value of 43.3, a 95% confidence interval from 36.5 to 47.6, and p < 0.001. This is the sponsor-reported result to use when describing the trial’s formal posted analysis.

The unadjusted recalculation uses the posted summary counts and proportions to estimate a risk difference of 0.433, with a 95% confidence interval from 0.391 to 0.475 and p < 0.001. It is a straightforward recalculation from the summary statistics, not a substitute for the trial’s own analysis. Different calculation methods can yield different interval estimates even when they concern the same observed comparison.

The registry marks the discrepancy indicator as false. Accordingly, the recalculation does not take precedence over the sponsor’s result. The sponsor analysis and recalculation both report a positive treatment contrast and p < 0.001, but their estimates and confidence intervals should be presented alongside their methods rather than blended into a single figure.

The registry does not report a fuller explanation of the sponsor’s statistical choices beyond identifying the Fisher Exact method and reporting the treatment difference, confidence interval, and p-value. Details such as the precise interval construction are not reported in the registry record.

13. Multiplicity, Missing Data and Analysis Populations

The record lists a primary endpoint and a substantial set of secondary outcomes, but the multiplicity strategy is not reported in the registry record. In general, multiplicity matters because repeated testing across outcomes can increase the chance of observing at least one small p-value by chance. Prespecifying a testing hierarchy or applying an adjustment can help control that issue. No particular strategy should be assumed for this trial.

The registry identifies the primary analysis population as the mITT set, comprising all randomized and exposed participants, analyzed according to planned treatment. This is useful information about who was included and how the assigned groups were used. The registry does not report a full participant-flow account or the number of participants with missing primary outcome data. The handling of missing outcomes, including whether any imputation or sensitivity analyses were used, is not reported in the registry record.

In general, missing outcome information can affect an estimated event rate if the participants without observed outcomes differ from those with observed outcomes. The direction and size of any such effect depend on why data are missing and how the analysis handles them. Since those details are not reported, the extent to which missingness could influence the primary result cannot be assessed from the registry record.

The record also does not report an interim-analysis plan, stopping rules, or a sample-size justification. These details should not be inferred from the phase, enrollment, or observed p-value. The planning illustrations associated with some secondary outcomes are not the trial’s design justification: they are calculations based on observed effects under stated illustrative assumptions.

Overall, the posted endpoint result can be interpreted using the stated analysis population and reported methods, while the absence of reported multiplicity and missing-data details limits assessment of the broader statistical plan. That uncertainty is distinct from the confidence interval around the primary treatment contrast.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ectopic pregnancy (0.2%), hyperemesis gravidarum (0.2%).

The registry reports serious adverse events affecting 2 participants in the FE 999049 group and 0 in the placebo group. It lists ectopic pregnancy and hyperemesis gravidarum among the leading serious adverse event terms, each recorded as 0.2%. The registry reports 0 deaths in each group.

The record also gives counts for other adverse events: 151 in the FE 999049 group and 2 in the placebo group. These figures are separate from the serious adverse event counts and should not be read as counts of serious events. The registry does not provide further detail about event severity, duration, relatedness to treatment, or how multiple events in one participant were handled.

In general, adverse event counts describe events recorded during the study and do not by themselves establish that a treatment caused an event. Interpretation of safety comparisons also depends on the definitions, observation period, and completeness of event reporting. Further details on these aspects are not reported in the registry record. The small serious-event counts, including no serious events recorded in the placebo group, limit how much can be concluded from a simple between-group count comparison.

15. What the Result Does, and Does Not, Mean

The posted data show a higher observed cumulative ongoing pregnancy percentage in the FE 999049 group than in the placebo group for the trial’s stated mITT population and endpoint. The registry reports 43.3% and 0.0%, respectively. The sponsor’s Fisher Exact analysis reports a treatment difference of 43.3, a 95% confidence interval from 36.5 to 47.6, and p < 0.001. These figures describe the trial results under its recorded outcome definition and analysis.

They do not establish what any individual participant’s outcome would have been under either treatment. A group-level trial result is not a personal prediction. Nor does the result, by itself, establish how the comparison would apply to people outside the studied population, to other treatment settings, or to different outcome definitions. The registry identifies women aged 35-42 years undergoing assisted reproductive technology as the population of interest.

The result also does not describe every pregnancy-related outcome. The primary endpoint is ongoing pregnancy, defined as at least one intrauterine viable fetus 8-9 weeks after transfer, across the fresh cycle and eligible cryopreserved cycles. It is not interchangeable with the secondary measures of positive beta human chorionic gonadotropin, clinical pregnancy, implantation, or other outcomes listed in the registry.

Statistical evidence and clinical importance are different questions. A small p-value does not quantify benefit or determine whether the observed contrast is important for patients or clinicians. The registry does not report a clinical threshold for interpreting the primary treatment difference. The confidence interval communicates statistical uncertainty under the method used, but does not resolve every limitation, including unreported missing-data handling and multiplicity procedures.

The safety figures are also limited to the adverse-event information recorded in the registry. They should not be used alone to conclude that one treatment is safer or less safe. The complete clinical interpretation requires the trial context, endpoint definition, reported analysis, and limitations to be considered together.

16. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation depends on more than a treatment-group percentage. The primary outcome is cumulative across a defined fresh and cryopreserved cycle window, and it uses a specific ongoing-pregnancy definition. Reading the endpoint carefully prevents the result from being mistaken for a rate confined to the fresh cycle or for a different pregnancy measure.

The posted comparison also illustrates the value of distinguishing the sponsor’s analysis from a simple recalculation. The registry identifies Fisher Exact as the method for its reported treatment difference, while the recalculation uses the posted summary statistics. Both give p < 0.001, but their confidence intervals are not identical. Keeping the method attached to each estimate avoids treating different statistical procedures as if they were the same analysis.

The observed placebo result is 0.0%, and the serious adverse event count in that group is 0. These zero counts are observations, not proof that the corresponding outcomes cannot occur. Sparse outcomes make the choice of statistical method and the interpretation of uncertainty especially important. The registry’s reported Fisher Exact analysis provides the formal sponsor result, while the simple recalculation offers a transparent supplementary summary.

The record also highlights the importance of details that are not reported. Missing-data handling, multiplicity strategy, interim analyses, and sample-size justification can shape how a trial’s evidence is assessed. Their absence does not erase the posted result, but it limits what can be concluded about the full statistical plan. Finally, planning calculations based on observed effects are not observed power and are not evidence that a future study would reproduce the same estimates.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the multiplicity strategy for the many listed outcomes. It also does not report how missing primary outcome data were handled, whether sensitivity analyses were conducted, or a detailed account of participant flow. These omissions limit assessment of how robust the primary estimate is to missingness and how secondary findings should be interpreted.

The primary outcome combines the fresh cycle with cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. The result is therefore tied to that cycle window and the stated timing of pregnancy assessment. The record does not provide additional detail about the number or distribution of eligible cryopreserved cycles, so those features cannot be examined from the posted information.

The arm summaries are unequal in size, and the placebo group had no observed primary events. Such features make it important to retain the distinction between the sponsor’s Fisher Exact result and the unadjusted recalculation. The latter is a simple calculation from posted summaries and does not adjust for other factors. The registry record does not report adjusted primary estimates or additional sensitivity analyses.

The registry does not report a sample-size justification or interim-analysis plan. The planning illustrations for some continuous secondary endpoints use observed effects and stated assumptions; they are not evidence of the study’s original design rationale. The registry also does not report a clinical threshold for interpreting the size of the primary treatment difference.

Safety interpretation is limited by the reported counts and lack of further event detail. The registry does not provide additional information about event relatedness, duration, observation periods, or participant-level event patterns in the record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2) — NCT03738618.
• Registry record last updated 2024-01-18; status last verified 2023-08.
• Results first posted 2024-01-18.
• 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.

21. Record Summary

RITA-2 is recorded as a completed phase 3 randomized, double-blind, placebo-controlled, parallel-groups, multicenter trial with quadruple masking. It compared FE 999049 (follitropin delta) with placebo in women aged 35-42 years undergoing assisted reproductive technology. The registry lists enrollment of 588.

The primary endpoint was cumulative ongoing pregnancy after the fresh cycle and cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. The posted rates were 43.3% for FE 999049 and 0.0% for placebo. The sponsor’s Fisher Exact analysis reported a treatment difference of 43.3, a 95% confidence interval from 36.5 to 47.6, and p < 0.001. The simple unadjusted recalculation reported a risk difference of 0.433, with a 95% confidence interval from 0.391 to 0.475 and p < 0.001.

The primary analysis population comprised randomized and exposed participants analyzed according to planned treatment. Details of the multiplicity strategy and missing-data handling are not reported in the registry record.