Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact (NCT01688895), a registered phase not stated study. The primary outcome is The Hospital Anxiety and Depression Scale (HADS).

2. Clinical Question

3. Trial Design

This record concerns a research protocol titled “Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact.” Its initial objective was to assemble a well-documented group of people with confirmed erythropoietic protoporphyria, including EPP and XLP, for clinical, biochemical, and genetic studies. The stated longer-term objectives include longitudinal investigation of natural history, complications, and therapeutic outcomes; study of psychological effects in children and adults; and investigation of genotype-phenotype correlations and possible interactions with other genetic markers.

The registry lists one arm, “Participants with Protoporphyrias,” consisting of individuals with a documented EPP or XLP diagnosis. It does not describe random assignment or a like-for-like control arm. Allocation is not stated. This is therefore not presented as a randomized comparison of treatments. The listed enrollment is 150. The sponsor is Icahn School of Medicine at Mount Sinai, the start is recorded as 2012-07, the primary completion as 2019-07-01, and the status as completed.

HADS is the primary outcome measure named in the record. Sleep Disturbance PROMIS Scores are listed as a secondary outcome, and the record lists four outcome measures overall. However, it lists zero analysis entries and provides no HADS summary statistics or inferential results. Completion status describes the registry status of the study; it does not, by itself, establish that every planned objective was completed or that outcome results were reported. The number of participants contributing to any particular measure is not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Data only for those who completed instrument included. A protocol modification to add the HADS tool was done after study initiation, therefore not all subjects received all tools.

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.

6. Primary Endpoint

The registry lists the primary outcome as The Hospital Anxiety and Depression Scale (HADS), measured over 1 weeks.

The primary endpoint is the Hospital Anxiety and Depression Scale (HADS), reported as a mean score with standard deviation. The questionnaire has seven anxiety items and seven depression items. Each item is scored on a 4 point response from 0 - 3; the anxiety and depression subscales each range from 0-21, and the full range is 0 to 42. The record says that a higher score indicates more severe anxiety or depression.

As a general statistical interpretation, a mean describes the average score among the participants included in an analysis, while the standard deviation describes how dispersed individual scores are around that mean. HADS is used to quantify symptoms in a consistent questionnaire format, rather than to establish a diagnosis or explain the cause of a score. The registry describes the outcome as a score on a scale and gives a timeframe of “1 weeks.” It does not report an observed mean, standard deviation, or score distribution, so the actual level and variability of HADS scores cannot be assessed from this record.

The record also states that HADS was added through a protocol modification after study initiation and that only participants who completed the instrument were included in its data. Not all subjects received all tools. This makes the population contributing to HADS potentially different from the full enrolled group; the number included is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean and standard deviation describe?

The record specifies a mean and standard deviation for the HADS outcome. In general, the mean is a measure of the central level of scores in the analyzed group. The standard deviation describes the spread of scores around that mean. They answer different questions: a mean alone does not show whether individual scores are tightly clustered or widely dispersed, while a standard deviation alone does not show the average score level.

Both measures depend on which observations are included. Here, the record states that only participants who completed HADS were included in its data. Because the instrument was added after study initiation and not all subjects received all tools, the included participants may not represent every enrolled participant. The number contributing to HADS and the pattern of noncompletion are not reported in the registry record. No mean or standard deviation is posted, so these methods describe what the specified statistics would mean, not an observed result.

How should the HADS scale be read?

HADS includes anxiety and depression items, with separate subscales and a full score range stated in the record. Each item uses a 4 point response scored from 0 - 3. The anxiety and depression subscales each range from 0-21, while the full range is 0 to 42. Higher scores are described as indicating more severe anxiety or depression. That direction helps interpret a reported score, but it does not provide a clinical threshold or tell readers how many participants had particular symptoms. Such thresholds, distributions, or participant-level results are not reported in the registry record.

As a general point, a continuous score can retain more gradation than a simple category, but its interpretation still depends on the instrument, the population, and the analysis. A numerical score is not, on its own, a diagnosis or evidence about what caused the score. The registry specifies a mean outcome and a standard deviation but does not report the actual values, distribution, or any subgroup results.

What can a comparison establish?

In general, a between-group comparison estimates how an outcome differs between the groups defined by a study design. Random allocation, an appropriate comparator, and a prespecified analysis can help address sources of bias, although they do not remove every concern. This registry lists one arm of participants with EPP or XLP and does not report a comparator for HADS. Allocation is not stated, and the record does not describe a randomized treatment comparison. It is therefore inappropriate to interpret the outcome as an estimate of a treatment effect or to invent a comparison that is not reported.

A comparison also requires a clearly defined estimand: what outcome is being compared, in which population, and at what time or follow-up point. The record names HADS and gives a timeframe of “1 weeks,” but does not report a contrast or detailed analysis population. The protocol’s natural-history and psychosocial aims describe research questions, not a posted statistical contrast.

What do precision and statistical significance mean?

In general, a confidence interval expresses uncertainty around an estimate under the stated statistical model and method. A narrower interval indicates greater precision on the scale used, while a wider interval indicates more uncertainty. A p-value summarizes how compatible data are with a statistical null hypothesis under a specified test and its assumptions. Neither measure is a direct measure of clinical importance, and neither replaces a clear estimate with its uncertainty.

The registry record contains no HADS confidence interval, p-value, test statistic, or model output. It also does not describe an inferential analysis for this endpoint. Statistical significance cannot be evaluated, and no precision claim can be made from the record. The absence of a posted analysis is not evidence that an analysis was or was not conducted outside the registry; that information is not reported in the registry record.

Why can over-dispersion matter?

As general context, over-dispersion is a concern most often associated with count outcomes: observed variability can exceed what a simple statistical model assumes. If ignored, uncertainty estimates from that model can be too small. It is not an identified analysis issue for the registry’s stated primary endpoint, which is a continuous HADS score summarized by a mean and standard deviation. No over-dispersion assessment or statistical model is reported, and there is no count outcome result in the primary endpoint description to which such an adjustment could be applied.

What analysis details remain unknown?

The registry record does not report a statistical analysis plan, model specification, covariate adjustment, handling of repeated observations, missing-data method, or multiplicity procedure. It does not provide a rationale for the listed enrollment or a sample-size justification. These details should not be inferred from the study’s objectives or its completed status. For HADS, the concrete information available is its name, score description, mean and standard deviation summary, stated timeframe, and the restriction to participants who completed the instrument.

10. Multiplicity, Missing Data and Analysis Populations

The record lists four outcome measures, identifies HADS as primary, and names Sleep Disturbance PROMIS Scores as a secondary outcome. It does not report how the outcomes were prioritized for analysis beyond those labels, whether subscales or additional comparisons were tested, or whether any multiplicity adjustment was planned or used. A correction for multiple testing is therefore not reported in the registry record. Without a reported analysis plan or results, the family of statistical tests and the implications of any multiplicity cannot be assessed.

For missing data, the record gives one important detail: only participants who completed HADS were included in its data. It also says a protocol modification added HADS after study initiation, so not all subjects received all tools. The number of participants who were eligible to complete HADS, the number who completed it, and reasons for any missing responses are not reported in the registry record. There is no description of imputation, weighting, sensitivity analysis, or another method for addressing missing data.

As a general statistical concern, an analysis restricted to people with completed questionnaires may be affected if completion is related to symptom severity or other participant characteristics. The direction and extent of any such bias cannot be determined without information about completion and noncompletion. The registry’s statement about the included population should therefore be kept distinct from the enrollment figure: the number enrolled does not establish the size or representativeness of the HADS analysis population.

The record does not describe an intention-to-treat population or another formal analysis population for HADS. Because this is not presented as a randomized treatment comparison, an intention-to-treat treatment contrast is not specified. More generally, the exact population and missing-data handling remain unclear beyond the completed-instrument statement.

11. 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 0% reporting threshold.

The safety information lists an “Adult Patients With EPP/XLP” group with 150 participants at risk for serious adverse events and 0 affected. For other adverse events, the record also lists 150 at risk and 0 affected. Deaths are listed as 0, and no top serious adverse event terms are listed. These are the safety figures posted in the registry record.

At-risk counts describe the group for which the safety information is reported; affected counts describe participants recorded as having the relevant event category. These figures should not be read as comparative safety estimates because the record lists one group and does not provide a control group or a treatment contrast. Nor do the figures supply information about event severity beyond the serious-event classification, timing, duration, or ascertainment procedures. Those details are not reported in the registry record.

The safety entries should also be distinguished from the study’s enrollment listing and from the HADS population. The record does not explain whether the safety group corresponds to all enrolled participants, nor does it provide participant-level follow-up detail. The posted zero affected counts describe what the registry reports; they do not establish the absence of unrecorded events or provide a basis for comparing risks with another group.

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

The record establishes that a study of people with EPP or XLP had broad aims that included clinical, genetic, natural-history, and psychosocial research. It identifies HADS as the primary outcome and supplies the instrument’s score structure and the rule that only completed questionnaires were included. It also reports that the instrument was added after study initiation, so not all subjects received all tools. These details are useful for understanding what was intended to be measured and why the HADS analysis population may not equal the enrolled population.

The record does not provide HADS means, standard deviations, or other outcome estimates. It therefore does not show the actual symptom-score level among participants, how variable the scores were, or how scores related to genotype, clinical presentation, or other characteristics. Although the protocol’s objectives include therapeutic outcomes, the record does not provide a treatment comparison or results establishing a treatment effect. The listed design information does not support a causal claim about any intervention.

As a general matter, an outcome measure can describe a domain without resolving every question about that domain. A questionnaire score is not itself a diagnosis, and an average cannot reveal every individual participant’s experience. Interpreting scores also requires an understanding of who completed the instrument, when it was completed, and how missing data were handled. The registry provides only some of that context; the remaining analysis details are not reported in the registry record.

The completed status and the listed enrollment of 150 should not be mistaken for a posted result or a confirmed HADS sample size. A completed registry record can still lack outcome analyses. Here, the appropriate conclusion is that the registry documents the study’s aims and HADS measurement approach, while leaving its primary outcome findings unreported. No claim about the presence, absence, size, or precision of an anxiety or depression result can be drawn from the posted record.

13. Why This Trial Matters Statistically

Statistically, this record illustrates why a named endpoint is not the same as a reported finding. HADS is clearly identified as the primary outcome, with its score range, direction, and planned summary as a mean with standard deviation. Yet no observed value or analysis is posted. Without those estimates, readers cannot assess the level of scores, their variability, or the precision of any conclusion. The endpoint definition supports interpretation of a result if one is reported, but cannot replace the result itself.

The record also makes the analysis population especially important. HADS was added after study initiation, and only people who completed the instrument were included. Not all subjects received all tools. Those details mean that enrollment and HADS completion are not interchangeable quantities. Because the number completing HADS and the characteristics of those included are not reported, representativeness and potential selection effects remain uncertain.

Finally, the registry’s objectives span several research domains, while the posted information does not include an analysis plan or results. This distinction matters when interpreting protocol aims: planned investigation of natural history, psychosocial effects, and genotype-phenotype correlations is not evidence that a particular association was found. The record is useful for identifying the measurement and design context, but its statistical contribution is limited by the absence of posted outcome estimates and analysis details.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting the primary endpoint is that the registry record does not report HADS results. There is no mean, standard deviation, score distribution, confidence interval, or inferential test. The record also lists zero analysis entries, so it offers no posted statistical analysis to evaluate. The completed status does not resolve this absence.

The HADS tool was added after study initiation, and only participants who completed it were included in its data. Not all subjects received all tools. The registry does not report how many participants completed HADS, why others did not complete it, or whether completion differed by participant characteristics. This limits assessment of the endpoint’s analysis population and the possibility of selection bias.

The design information does not include a comparator for HADS or describe random allocation. The listed participant arm is not a like-for-like control comparison. As a result, no comparative or causal interpretation is supported by the record. The broader protocol objectives include longitudinal investigation and therapeutic outcomes, but the record does not give details about follow-up observations or analyses for those aims.

Other statistical details are also absent: the analysis plan, missing-data approach beyond inclusion of completed instruments, multiplicity handling, model specification, and sample-size justification are not reported in the registry record. The stated timeframe is “1 weeks,” but further measurement or follow-up details are not given. These limitations do not show that the study lacked such procedures; they mean the registry record does not document them.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact — NCT01688895.
• Registry record last updated 2020-04-17; status last verified 2020-04.
• Results first posted 2020-04-17.
• 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.

18. Record Summary

This completed registry record describes a protocol to study erythropoietic protoporphyria, including EPP and XLP, through clinical, biochemical, genetic, natural-history, and psychosocial research. It lists enrollment of 150 and one participant arm comprising individuals with a documented EPP or XLP diagnosis. HADS is the primary outcome, with Sleep Disturbance PROMIS Scores listed as a secondary outcome.

The HADS outcome is described as a mean score with standard deviation. The record notes that the tool was added after study initiation and that only participants who completed it were included; not all subjects received all tools. It provides no HADS estimates or analysis results, and the number of HADS completers is not reported in the registry record. The safety entries list 0 affected for serious and other adverse events, with 0 deaths. The registry does not report a comparator or a statistical analysis plan.