Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults (NCT00119379), a randomized phase 2 study. The primary outcome is Change in Fat mtDNA Content.

2. Clinical Question

The trial addresses whether two strategies for changing antiretroviral treatment or supplementation are associated with a change in a biological marker of fat mitochondrial content in adults with HIV lipoatrophy. The registry describes lipoatrophy as fat loss and frames mitochondrial toxicity as a possible contributor. Its stated hypotheses connect changes in mitochondrial DNA content with mitochondrial function and markers of cellular damage; the primary endpoint is a measure of mitochondrial DNA in fat, not a direct measure of symptoms or overall health.

The two strategies are therefore compared through their observed group summaries, while the primary endpoint itself is a change in a tissue biomarker. The registry does not report a numerical treatment contrast or an inferential test for that contrast. Interpretation should distinguish the results within each randomized group from evidence about whether the strategies differ.

3. Trial Design

The registry describes a randomized, non-masked, parallel-group phase 2 study. It reports enrollment of 50 and a completed status. The study start is listed as 2005-04, and primary completion as 2008-10. The registry does not report the method used to generate or conceal the random allocation sequence, nor does it describe any blinding procedures beyond masking being listed as none.

The randomized groups were uridine supplementation and switch to TDF. The NucleomaxX regimen is recorded as 36 grams TID every other day. The switch strategy replaced AZT or d4T with Tenofovir Disoproxil Fumarate. Both groups had arm-level primary outcome results at baseline to Week 48. The registry does not establish from the posted summaries how many participants contributed an endpoint measurement, whether all enrolled participants completed follow-up, or how participants were assigned to the analysis population.

A parallel design assigns participants to a group whose intervention is followed over time; it does not mean that each participant receives both strategies. Randomization can help balance factors that are measured or unmeasured at the start, on average, but it does not remove uncertainty in a small study or guarantee identical groups. Because masking is listed as none, participants and study personnel were not reported as masked. The registry does not describe whether outcome assessment or laboratory measurement was masked.

The study concerns HIV infection and lipoatrophy, within the broader registry condition categories of metabolic diseases and nutrition disorders. Specific eligibility criteria, sites, participant demographics, treatment duration beyond the endpoint timeframe, and details of routine care are not reported in the registry record. The record also does not report the rationale for the enrollment target or a statistical sample-size justification. The enrollment figure is not, by itself, evidence that the study had adequate precision for the primary comparison.

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 Change in Fat mtDNA Content, measured over Baseline to Week 48.

The primary endpoint is change in subcutaneous abdominal fat mitochondrial DNA (mtDNA) content, measured in copies/cell, from baseline to Week 48. Mitochondrial DNA is genetic material within mitochondria, the cell structures involved in energy production. In this study, its amount in fat tissue serves as a biological marker relevant to the proposed mitochondrial-toxicity explanation of lipoatrophy.

The registry records the endpoint parameter as a median and its dispersion as an inter-quartile range. The reported group summaries are a median change of -169.0 copies/cell for uridine supplementation, with limits of -778.0 and 64.0, and a median change of 321.0 copies/cell for switch to TDF, with limits of -298.0 and 669.0. Those limits describe the reported inter-quartile ranges; they are not confidence intervals for the median or for a difference between groups.

General: a tissue biomarker can help investigate a biological process, but it is not automatically a measure of how a person feels, functions, or experiences a clinical outcome. The registry's hypotheses propose links between mtDNA content, mitochondrial function, and other biological changes. The posted primary endpoint measures mtDNA content only. It does not itself establish those links or show that a change in this marker translates into a clinical benefit. How the tissue measurements were collected and processed is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a median as the summary measure for the primary endpoint and an inter-quartile range as its dispersion measure. It reports the endpoint as change in subcutaneous abdominal fat mtDNA content in copies/cell from baseline to Week 48. The medians are -169.0 for uridine supplementation and 321.0 for switch to TDF. The reported inter-quartile range limits are -778.0 and 64.0 for uridine supplementation, and -298.0 and 669.0 for switch to TDF.

What does a median describe?

General: the median is the central value when observations are ordered. It is less affected by unusually high or low observations than the mean. It describes the center of a distribution, not the amount of variation around that center and not the change experienced by every participant. For a change score, a negative median indicates that the central observed change was a decrease; a positive median indicates that it was an increase. That description does not imply that all observations had the same sign.

What does the inter-quartile range add?

General: the inter-quartile range describes the middle portion of a distribution, running from the lower quartile to the upper quartile. It communicates how spread out the central observations are, without showing the full range or the shape of the distribution. Here, the registry labels the dispersion as inter-quartile range and supplies lower and upper limits for each group. These limits should not be read as confidence limits for the median. They also do not provide a confidence interval for a difference between groups.

How should the groups be compared?

The arm-level medians describe outcomes within each randomized group. A comparison between treatment strategies requires an estimate of the difference between groups and an account of its uncertainty. The registry does not report such an estimate, a standard error, a confidence interval, or a p-value for the primary endpoint. A numerical contrast could be constructed from the group medians, but that would be a new calculation and would not provide a formal analysis. It could also be a different estimand from a comparison based on individual participant data.

General: a confidence interval gives a range of values compatible with data under the assumptions of a statistical procedure. Its width reflects precision, and its interpretation depends on the method and assumptions. No confidence interval for the primary between-group effect is reported in the registry record. A p-value, if reported, would address compatibility with a specified null hypothesis under a model; it would not measure the size or clinical importance of an effect. No primary-endpoint p-value is reported in the registry record.

Why does dispersion matter?

General: when observations vary considerably, a group summary may be an imprecise description of the treatment effect, especially in a small study. Some biological measurements can also have skewed distributions or more variation than a simple statistical model expects. Over-dispersion means that variability exceeds what a model assumes; ignoring it can make uncertainty estimates too small. The registry does not report a distributional assessment or model-based variance estimate for this endpoint, so it is not possible to say whether over-dispersion was assessed or how it was handled.

The fact that the registry reports medians and inter-quartile ranges is consistent with describing distributions without assuming that the mean alone adequately represents them. However, the statistical test or estimator used to compare the groups is not reported. The record does not report an adjustment for baseline mtDNA content, other covariates, or repeated measurements. It also does not report whether the primary analysis used changes from baseline directly or a model that included baseline values.

What do the planning illustrations mean?

The registry describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between the groups, and a normal approximation. The planning effect is specified as a fraction of the observed effect. These are planning scenarios, not evidence about the study's observed power. Sample-size calculations describe how a future design might perform under assumptions; they do not establish the probability that this completed trial found an effect, and they do not replace the uncertainty around the observed results. The registry does not report its own design justification or say that these illustrations were used to plan the trial.

The assumptions behind a planning calculation matter. In general, the required sample size depends on the effect a study aims to detect, outcome variability, the chosen error rate, allocation, and analysis method. If the effect used for planning comes from a noisy estimate, the resulting illustration can be unstable. The registry record does not report a separate planning estimate, a target effect selected before enrollment, or the method used to justify enrollment of 50. The posted illustrations therefore should not be interpreted as a retrospective validation of the study design.

The registry lists the study as randomized and parallel, but the details needed to reproduce an analysis are not reported: the statistical test or model, handling of baseline values, treatment of missing outcomes, population analyzed, and any adjustments. Without those details and participant-level results, an independent reconstruction of the primary comparison is not possible from the arm summaries alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry names four secondary outcomes: change in limb fat, change in trunk fat, change in lumbar spine bone mineral density, and change in hip bone mineral density. It also records six outcome measures overall. The registry does not explain the relationship between the total number of outcome measures and the four named secondary outcomes, or report a full list of all outcome measures and their analysis plans. The secondary outcome results are not included in the primary endpoint summaries.

When a study evaluates multiple outcomes or multiple comparisons, the chance of obtaining at least one apparently notable result can increase. General: multiplicity procedures, such as adjusting testing thresholds or defining a hierarchy of outcomes, can address this issue. The registry does not report whether any multiplicity adjustment or prespecified testing hierarchy was used. No conclusion about the control of multiplicity can therefore be drawn from the record.

Missing-data methods are not reported in the registry record. The record does not describe how participants with unavailable Week 48 measurements were handled, whether any values were imputed, or how losses to follow-up were addressed. It also does not report the number of participants with observed primary outcome measurements at the endpoint. The arm-level enrollment figures should not be taken as proof that every enrolled participant contributed a Week 48 value.

The analysis population is not reported in the registry record. It is not stated whether the primary analysis followed randomized assignment for all participants, included only participants with measured outcomes, or used another population definition. The registry also does not report sensitivity analyses for missing data or deviations from assigned strategies. These omissions limit assessment of how robust the posted group summaries are to incomplete follow-up and analysis choices.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: elevated ck gr. 3 & 4 (12.5%), hypertrigliceridemia gr. 3 & 4 (7.7%), abnormal phos. gr. 3 (4.2%), pancreatitis gr. 3 (4.2%), vertigo gr. 3 (4.2%).

The registry reports serious adverse events and other adverse events separately for the randomized groups. In the uridine-supplementation group, 8 of 26 participants at risk had a serious adverse event, and 18 of 26 had an other adverse event. In the switch-to-TDF group, 6 of 24 participants at risk had a serious adverse event, and 13 of 24 had an other adverse event. Deaths are reported as 0 in each group.

The registry also lists serious adverse event terms with percentages: Elevated CK Gr. 3 & 4, 12.5%; Hypertrigliceridemia Gr. 3 & 4, 7.7%; Abnormal phos. Gr. 3, 4.2%; Pancreatitis Gr. 3, 4.2%; Vertigo Gr. 3, 4.2%; and Dysuria Gr. 3, 4.2%. The denominator for each term percentage is not reported in the registry record. These percentages should not be treated as directly comparable group-specific rates unless their denominators and coding rules are known.

General: adverse-event counts describe events recorded during study follow-up, not necessarily events caused by the assigned strategy. Counts alone do not show event timing, duration, severity beyond the listed terms, recurrence, or whether an event led to treatment discontinuation. The registry does not report those details in the safety figures. These data are descriptive and should be interpreted alongside the study's size and follow-up information, which is limited in the registry record.

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

The primary outcome is a tissue biomarker, not a direct measure of fat appearance, physical function, symptoms, or quality of life. The registry's biological rationale proposes that mitochondrial changes may be related to lipoatrophy. The posted endpoint measures change in mtDNA content in subcutaneous abdominal fat; it does not establish that mitochondrial function changed or that fat loss was reversed.

The group medians were -169.0 copies/cell for uridine supplementation and 321.0 copies/cell for switch to TDF. Their inter-quartile ranges were -778.0 to 64.0 and -298.0 to 669.0, respectively. These are descriptive summaries of observed changes. The registry does not report a formal test or a confidence interval for the difference between the randomized groups. Thus, the summaries do not establish whether the strategies differ, whether either strategy changed the outcome relative to no treatment change, or whether the groups are equivalent.

The randomized design gives the study a structure intended to support a comparison, but interpretation also depends on precision, missing outcomes, analysis choices, and outcome measurement. The registry does not report the statistical analysis plan, the analysis population, missing-data handling, or the number of participants with endpoint measurements. Those missing details make it difficult to assess whether the summaries reflect all randomized participants and how much uncertainty surrounds any comparative effect.

Nor do the primary results establish findings for the secondary outcomes of limb fat, trunk fat, lumbar spine bone mineral density, or hip bone mineral density. Their names appear in the registry, but results are not reported in the primary summaries. Safety counts and listed serious adverse event terms are descriptive and do not establish causation or provide a complete account of event timing or individual clinical circumstances.

The most defensible interpretation is limited: the registry records differing group-level median changes in fat mtDNA content, with wide inter-quartile ranges that span decreases and increases. A complete comparative conclusion would require an estimated between-group effect with its uncertainty and clearer information about the analysis and outcome completeness. No medical recommendation follows from these summaries.

13. Why This Trial Matters Statistically

Statistically, this trial is useful as an example of the distinction between a biological rationale and an estimable treatment comparison. The hypotheses describe a chain of proposed processes involving mtDNA content, mitochondrial function, and fat loss. The primary endpoint observes only mtDNA content in subcutaneous abdominal fat. That endpoint can contribute evidence about a biological pathway, but it does not test every link in the proposed chain or directly measure a clinical outcome.

The reported medians and inter-quartile ranges make the distribution of changes more visible than a single central estimate would. The ranges include both negative and positive values in each group, indicating variation in direction as well as magnitude. This is a reminder that a group median is not a prediction for an individual and that a central estimate needs an accompanying measure of precision for comparative interpretation.

Randomization is important because it supports a fair comparison of assigned strategies, but randomization does not make a result self-interpreting. A clearly reported between-group estimate, confidence interval, analysis population, and missing-data approach would help readers evaluate the strength and precision of evidence. Those elements are not reported in the registry record for the primary comparison. As a result, arm-level summaries cannot answer all the questions that a randomized trial is intended to address.

The registry also illustrates why sample-size planning and observed results should be kept distinct. Planning illustrations based on an observed effect and stated assumptions are not observed power and do not establish how precise the completed trial's estimates are. Precision is judged from the actual estimate and its uncertainty, with attention to the data and analysis method.

Finally, the safety summaries require their own statistical context. Event counts, denominators, event definitions, follow-up, and attribution all affect interpretation. The record reports group counts and a list of serious event terms with percentages, but does not report the denominator for each term percentage. Clear reporting of these details is necessary for readers to understand what the safety figures can and cannot support.

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 primary result is reported as group medians and inter-quartile range limits, without a reported between-group estimate, confidence interval, or p-value. This prevents direct evaluation of the magnitude and precision of the randomized comparison. The limits around the medians are measures of distribution, not uncertainty in the treatment contrast.

The registry does not report baseline mtDNA values, individual participant measurements, or a distribution plot in the registry record describing the primary result. It therefore does not allow assessment of baseline balance for this endpoint, the shape of each group's outcome distribution, or the influence of unusually large changes. The method used to measure mtDNA and the handling of laboratory samples are not reported in the registry record.

Details of eligibility criteria, participant characteristics, and outcome completion are not reported. The analysis population and missing-data methods are also not reported, so the degree to which the summaries include all randomized participants cannot be assessed. The registry does not state how treatment discontinuations, deviations from assigned strategies, or unavailable Week 48 measurements were handled.

The statistical analysis plan, choice of test or model, covariate adjustment, and multiplicity approach are not reported. Results for the listed secondary outcomes are not included in the primary summaries. The record does not provide enough information to establish whether those outcomes were analyzed or how their results should be interpreted alongside the primary endpoint.

Safety reporting is limited to group counts, deaths, and selected serious adverse event terms with percentages. The denominator for each term percentage is not reported in the registry record, and timing, duration, recurrence, attribution, and discontinuation related to events are not described in these safety figures.

These limitations do not erase the reported observations, but they constrain the conclusions that can be drawn from them. In particular, the arm-level summaries cannot establish a comparative effect with quantified uncertainty or a clinical consequence of the biomarker changes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults — NCT00119379.
• Registry record last updated 2017-06-07; status last verified 2017-05.
• Results first posted 2017-05-12.
• 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 randomized, non-masked, parallel phase 2 trial enrolled 50 and compared uridine supplementation with switching to Tenofovir Disoproxil Fumarate in adults with HIV lipoatrophy. The primary endpoint was change in subcutaneous abdominal fat mtDNA content, measured in copies/cell from baseline to Week 48.

The reported median changes were -169.0 in the uridine-supplementation group and 321.0 in the switch-to-TDF group. The registry gives inter-quartile range limits for both groups but does not report a formal between-group estimate, confidence interval, or p-value. The endpoint is a biological marker, and the summaries do not by themselves establish a clinical effect or reversal of lipoatrophy.

The registry lists four secondary outcomes and describes serious and other adverse event counts. The statistical analysis plan, analysis population, missing-data handling, and multiplicity approach are not reported in the registry record. The results are therefore best read as descriptive group summaries with important uncertainty about the comparative analysis.