Copper Histidine Therapy for Menkes Diseases: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Copper Histidine Therapy for Menkes Diseases (NCT00001262), a na phase 1, phase 2 study. The primary outcome is Gross Motor Development at 36 Mos of Age or at Death (Mos).

2. Clinical Question

3. Trial Design

This completed registry record describes a Phase 1 and Phase 2 study of copper histidine therapy for Menkes disease. Its official title is “Early Copper Histidine Therapy in Menkes Disease,” and the recorded condition is Kinky Hair Syndrome. The sponsor is the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The recorded study start is 1990-06, primary completion is 2012-07, and status is completed. Enrollment is listed as 60.

The design is recorded as single-group. Allocation is listed as not applicable, and masking is listed as none. These details distinguish the study from a randomized, masked comparison. The record does not describe a control group, a randomized allocation process, or a treatment comparison that would support a like-for-like contrast. The Early, Late, and Mild categories in the adverse-event record should not be treated as randomized arms; the registry does not establish that they are comparable groups.

The registered intervention is copper histidine, categorized as a drug. The brief summary explains the rationale as delivering copper while bypassing the usual gastrointestinal absorption route. It also emphasizes that copper replacement does not itself correct the genetic abnormalities responsible for Menkes disease. The available record does not state the treatment dose, timing details, duration, adherence, or rules for treatment changes.

The primary outcome is gross motor development at 36 months of age or at death, recorded in months. The registry also lists somatic growth percentiles at 3 years of age or at age of death for weight, length, and head circumference. Although the record is marked completed, completion status alone does not establish that every planned outcome was measured or analyzed. Outcome-specific participant counts and analysis populations are not reported in the registry record.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

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 Gross Motor Development at 36 Mos of Age or at Death (Mos), measured over 36 months or death.

The primary endpoint is gross motor development at 36 months of age or at death, expressed in months. The registry says that assessment was based on the Denver Developmental Screening Test (DDST) I or II. The test uses a grid to assess expected developmental milestones in relation to chronological age, and the endpoint description specifies age-appropriate gross motor development in apparently normal healthy subjects at particular ages.

In general, developmental milestones can provide a structured way to describe whether a child has attained skills associated with different ages. Expressing the endpoint in months gives the outcome an age-related scale, but it does not, by itself, explain how scores were summarized, whether higher values represent a particular direction of development, or how observations at death were handled analytically. Those details are not reported in the registry record.

The endpoint is clinically relevant to the study’s stated focus on development, but interpreting it statistically requires the observed values, their variability, and the number of participants assessed. The registry lists a mean as the outcome parameter and standard deviation as the dispersion measure. It does not report the mean, standard deviation, confidence interval, or another estimate for this primary endpoint. It therefore specifies what was intended to be measured without providing a numerical result from which the outcome’s magnitude or precision can be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the trial as single-group, with allocation listed as not applicable and masking listed as none. These design features matter because statistical comparisons depend on what groups were formed and how participants entered them. In general, random allocation helps balance measured and unmeasured characteristics across study groups, while masking can reduce some forms of influence on care or measurement. Neither feature is reported for this study. The record therefore does not support interpreting the Early, Late, and Mild categories as randomized, comparable treatment groups.

What does a mean and standard deviation describe?

The primary outcome is identified as a continuous measure summarized by a mean and standard deviation. In general, a mean describes the center of a set of measured values, while a standard deviation describes how spread out those values are around the mean. Both are useful for describing an outcome, but neither is reported numerically for gross motor development in this registry record. Without those values, readers cannot assess the observed outcome level or its variability.

What would an estimate and confidence interval add?

In general, an estimate gives a numerical summary of an outcome or contrast, and a confidence interval conveys uncertainty around that estimate under the specified analysis. A narrower interval indicates greater precision than a wider interval, although precision alone does not establish clinical importance or remove bias. The registry record does not report an estimate or confidence interval for the primary endpoint. It also reports zero analyses, so there is no posted primary analysis result to interpret.

How should the planning calculations be understood?

Any sample-size calculations based on an observed effect are planning illustrations, not observed trial results and not evidence of the trial’s original design justification. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These assumptions describe hypothetical planning, rather than the recorded single-group study design. The registry does not report the study’s own sample-size justification. A calculated sample size is not “observed power”; it is an illustration of what a design might require under specified assumptions.

In general, a two-sided significance level specifies how a hypothesis-testing procedure treats departures in either direction under its null model. Equal allocation is an assumption about how participants would be assigned across two groups. A normal approximation is a mathematical simplification used in some planning calculations. Because this study is recorded as single-group and does not report a comparator, those hypothetical two-arm assumptions should not be mistaken for the way participants were assigned or analyzed in the trial.

What does the missing analysis information mean?

The record does not report a statistical analysis plan, analysis populations, missing-data procedures, or a method for handling the endpoint at death. These details affect interpretation. In general, an analysis population specifies which participants contribute to an estimate, and a missing-data method describes how unavailable measurements are addressed. Different choices can lead to different estimates, particularly when the reasons for missingness relate to outcome. No assumptions about those choices can be made from the registry entry.

The registry lists seven outcome measures, including the primary gross motor endpoint and secondary somatic growth percentiles for weight, length, and head circumference at 3 years of age or at age of death. In general, when several outcomes or statistical tests are considered, multiplicity can increase the chance of at least one apparently notable finding if each is interpreted separately. Procedures for addressing multiplicity are not reported in the registry record. Since numerical outcome analyses are also absent, the record does not permit assessment of how outcomes were modeled, whether estimates were adjusted, or how uncertainty was quantified.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Early", "Late", "Mild")
n   <- c(35, 22, 3)
m   <- c(13.743, 2.455, 15.667)
sp  <- c(12.2, 2.154, 9.815)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Early  35  13.743  12.200  9.552  17.934
CARM  Late  22  2.455  2.154  1.500  3.410
CARM  Mild  3  15.667  9.815  -8.715  40.049

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures. The primary outcome is gross motor development at 36 months of age or at death. The named secondary outcomes concern somatic growth percentiles at 3 years of age or at age of death: weight, length, and head circumference. The registry record does not report numerical results or analyses for these outcomes.

In general, multiplicity arises when several outcomes, time points, subgroups, or statistical tests are considered. If each test is interpreted without a plan for the collection of tests, the chance of at least one result appearing noteworthy can increase. This is a general statistical concern, not a claim that a particular finding occurred in this study. A multiplicity strategy, including whether any outcomes were designated for adjustment, is not reported in the registry record.

Missing-data handling is also not reported. The record does not state how many participants had primary or secondary outcome measurements, why any measurements might be unavailable, or whether any imputation or other missing-data method was used. Enrollment of 60 does not establish that 60 participants contributed to every outcome analysis. The analysis populations and any participant flow by outcome are not reported in the registry record.

The registry specifies measurement at 36 months or at death for the primary endpoint, and at 3 years of age or at age of death for the named growth outcomes. It does not explain how measurements associated with death were incorporated into the statistical analyses. A statistical analysis plan, prespecified model, and any adjustment strategy are not reported. These omissions prevent assessment of whether the analyses followed a prespecified approach and how the reported estimates, if any, would relate to the full enrolled group.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: death (50.0%), dehydration (2.9%).

The adverse-event record divides participants into categories labelled Early, Late, and Mild. In the Early category, 10 participants are listed as affected by serious adverse events among 35 at risk. In the Late category, 11 are listed as affected among 22 at risk. In the Mild category, zero are listed as affected among 3 at risk. These are counts recorded for the categories, not evidence that the categories were randomized treatment arms or directly comparable groups.

The top serious-event terms are Death, listed as 50.0%, and Dehydration, listed as 2.9%. The registry record does not provide enough context alongside these terms to establish their denominators, timing, category-specific distribution, or relationship to copper histidine. A listed adverse event does not, by itself, establish that the intervention caused it. The death entries in the serious-event terms also should not be conflated with the primary endpoint’s “at death” timeframe; the record does not explain how those data relate.

In general, safety counts describe events recorded in a defined population and period. Their interpretation depends on consistent event definitions, exposure time, ascertainment, and attribution procedures. Those details are not reported in the registry record. The figures therefore describe the posted serious-event summaries, but do not support a causal safety comparison or a comparison of event rates between treatment arms.

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

The record establishes that a completed Phase 1 and Phase 2 study of copper histidine was registered as a single-group study with enrollment of 60. It identifies gross motor development at 36 months of age or at death as the primary endpoint and describes assessment using the Denver Developmental Screening Test I or II. It also lists somatic growth percentile outcomes and serious adverse-event summaries.

Those descriptions do not provide the primary outcome result. The registry lists no analyses, and it reports no numerical estimate or uncertainty measure for gross motor development. Thus, the posted information cannot show the size, direction, or precision of a primary outcome finding. The absence of a result in this record does not show that the study found no effect, nor does it show that a particular effect occurred.

The single-group design is important to interpretation. Without a randomized comparator, the record does not provide a controlled estimate of what would have happened under a different treatment or without treatment. General statistical reasoning also cautions that an observed outcome in a treated group alone cannot separate treatment-related change from other explanations. This is a limitation of the design information available, not a judgment about the treatment.

The serious-event counts and listed terms are descriptive registry entries. They do not establish that events were caused by the intervention, and the Early, Late, and Mild categories do not establish a controlled safety comparison. Details about event definitions, timing, attribution, and the relevant denominators for the listed terms are not reported in the registry record.

Overall, the registry record is informative about the study’s registered design, intervention, outcome definitions, and selected safety summaries. It does not provide the outcome analyses needed to quantify developmental findings or treatment effects. Any conclusion beyond those descriptive details would require results or methods that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable because it pairs a defined developmental endpoint with a design that does not include a randomized comparator in the registry record. That distinction is essential: measuring an outcome and summarizing it within a group are not the same as estimating a comparative treatment effect. The record identifies the primary measure and its assessment instrument, but does not report the result or an analysis.

The endpoint is also specified at 36 months of age or at death. That timeframe makes the handling of observations associated with death relevant to interpretation, yet the registry does not describe the analytical approach. More generally, an endpoint definition is only one part of a statistical result; the number assessed, summary estimate, variability, missingness, and analysis population are also important. These are not reported for the primary outcome.

The adverse-event summaries illustrate another general issue: labels and counts should not be read as a controlled comparison unless the design and group definitions support that interpretation. Here, the Early, Late, and Mild categories are recorded in the safety data, but the trial itself is listed as single-group with allocation not applicable. The categories therefore do not, on the information in the record, provide a randomized comparison.

Finally, the record lists multiple outcome measures, while reporting no analyses. This makes multiplicity and missing-data methods impossible to evaluate from the posted registry information. The trial matters statistically as an example of why design, outcome definition, and results need to be read together: a clearly named endpoint does not substitute for an estimate, and completion status does not supply the missing analysis.

15. 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 central limitation of the registry record is that it does not report a numerical result or analysis for the primary endpoint. Although the endpoint is specified and a mean and standard deviation are identified as summary measures, neither is reported. The number of primary outcome analyses is recorded as zero. No confidence interval, p-value, or other estimate is available in the registry record.

The study is recorded as single-group, with allocation not applicable and no masking. A concurrent randomized comparator is not reported, so the record does not support a controlled estimate of treatment effect. The Early, Late, and Mild categories in the adverse-event data should not be interpreted as randomized arms or like-for-like comparators.

Enrollment is listed as 60, but outcome-specific sample sizes and the analysis population are not reported. It is therefore not possible to determine how many participants contributed to the developmental or growth outcomes. The registry does not describe missing-data procedures, how the endpoint at death was handled, or whether analyses included all enrolled participants.

The record lists seven outcome measures, but does not report results for them or an approach to multiplicity. It also does not report a statistical analysis plan, outcome models, treatment exposure details, or a sample-size justification for the study itself. The sample-size assumptions described for planning illustrations do not fill those gaps and should not be treated as the trial’s design assumptions.

For safety, the record gives counts in the Early, Late, and Mild categories and lists top serious-event terms. It does not report the event definitions, time windows, attribution, or enough context to interpret the listed percentages. These limitations constrain both efficacy and safety interpretation; they do not establish that any particular result was favorable or unfavorable.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Copper Histidine Therapy for Menkes Diseases — NCT00001262.
• Registry record last updated 2015-10-30; status last verified 2015-09.
• Results first posted 2015-10-30.
• 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.

19. Record Summary

The registry record describes a completed Phase 1 and Phase 2, single-group study of copper histidine therapy in Menkes disease, with Kinky Hair Syndrome listed as the condition. Allocation is recorded as not applicable, masking as none, and enrollment as 60. The sponsor is the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The primary endpoint is gross motor development at 36 months of age or at death, measured in months using the Denver Developmental Screening Test I or II. Secondary outcomes include weight, length, and head circumference percentiles at 3 years of age or at age of death. The registry record lists no outcome analyses and does not report a numerical primary result. Serious adverse-event summaries are recorded by Early, Late, and Mild categories, with Death and Dehydration among the top serious-event terms. The record does not establish a controlled treatment comparison or provide enough detail to attribute adverse events to the intervention.