Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss (NCT01649869), a randomized phase 2 study. The primary outcome is Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing..

2. Clinical Question

Statistically, the question is about a categorical hearing classification assessed over time, with the ear as the stated unit for the primary count. The registry describes audiology assessments at study visits and a masked study audiologist who classifies hearing based on thresholds. It also explains that a participant’s best-ear classification is determined separately at each visit. These definitions matter because the primary count is based on ears, while some secondary outcomes use the best ear for a participant.

The record lists additional hearing outcomes, including changes in best-ear and total-ear assessments between baseline and Study Month 6, as well as an association between change in blood viral load and change in total-ear hearing. Those outcomes broaden the clinical questions beyond the primary classification, but their results are not reported in the registry record.

3. Trial Design

This was a Phase II randomized, controlled, parallel-group trial comparing valganciclovir with placebo. The registry lists triple masking and describes the study in its summary as double-blind. It does not specify in the registry record which roles were included in the masking categories, so the precise meaning of the difference between those descriptions is not reported.

The planned enrollment was 54, with 27 children assigned to each arm in the arm descriptions. The trial is described as international and multicenter. Children were to be stratified according to age, according to the study summary. The specific strata and the method used to generate or conceal the allocation are not reported in the registry record.

The treatment period was 6 weeks, and participation was described as lasting over a six-month period. The primary outcome timeframe is Day 1 through Day 180. The study is listed as completed, with a start date of 2015-02-24 and a primary completion date of 2019-12-24. These dates describe the trial record and do not, by themselves, indicate when results were analyzed or posted.

The placebo comparison supports an evaluation of outcomes between assigned groups, while random allocation is intended in general to reduce systematic differences at baseline. Those are design principles, not evidence that the groups were balanced in this particular trial. Baseline characteristics by arm, adherence, treatment discontinuation, and the actual analysis population are not reported in the registry record.

The primary outcome was classified by a study audiologist masked to treatment assignment. The registry specifies that hearing classifications were assigned by ear, and that not every participant had both ears evaluable. It does not describe how this incomplete ear-level assessment was handled in the primary analysis, or whether the analysis accounted for dependence between ears belonging to the same child.

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 Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing., measured over Day 1 through Day 180.

The primary endpoint is a count of ears classified as having improved hearing or no change, compared with ears classified as having worsened hearing. Hearing status is assigned using audiology test results and categories based on hearing thresholds: normal, mild loss, moderate loss, or severe loss. The registry describes the outcome timeframe as Day 1 through Day 180.

This endpoint is intended to capture whether hearing classifications remain stable or worsen during follow-up, which reflects the study’s stated objective of assessing hearing stability. Grouping improvement with no change creates a contrast between ears that did not worsen and ears that did. This is a particular way of summarizing an ordered clinical classification; it does not preserve all distinctions among improvement, stability, and worsening in the primary comparison.

The audiologist was to assess the test battery while masked to treatment assignment, which can reduce the possibility that knowledge of assigned treatment influences classification. The registry also explains that classifications are made for each ear, while the participant-level best ear is determined separately at a visit. Not both ears were evaluable for all participants; in some cases only one ear was evaluable.

The primary endpoint is therefore an ear-level count, not simply a participant-level measure. The number of ears analyzed, the treatment-group counts for each outcome category, and the statistical comparison are not reported in the registry record. The methods used to address missing ear assessments or correlation between ears are also not reported.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, parallel-group comparison, with placebo as the control and valganciclovir as the active treatment. In general, random allocation is used to reduce the chance that prognostic factors systematically favor one assigned group. It does not guarantee that groups will be identical, and the registry record does not report baseline characteristics or details of the allocation procedure.

What does the endpoint count?

The primary measure is a count of ears classified as improved or unchanged versus worsened. The hearing classification is based on thresholds assessed through an audiology test battery and is assigned separately for each ear. This means that the observation unit described for the primary outcome is the ear, even though treatment is assigned to children. The registry notes that some children have only one evaluable ear, but does not report how the analysis handled this variation.

General statistical interpretation of ear-level data requires attention to clustering: measurements from the same child may be related rather than independent. Treating related observations as independent can make uncertainty estimates too optimistic. This is a general concern for analyses with multiple observations per participant; the registry record does not say whether the primary analysis adjusted for such dependence.

How could a count outcome be analyzed?

In general, count outcomes may be analyzed using methods that model the expected count or compare counts between groups. The appropriate method depends on the data structure, the exposure or observation time, and the distribution of the counts. If variability exceeds what a chosen count model expects, over-dispersion can lead to standard errors that are too small unless the analysis accounts for it. These are general methodological considerations, not a description of the method used in this trial.

The registry record does not report a statistical model, a contrast definition, an adjustment set, or a method for calculating uncertainty for the primary outcome. It also does not report whether the outcome was analyzed as a count, as a binary classification, or through another approach. The presence of a count endpoint alone is not enough to infer which statistical method was used.

What would uncertainty measures mean?

In general, a confidence interval describes uncertainty around an estimated effect under the assumptions of the analysis. Its width depends on factors such as the amount of information and the variability in the outcome. A p-value, if reported, would describe how compatible the observed data are with a specified null hypothesis under the chosen model; it would not measure the probability that a treatment is effective. Neither a primary effect estimate, confidence interval, nor p-value is reported in the registry record.

Because no primary comparison is reported, there is no basis for judging statistical precision or distinguishing a small estimated difference from a larger but uncertain one. The planned enrollment does not resolve that issue: enrollment is a design target, not the observed number contributing to a specific outcome analysis.

How should multiple outcomes be considered?

The registry lists 26 outcome measures and 19 analyses. In general, examining many outcomes or contrasts creates multiplicity: even when each test uses a conventional threshold, the chance of at least one apparently unusual result can increase as more tests are considered. A prespecified hierarchy, adjustment procedure, or clear distinction between primary and exploratory analyses can help readers interpret a set of findings. Such procedures and the analysis hierarchy are not reported in the registry record.

The primary outcome has several categories or time points and is not reduced in the record to a single comparison. The registry does not specify how the categories or repeated assessments were combined in the analysis beyond the stated endpoint definition, nor does it state whether any secondary outcomes were adjusted for multiplicity.

What do planning calculations represent?

In general, sample-size calculations are planning tools that estimate how much information a future study might need under stated assumptions. They are not observed results and should not be interpreted as observed power. The registry record does not report the trial’s own sample-size justification or the assumptions used in its original design. Any planning illustration based on an observed effect would be a separate calculation and would not replace the trial’s prespecified design rationale.

The registry does not report interim analyses, stopping rules, the primary statistical analysis plan, or the handling of missing data. These absences limit assessment of whether the reported endpoint definition, statistical model, and multiplicity approach were established before results were examined. They do not establish that such methods were absent from other study documents; they are simply not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 26 outcome measures and 19 analyses, including the primary hearing count and several secondary hearing outcomes. In general, testing multiple outcomes raises a multiplicity concern because the opportunity to observe a result that appears unusual by chance increases when many comparisons are made. Interpretation typically depends on knowing which outcome was primary, which comparisons were prespecified, and whether adjustment or a testing hierarchy was used. Those details are not reported in the registry record.

The primary endpoint covers Day 1 through Day 180, and the secondary outcomes include changes between baseline and Study Month 6. The registry record does not explain how repeated assessments or multiple hearing categories were handled analytically. It also does not report whether the listed secondary analyses were confirmatory or exploratory.

Missingness is relevant because the record states that not both ears were evaluable for all participants and that some participants had only one evaluable ear. The number and pattern of missing ear assessments, the reasons for missingness, and the methods used to address it are not reported in the registry record. It is also not reported whether missingness differed by assigned arm or study visit.

The analysis populations are not described. The registry record does not state whether analyses followed assigned treatment, included only participants who completed treatment, or used another population definition. It does not report adherence, withdrawals, or the number included in the primary analysis. These omissions make it difficult to assess how closely the analyzed groups corresponded to the randomized groups and how missing information may affect interpretation.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: respiratory distress (5.9%).

The registry reports serious adverse event counts separately for the placebo and active arms. For serious events, the at-risk counts are 18 in the placebo arm and 17 in the active arm; the affected counts are 0 and 1, respectively. Deaths are recorded as 0 in each arm. The registry also reports other adverse event counts, with 35 at risk in each arm and 18 affected in the placebo arm and 17 in the active arm.

These figures should be read within their stated categories. The at-risk counts for serious events differ from the at-risk counts for other events, and the reason for that difference is not reported in the registry record. They also differ from the planned allocation described in the trial arms. The record does not explain whether these denominators reflect different reporting rules, availability of safety information, or another reason; none should be assumed.

The registry lists Respiratory Distress among the top serious terms at 5.9%, but the arm attribution and calculation context for that percentage are not reported in the registry record. The counts and term listing do not establish a causal relationship with treatment. They are descriptive safety data, and the registry record does not provide enough detail to assess comparative safety statistically.

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

This trial was designed to compare six weeks of oral valganciclovir with placebo in children with congenital CMV infection and hearing loss. Its primary outcome focuses on ears classified as improved or unchanged versus worsened during Day 1 through Day 180. The study design and outcome definitions indicate what the investigators intended to assess; they do not show what the comparison found.

The primary outcome results are not reported in the registry record. Consequently, the record does not establish whether the groups differed, how large any difference was, or how precisely it was estimated. It also does not provide the results for the secondary hearing outcomes or the listed association between change in blood viral load and change in total-ear hearing at 6 months.

Even if a result for the primary grouped endpoint were available, it would answer a defined question about the combined category of improvement or no change versus worsening. It would not necessarily describe each hearing category separately or establish what happened to every child. The primary endpoint is ear-based, and the registry notes that not all children had both ears evaluable. The record does not report how those features were handled in the analysis.

The safety counts are also descriptive. They report affected counts and at-risk counts for serious and other adverse event categories, but the denominators differ and the record does not explain why. Those counts do not provide a complete assessment of comparative safety or causation.

In general, a randomized comparison can help estimate differences between assigned groups when the analysis and follow-up are appropriately reported. Here, the registry record does not provide the primary effect estimate, uncertainty interval, statistical test, missing-data approach, or analysis population needed to evaluate that comparison. The record therefore supports an account of the trial’s question and design, not a conclusion about treatment effects.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are especially relevant to hearing outcomes in children. The primary measure is based on ears, while treatment assignment is at the child level. When a child contributes information from both ears, those observations may be related. Analyses that recognize the structure of the data can give more appropriate uncertainty estimates than methods that treat all ear observations as independent. The registry record does not report how this issue was handled.

The hearing classifications are ordered categories, and the primary endpoint groups improvement with no change while contrasting that group with worsening. That grouping makes the endpoint easier to express as a count comparison, but it also compresses clinically distinct patterns. The registry’s secondary outcomes include other ways of classifying changes in best-ear and total-ear assessments, reflecting the importance of how outcomes are defined.

Availability of ear assessments is another statistical concern. The record says that not all participants had both ears evaluable. Without the number, pattern, and handling of missing assessments, readers cannot determine how much information contributed to the primary comparison or whether the analyzed assessments represent the enrolled groups.

The record also lists many outcomes and analyses. A clear distinction between primary and secondary questions and a prespecified approach to multiple testing help readers judge how much weight to place on a set of findings. Those statistical details, and the primary results themselves, are not reported in the registry record. The trial therefore illustrates why endpoint definitions, analysis units, missing-data handling, and multiplicity procedures are necessary for interpreting a clinical comparison, not merely technical details added after the clinical question is posed.

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.

A key limitation of the registry record is that the primary outcome comparison is not reported. There are no group-specific primary outcome counts, effect estimate, uncertainty interval, or test result to assess. The listed endpoint and study design cannot substitute for those results.

The record describes hearing categories assigned by ear and notes that some participants had only one evaluable ear. It does not report how many ears were evaluable by arm, how missing assessments were addressed, or whether the analysis accounted for dependence between ears from the same child. These details are important for both the estimated effect and its precision.

The statistical analysis plan is not reported in the registry record. The record does not specify the model, the handling of repeated assessments, the analysis populations, adjustment variables, multiplicity approach, or interim analyses. It also does not report adherence, withdrawals, or reasons for missing data. The absence of these details in the registry record does not show whether they were documented elsewhere.

The registry describes masking as triple in the design information and as double-blind in the summary, without explaining the roles covered by masking. It also does not report baseline characteristics by arm. These limitations restrict assessment of implementation and group comparability.

Finally, the safety denominators differ across the serious and other adverse event categories, and their relationship to the planned arm sizes is not explained. The serious-event term listed at 5.9% lacks a reported arm attribution in the record. The safety information is therefore limited to the recorded counts and term listing.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss — NCT01649869.
• Registry record last updated 2024-10-16; status last verified 2018-03-22.
• Results first posted 2021-06-02.
• 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

NCT01649869 is a completed Phase II randomized, placebo-controlled, parallel-group trial of oral valganciclovir in children with congenital CMV infection and hearing loss. The planned enrollment was 54, with 27 children described in each arm. Treatment was given twice a day for 6 weeks, and the primary outcome timeframe was Day 1 through Day 180.

The primary endpoint counts ears classified as improved or unchanged versus worsened. A masked audiologist was to classify hearing using audiology assessments, and the registry notes that not every participant had both ears evaluable. The record lists 26 outcome measures and 19 analyses, but does not report the primary comparison or its statistical uncertainty. Safety counts are reported for serious and other adverse event categories, with different at-risk counts. The analysis plan, missing-data methods, and analysis populations are not reported in the registry record.