Otoprotection With SPI-1005 for Prevention of Temporary Auditory Threshold Shift: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Otoprotection With SPI-1005 for Prevention of Temporary Auditory Threshold Shift (NCT01444846), a randomized phase 2 study. The primary outcome is Change in Temporary Threshold Shift at 4 kHz--Intent To Treat (ITT) Population.

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel phase 2 study sponsored by Sound Pharmaceuticals, Incorporated. The registry gives enrollment as 83, with study start in 2011-09 and primary completion in 2013-12; the study status is completed. Its stated purpose was to assess the safety and efficacy of oral SPI-1005 for prevention of temporary auditory threshold shift after a controlled sound challenge. The brief description refers to listening to music through an iPod or personal music player, while the primary endpoint description refers to a controlled sound exposure.

The parallel treatment groups were SPI-1005 low dose, SPI-1005 middle dose, SPI-1005 high dose, and placebo. The arm descriptions specify 200mg, 400mg, and 600mg SPI-1005, each as a capsule taken twice daily by mouth for 4 days; placebo is described as 0mg on the same schedule. The primary efficacy endpoint was collected in the ITT Population. The arm results list 20, 20, 21, and 20 participants, respectively, for this outcome.

Baseline hearing thresholds were measured before sound exposure. Thresholds after exposure were compared with baseline to calculate change from baseline for each ear, frequency, and post-sound time point. The primary time point was 15 minutes post Controlled Sound Challenge at 4 kHz. The analysis description specifies mixed-effects model repeated measures (MMRM), with treatment, ear, frequency, and time as fixed effects, their stated interactions, and a subject-level random effect nested within treatment.

The registry record does not report the randomization procedure, allocation concealment details, sample-size justification, or further operational details of masking. It also does not state the protocol’s complete statistical analysis plan.

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: Intent To Treat (ITT) Population

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 study design included subjects with normal to slight hearing loss. Normal hearing is defined as having a baseline threshold of -10 dB to 15 dB at one or more tested frequencies. Slight hearing loss is defined as having baseline thresholds greater than 15 dB HL and up to 25 dB HL at one or more tested frequencies.

6. Primary Endpoint

The registry lists the primary outcome as Change in Temporary Threshold Shift at 4 kHz--Intent To Treat (ITT) Population, measured over 15 minutes post Controlled Sound Challenge.

The primary endpoint is the change from baseline in air-conduction hearing threshold at 4 kHz, measured 15 minutes post Controlled Sound Challenge. It is reported as a mean in dbHL with a 95% Confidence Interval. Baseline values were collected before sound exposure, and post-exposure values were compared with baseline. A change score expresses how the measured threshold at the specified time differs from the participant’s baseline; it is not the same as a single post-exposure threshold.

Focusing on one frequency and a defined post-challenge time point makes the primary outcome specific to the hearing response being studied. The registry description also indicates that measurements were taken across ears, frequencies, and post-sound time points, with repeated observations handled in an MMRM. The reported group means at the primary endpoint are 3.23 for low dose, 1.32 for middle dose, 3.81 for high dose, and 4.07 for placebo. Their 95% Confidence Intervals are, respectively, 1.97 to 4.49, 0.06 to 2.58, 2.57 to 5.04, and 2.81 to 5.34.

These are group-level estimates of change, not treatment-versus-placebo effects. The registry record does not report a pairwise estimate and confidence interval for each dose compared with placebo. The endpoint therefore describes the observed mean change within each group, while the size and precision of between-group differences remain unavailable in the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a mean change in hearing threshold, rather than a count or a time until an event. A mean summarizes the central level of the measured changes in a group. The accompanying 95% Confidence Interval communicates the estimate’s statistical uncertainty under the analysis used. A narrower interval indicates greater precision than a wider one, but precision is not the same as clinical importance. The registry reports group means and intervals, but it does not report a confidence interval for a dose-versus-placebo contrast.

Why use a repeated-measures model?

The endpoint description says measurements were obtained for each ear, frequency, and post-sound time point. Measurements taken repeatedly from the same participant are related; treating them as if they came from unrelated people can misrepresent uncertainty. In general, a repeated-measures model accounts for the correlation among observations from the same participant while estimating treatment patterns across the measurements.

The registry names a mixed-effects model repeated measures approach. It describes fixed effects for treatment, ear, frequency, and time, all two-way interactions, and the three-way interaction treatment by-frequency-by-time. It also specifies a random effect for subject nested within treatment. In general, fixed effects represent the modeled factors and their relationships, while a subject-level random effect can account for participant-specific clustering. The registry record does not report the model’s covariance structure, estimation method, convergence information, or diagnostics, so those aspects cannot be evaluated from the posted description.

What does the reported p-value tell us?

A p-value measures how incompatible the observed data are with a stated null hypothesis, under the assumptions of the statistical test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry lists p <0.05 for two mixed-model entries involving all four groups, but it does not state the null hypothesis or identify the contrasts represented. Without that context, the p-values cannot be assigned to a specific dose-versus-placebo comparison. They also cannot supply the missing effect estimate or confidence interval.

In general, an overall test across treatment groups and a pairwise test of one dose against placebo answer different questions. An overall test can indicate evidence of some variation among groups without identifying which groups differ. Pairwise comparisons require their own estimates and uncertainty, and interpretation may depend on how multiple comparisons were handled. The registry record does not describe the scope of the reported tests or a multiplicity adjustment.

Why are group intervals not a replacement for contrasts?

Each displayed confidence interval pertains to a group mean. A treatment comparison instead estimates the difference between groups, potentially adjusted according to the specified model. That contrast has its own standard error and confidence interval. The uncertainty of a difference depends on the estimates’ variances and, when measurements are related, their covariance. Consequently, separate group means and intervals do not by themselves determine the model-based contrast or its precision. Visual comparison can be descriptive, but it is not a formal substitute for the planned comparison.

What can be inferred from the posted analysis?

The arm results describe mean change and its interval at the primary time point. The mixed-model entries report p <0.05, but the registry record does not provide enough information to identify the tested effect. No recalculated two-arm comparison is available for this continuous endpoint; the record notes that values were missing or not estimable for a two-arm comparison. A recalculation based on group summaries would in any case be an unadjusted analysis and would not reproduce the MMRM, which uses the repeated measurements and model terms described in the record.

Sample-size calculations, when used as planning illustrations, answer a design question under stated assumptions; they are not observed power and do not change the evidence in the completed trial. The record states that planning illustrations use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with effects defined as fractions of the observed effect. It does not report the trial’s own sample-size justification. Such illustrations should not be read as proof that the study was adequately powered for any specific contrast.

General statistical interpretation also depends on model assumptions and data handling. The record does not report diagnostics, missing-data counts, or sensitivity analyses. Those omissions limit assessment of whether the fitted model adequately represents the data and whether conclusions would be robust to alternative assumptions. The available results can be described, but the unreported details should not be reconstructed by inference.

10. Analyses Reported by the Sponsor

The registry lists two mixed-model analysis entries, each reporting p <0.05 and naming all four groups. Neither entry supplies a model-based effect estimate, confidence interval, test statistic, or explanation of the hypothesis tested. The record therefore does not establish whether these entries are overall tests, specific contrasts, or separate analyses. It also does not explain why the entries are duplicated.

The reported group means and 95% Confidence Intervals are descriptive estimates for each arm. They are not a substitute for the sponsor’s model-based comparison. A recalculated two-arm comparison is not available because the registry record states that values were missing or not estimable for a two-arm comparison of this continuous endpoint. Even if an unadjusted comparison could be calculated from summary data, it would not reproduce the repeated-measures model described in the record.

The available information does not allow a direct comparison between a sponsor-reported numerical effect estimate and a recalculated estimate, because no such sponsor estimate is posted and no recalculated contrast is available. The registry record does not report a discrepancy between sponsor and recalculated results. The mixed-model p-values should therefore be read as the posted analysis result, with their precise target left unclear, rather than as confirmation of any particular dose-versus-placebo effect.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies the primary endpoint and describes repeated measurements across ears, frequencies, and time points. Its MMRM includes treatment, ear, frequency, and time effects, together with specified interactions. The posted results, however, do not explain how the primary hypothesis relates to the full set of model terms or which contrasts were designated as confirmatory. The record does not report a multiplicity adjustment or describe how testing across doses, frequencies, times, or outcomes was controlled. This matters because repeated testing can increase the chance of at least one nominally significant result even when the underlying effects are absent. That general concern cannot be quantified from the information recorded.

The registry lists two mixed-model entries with p <0.05, but does not explain whether they represent different endpoints, model terms, or analyses. No further interpretation of the duplicate entries is possible from the record. The number of outcome measures is listed as 2, while no secondary results are posted. The record does not identify the status of the other measure or provide a secondary outcome analysis.

The primary analysis population is named as ITT. The record does not provide a fuller definition of the population, a participant flow, or the numbers included in each stage of analysis. It also does not report missing outcome counts, reasons for missingness, imputation procedures, or sensitivity analyses. MMRM can use available repeated observations under assumptions about the missing-data process, but the registry description does not state the assumptions used or whether they were assessed. It would be inappropriate to infer that data were complete or that missingness had no effect.

Randomization and masking are recorded, but details of allocation concealment, protocol deviations, and adherence are not reported in the registry record. The trial’s statistical analysis plan, sample-size justification, interim analyses, and any prespecified hierarchy for testing are also not reported in the registry record. These gaps limit assessment of whether the reported tests align with a prespecified analysis and how robust the inference is to missingness and multiple testing.

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 non-serious adverse event terms

The registry reports zero serious adverse events in each listed group: low dose, middle dose, high dose, and placebo. The corresponding numbers at risk are 22, 20, 21, and 20. These figures describe the serious adverse event counts posted for the study; they do not establish that serious events were impossible or that the groups have identical safety profiles. The record does not list serious adverse event terms.

For other adverse events, the registry lists affected counts of 3, 5, 4, and 2 for the low-dose, middle-dose, high-dose, and placebo groups, respectively. These are counts, not model-based comparisons, and the record does not provide event-level descriptions in the information available for this analysis. The figures should not be interpreted as rates or used to compare risk without a defined outcome, analysis, and appropriate uncertainty assessment.

Deaths are recorded as null for all groups, rather than as a numerical count. Accordingly, the number of deaths is not reported in the registry record. Follow-up duration for adverse events and the methods used to collect or classify them are not reported in the registry record. The safety figures are therefore limited to the posted counts and at-risk values, and they should be read as a concise registry account rather than a comprehensive safety evaluation.

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

The results provide a description of mean threshold change at the primary time point for each treatment group. The group means are 3.23 for low dose, 1.32 for middle dose, 3.81 for high dose, and 4.07 for placebo, each with a reported 95% Confidence Interval. These estimates quantify the observed group-level outcome with uncertainty. They do not directly estimate the effect of a dose relative to placebo.

The registry also records mixed-model p-values of <0.05, but leaves their target unclear. A p-value without a stated hypothesis, contrast, or associated effect estimate cannot establish the magnitude or direction of a particular treatment difference. The posted record therefore does not show which dose, if any, differed from placebo, nor whether a difference would be clinically meaningful. The group intervals cannot fill that gap.

The study addresses temporary change after a controlled sound challenge and measures the endpoint at 4 kHz, 15 minutes after exposure. Those details define the setting and scope of the result. They do not establish effects at other frequencies, other time points, other sound exposures, or outside the study setting. The registry record does not report follow-up results that would clarify how threshold changes developed beyond the stated time point.

These findings should not be translated into a general claim that SPI-1005 prevents hearing loss or changes hearing outcomes in other circumstances. The study’s stated outcome is temporary auditory threshold shift under a specific challenge, not a broad measure of long-term hearing. Nor do the results establish the absence of adverse effects: serious adverse event counts are zero in the posted groups, while other adverse event counts are also listed, and important details of follow-up and event classification are not reported.

In short, the posted information documents group means, their confidence intervals, and a mixed-model p-value below 0.05 with an unspecified target. It does not provide the dose-versus-placebo estimates needed for a precise treatment-effect interpretation. The distinction between a reported statistical signal and a clearly quantified, clinically interpretable contrast is central to reading this record.

14. Why This Trial Matters Statistically

This trial illustrates why clinical results need both a statistical test and an interpretable effect estimate. The registry reports a mixed-model p-value below 0.05, but does not state exactly which hypothesis it addresses. The group means and their confidence intervals show the outcome within each arm, but do not quantify the modeled differences between doses and placebo. Without those contrasts, readers cannot assess the size and precision of a dose-specific result.

The endpoint also involves repeated measurements across ears, frequencies, and times. Such data are not simply a collection of independent observations. The specified MMRM reflects this structure through treatment and measurement factors, interactions, and a subject-level random effect. This makes the model description relevant to interpretation: a simple comparison of arm means would not necessarily answer the same question or account for the same data structure.

The record additionally shows why completeness of reporting matters. A named analysis method is useful, but readers also need to know the tested contrasts, estimates, uncertainty, multiplicity approach, missing-data handling, and alignment with the prespecified plan. Those details are not reported in the registry record. Their absence does not erase the posted results, but it constrains what can be concluded from them.

For biostatisticians and clinical researchers, the key lesson is to separate descriptive arm outcomes from comparative treatment effects, and to distinguish a p-value from the magnitude and precision of an effect. The study’s registered outcome and model provide context, while the missing contrast-level results limit inference. Clear reporting of estimates and uncertainty would make the result more useful for judging both statistical and clinical relevance.

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 most consequential limitation for interpreting efficacy is that the registry does not report dose-versus-placebo effect estimates and confidence intervals. The posted group means and intervals describe each arm separately, while the mixed-model p-values are not linked to an identified hypothesis or contrast. The record also contains two entries with the same reported threshold, without explaining their relationship. This leaves the comparative finding underspecified.

The endpoint is narrowly defined: change in air-conduction threshold at 4 kHz, 15 minutes post Controlled Sound Challenge. The posted information does not establish how findings relate to other frequencies or times. Although the study description refers to temporary hearing changes after music exposure and the endpoint description specifies a controlled sound challenge, further details of the challenge are not reported in the registry record.

Further limitations concern analysis transparency. The record names an ITT population and describes an MMRM, but does not report a detailed population definition, missing-data handling, model covariance structure, diagnostics, sensitivity analyses, or multiplicity procedures. The sample-size justification and full statistical analysis plan are not reported in the registry record. Consequently, it is not possible to assess from the posted information whether the analysis followed a prespecified hierarchy or how robust the findings are to alternative assumptions.

The safety information is also limited. Serious adverse event counts are posted, but serious event terms are not listed; deaths are null rather than numerical; and follow-up and event-collection details are not reported in the registry record. Other adverse event counts are available without detailed descriptions or comparative analyses. These constraints mean the safety summary should not be treated as a complete account of adverse outcomes.

Finally, the results pertain to the registered study setting and the stated endpoint. The record does not provide enough information to extend the findings to other populations, exposures, outcomes, or follow-up periods.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Otoprotection With SPI-1005 for Prevention of Temporary Auditory Threshold Shift — NCT01444846.
• Registry record last updated 2026-06-03; status last verified 2026-06.
• Results first posted 2026-06-03.
• 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

This completed randomized, quadruple-masked, parallel phase 2 study evaluated oral SPI-1005 at low, middle, and high doses against placebo for temporary auditory threshold shift after a controlled sound challenge. The registered primary endpoint was mean change in air-conduction threshold at 4 kHz, measured 15 minutes post challenge in the ITT Population.

The posted group means were 3.23, 1.32, 3.81, and 4.07 for low dose, middle dose, high dose, and placebo, respectively. The registry reports 95% Confidence Intervals for those means and mixed-model p-values of <0.05 in two entries. The entries do not identify the tested contrasts, and the record does not provide dose-versus-placebo estimates and confidence intervals.

Serious adverse event counts are zero in the listed groups; other adverse event affected counts are also reported. Important details about multiplicity, missing data, model diagnostics, sample-size justification, and the precise hypotheses behind the mixed-model results are not reported in the registry record.