Fatty Acid Oxidation Defects and Insulin Sensitivity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fatty Acid Oxidation Defects and Insulin Sensitivity (NCT02517307), a randomized na study. The primary outcome is Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min.

2. Clinical Question

The scientific question is about insulin action under two experimental infusion conditions, not about a clinical treatment outcome. Insulin infusion promotes glucose disposal into muscle and adipose tissue; the registry describes glycerol co-infusion as a condition in which disposal is expected to be high and Intralipid co-infusion as one that can temporarily reduce disposal. Comparing those conditions across the FAOD and control groups can help assess whether the response differs by group.

The main question is therefore an interaction question: whether the change associated with the infusion condition varies between participants with FAOD and controls. Separate contrasts between each group-condition combination and the control glycerol condition do not, on their own, establish that interaction. The registry's mixed-model result is the sponsor-reported overall analysis; its detailed estimates are not reported in the registry record.

3. Trial Design

The registry describes a completed randomized, unmasked crossover study with 41 enrolled participants. The study examined people with fatty acid oxidation disorders and normal matched controls. The listed conditions include very long-chain acyl-CoA dehydrogenase deficiency, trifunctional protein deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, carnitine palmitoyltransferase II deficiency, and normal volunteers. The phase is listed as NA.

The four result groups combine diagnostic group and clamp co-infusion: Glycerol/Saline FAOD, Intralipid FAOD, Glycerol/Saline Control, and Intralipid Control. The interventions listed are Intralipid/Heparin, Glycerol/Saline, and a hyperinsulinemic euglycemic clamp. The registry characterizes the model as crossover, but the order of conditions, randomization procedure, washout arrangements, and details of how the crossover was implemented are not reported in the registry record. Matching criteria are also not reported in the registry record.

The primary outcome was glucose disposal rate, measured during the last 30 minutes of a 300 minute clamp. The registry reports a mean and standard deviation for each group-condition combination. Its population description notes that 1 participant with FAOD withdrew after completing the glycerol clamp. It also notes that 2 control participants completed the protocol to establish study procedures but were excluded from statistical analysis, and that 1 control participant withdrew and 1 was discontinued. The description of the remaining primary-analysis population is truncated in the registry record.

The study start is listed as 2016-02, primary completion as 2021-01, and status as completed. The original sample-size justification, the planned analysis population, and any additional protocol details 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.

Before assignment: 2 initial control participants who did not have a comparable FAO matched participant completed the protocol procedures to establish the final protocol; the data was not included in the final analysis. 23 participants with a FAOD were randomized. Of those randomized, 2 did not meet inclusion criteria, and 2 declined to participate. 27 control participants were randomized. Of those randomized, 2 did not meet inclusion criteria and 3 declined to participate.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 1 participant with a FAOD withdrew after completing the glycerol clamp . 2 control participants completed the protocol to establish the study procedures, but are not included in the statistical analysis. 1 control participants withdrew and 1 was discontinued leaving 18 participants data for the intralipid clamp. In addition, 1 other control was discontinued and 1 control had technical challenges during the glycerol clamp leaving 16 control participants data for glycerol clamp.

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 Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min, measured over Calculated during the last 30 minutes of a 300 minute clamp..

The primary endpoint is glucose disposal rate (Rd), measured in mg/min. It represents the rate of glucose infusion needed to maintain euglycemia during steady-state insulin infusion. In this clamp setting, insulin stimulates glucose disposal into muscle and adipose tissue, so the rate provides a physiological measure of insulin action under the experimental conditions.

The registry states that Rd is calculated from the ratio of deuterated glucose to unlabeled glucose at the beginning and end of the clamp. The measurement is taken during the last 30 minutes of a 300 minute clamp, when the registry describes the clamp as being at steady state. The reported values are group means with standard deviations.

The endpoint is useful for the stated question because the investigators wanted to compare how Intralipid co-infusion changes glucose disposal in participants with FAOD relative to matched controls. A lower disposal rate during Intralipid than during Glycerol/Saline is consistent with the registry's description of a temporary insulin-resistant state. However, the central scientific comparison is whether that change differs between the two participant groups. An isolated mean or a contrast against one reference group is not itself the full group-by-condition comparison.

Rd is a continuous physiological measure, not a direct measure of long-term blood glucose control or a clinical outcome. The endpoint therefore addresses experimental insulin sensitivity during the clamp rather than everyday health outcomes.

7. Results Posted in the Registry

• Glycerol/Saline FAOD: mean 709.00 versus 842.00 on control; difference -133.00 (95% CI -309.44 to 43.44), standardized effect d = -0.51; z-test p = 0.140.
• Intralipid FAOD: mean 429.00 versus 842.00 on control; difference -413.00 (95% CI -607.73 to -218.27), standardized effect d = -1.42; z-test p = <0.001.
• Intralipid Control: mean 497.00 versus 842.00 on control; difference -345.00 (95% CI -539.73 to -150.27), standardized effect d = -1.19; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Glycerol/Saline FAOD: mean 84.70 versus 50.20 on control; difference 34.50 (95% CI 7.64 to 61.36), standardized effect d = 0.86; z-test p = 0.012.
  • Intralipid FAOD: mean 97.20 versus 50.20 on control; difference 47.00 (95% CI 18.07 to 75.93), standardized effect d = 1.09; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Glycerol/Saline FAOD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Intralipid FAOD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcome is endogenous glucose production (Ra), measured in mg/min during the last 30 minutes of a 300 minute clamp. The posted group means show a different broad pattern from Rd: under Glycerol/Saline, the FAOD group mean is higher than the control mean, while under Intralipid the FAOD group mean is lower than the control mean. The registry's mixed-model analysis for this endpoint reports p = 0.011. Its detailed modeled estimates and confidence interval are not reported in the registry record.

This secondary pattern adds physiological context but does not directly settle the primary question about glucose disposal. Ra concerns endogenous glucose production, whereas Rd concerns glucose disposal into muscle and adipose tissue. They describe related but distinct processes measured during the clamp. The secondary result therefore should not be treated as confirmation of a particular primary endpoint contrast or as a substitute for a direct group-by-condition estimate for Rd.

The sponsor's reported mixed-model result deserves priority over the unadjusted recalculations for this endpoint as well. The simple recalculations provide pairwise contrasts against the control glycerol group, but the registry does not show that these are the model's target comparisons. Their p-values are unadjusted and should be interpreted cautiously.

Secondary findings generally carry less evidential weight than a prespecified primary result, especially when the number of planned or explored analyses and any multiplicity strategy are not clear. The registry lists one secondary endpoint, but the analysis hierarchy and multiplicity adjustment are not reported in the registry record. The secondary pattern can inform interpretation and motivate further study, but it should not override the primary result or be presented as an independent definitive answer to the principal question.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous, so the registry reports group means and standard deviations. A mean describes the central value of the glucose-disposal measurements in a group-condition combination. A standard deviation describes how spread out individual measurements are around that mean. Neither quantity alone gives the uncertainty in a comparison; that depends on the group sizes and variability as well as on the analysis model.

What does the reported mixed model contribute?

The sponsor reports a Mixed Models Analysis involving the four combinations of participant group and infusion condition. In general, a mixed model can represent multiple sources of variation and account for the structure of repeated measurements when a design includes within-participant conditions. That feature can be relevant in a crossover study, where observations may be related because they come from the same participant. The registry does not report the model specification, covariance structure, adjustment variables, estimated contrasts, or the exact hypothesis tested by the reported p-value. It is therefore not possible to reconstruct the model or interpret its p-value as a particular pairwise comparison from the registry record alone.

The primary reported p-value is 0.136. A p-value summarizes how compatible the observed data are with a specified null hypothesis under the model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. Because the registry does not give the model estimate or confidence interval, the magnitude and precision of the sponsor's modeled result cannot be described from that analysis.

What are the unadjusted recalculations?

The recalculated comparisons use the posted group means and standard deviations to describe simple differences from the Glycerol/Saline Control group. They are unadjusted comparisons of summary statistics. For example, the primary outcome's recalculated mean difference for a listed group is expressed relative to the control glycerol mean. These contrasts can help readers understand the posted means, but they do not reproduce a mixed model for a crossover design and do not directly answer whether the change from glycerol to Intralipid differs between FAOD participants and controls.

A standardized mean difference expresses a contrast in units of pooled standard deviation, giving a scale-free description of magnitude. The recalculated standardized values are descriptive, and they do not supply a model-based estimate for the crossover interaction. Standardization also does not resolve limitations in the analysis population or missing design details.

The recalculated confidence intervals describe uncertainty around those unadjusted mean contrasts under the recalculation approach. In general, a confidence interval gives a range of effect values reasonably compatible with the data and the method used to construct it. It should be interpreted together with the estimate: a wide interval indicates less precision, and an interval spanning zero includes values corresponding to no difference under that contrast. This does not establish equivalence, because equivalence requires a prespecified margin and a suitable analysis. Neither an equivalence margin nor an equivalence analysis is reported in the registry record.

Why does the crossover structure matter?

In a crossover design, measurements made under different conditions within the same participant may be correlated. An analysis that accounts for that relationship can differ from one that treats group summaries as independent. The registry labels the study as crossover and reports a mixed-model analysis, but it does not provide enough detail to determine how participant-level pairing or other design features were handled. The simple recalculations are therefore best understood as supplementary descriptive contrasts, not as a replacement analysis.

Randomized allocation is reported, but the randomization method and the allocation details are not reported in the registry record. The record also lists no masking. The analysis plan, including whether covariates or period effects were included, is not reported in the registry record. These omissions limit the ability to assess the assumptions behind the sponsor's analysis or to reproduce it.

Why should separate contrasts not be mistaken for an interaction?

The scientific question concerns whether the infusion-related change in Rd differs by participant group. That requires comparing changes, or fitting a model that directly tests the group-by-condition relationship. Separate comparisons of each condition group against a single control mean do not provide that test. Even if one contrast has a small p-value and another does not, the difference between those p-values is not a test of the difference between effects. The registry's mixed-model analysis is the relevant reported overall analysis, but its target contrast and estimates are not detailed.

In general, over-dispersion means that observations vary more than a statistical model's assumed variability allows. It can make standard errors and tests unreliable if the model does not accommodate that extra variation. The registry's continuous endpoint is presented with standard deviations, but the record does not report a particular over-dispersion problem or diagnostic assessment; none should be inferred for this study.

Finally, multiplicity can arise when many outcomes, groups, contrasts, or analyses are examined. Repeated testing can increase the chance of finding apparently strong results by chance. The registry lists a primary endpoint and one secondary endpoint, but adjustment for multiple testing and a prespecified hierarchy are not reported in the registry record. This is one reason to give the primary reported model more weight than isolated unadjusted contrasts or secondary p-values.

11. Confidence Intervals and Precision

Precision is best assessed from an estimate together with its confidence interval. The registry posts the primary group means and standard deviations, but it does not post a confidence interval or model estimate for the sponsor's mixed-model analysis. That means the uncertainty around the sponsor-reported primary result cannot be fully assessed from the registry's model output.

The unadjusted recalculations give a 95% confidence interval of -309.4 to 43.44 mg/min for the Glycerol/Saline FAOD contrast with Glycerol/Saline Control. Because the interval spans zero, the recalculated contrast is compatible with both a negative difference and values near no difference under this simple comparison. Its breadth also signals limited precision.

For the Intralipid FAOD contrast with Glycerol/Saline Control, the recalculated interval is -607.7 to -218.3 mg/min. For the Intralipid Control contrast with Glycerol/Saline Control, it is -539.7 to -150.3 mg/min. Both intervals lie below zero for those unadjusted contrasts, but neither is an interval for the primary group-by-condition interaction. They do not show how precisely the difference in the Intralipid response between FAOD participants and controls was estimated.

Confidence intervals are not guarantees that the true effect lies within the stated range. In general, they reflect sampling uncertainty under the assumptions and method used. Here, the recalculated intervals accompany simple contrasts, while the sponsor's reported model result has no posted interval. The crossover structure, incomplete reporting of analysis details, and limited group sizes all make it important not to treat the recalculated intervals as if they summarized the sponsor's model. The key precision gap is the absence of a model-based estimate and interval for the central comparison of interest.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total event counts. They illustrate how many participants per arm would be needed under the listed assumptions to detect a specified fraction of the observed effect. The figures are not the trial's original enrollment target or its design justification; those original assumptions are not reported in the registry record.

The planning illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is set to the stated fraction of the observed effect. The 80% power column gives the number of participants per arm for a design with an 80% chance of detecting that assumed effect under the planning model, if the effect and assumptions are correct. The 90% power column expresses the corresponding per-arm count for a 90% chance.

Rows that plan for 75% or 50% of the observed effect represent smaller target effects than a plan using the full observed effect. Smaller effects are harder to distinguish from random variation, so they require more participants per arm under these assumptions. This is a planning illustration, not observed power. It does not establish what the completed study was capable of detecting, and it does not change the interpretation of the sponsor's reported analysis.

The illustration uses an observed effect from a simple comparison and a normal approximation. It may not reflect the actual crossover structure, the sponsor's mixed-model analysis, or any features of the original study design. It should be read as a conditional planning aid, not as a recommended sample size or a retrospective verdict on the study.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -133.000; pooled standard deviation σ = 261.957.
2. n = 2 × (1.96 + 0.842)² × 261.957² / -133.000² = 60.9, rounded up to 61 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -133                      # observed difference in means
sigma <- 261.956970789965                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2517307)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 61 (80% power), 82 (90% power)
 75% of observed effect: n per arm = 109 (80% power), 145 (90% power)
 50% of observed effect: n per arm = 244 (80% power), 327 (90% power)
power.t.test: 61.9 
Simulated power at n = 61 per arm: 0.793 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports a Mixed Models Analysis for the primary endpoint across the four groups, with p = 0.136. For the secondary endpoint, it reports a Mixed Models Analysis with p = 0.011. The record does not give model estimates, confidence intervals, model details, or the exact contrasts associated with these overall results.

The recalculated primary contrasts are simple unadjusted comparisons based on the posted group means and standard deviations. They are not the sponsor's own model. The primary recalculation for Glycerol/Saline FAOD gives p = 0.14, while the sponsor reports p = 0.136 for the mixed-model analysis. Although the displayed values are numerically close, they come from different analyses and should not be treated as interchangeable. The sponsor's own analysis takes precedence.

The other recalculated primary contrasts compare Intralipid groups with the Glycerol/Saline Control mean. Their p-values do not replace the sponsor's overall mixed-model result and do not directly test whether the Intralipid-related change differs between diagnostic groups. The registry does not provide enough information to verify that the recalculations target the same hypothesis as the reported model.

For the secondary endpoint, the same distinction applies: the recalculated comparisons are not substitutes for the sponsor's mixed-model result. The sponsor's reported model is the primary reference for the trial's own analysis, while the recalculations serve only as unadjusted supplementary descriptions of group contrasts.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies glucose disposal rate as the primary outcome and endogenous glucose production as a secondary outcome. It reports an overall mixed-model p-value for each. However, the analysis plan, the prespecified contrast for each outcome, and any hierarchy for interpreting outcomes are not reported in the registry record.

Multiplicity refers to the increased chance of a false-positive finding when multiple hypotheses are tested. Tests may arise from multiple endpoints, pairwise group comparisons, time points, subgroups, or alternative models. Even with one primary endpoint, examining several contrasts can create a multiplicity issue. Whether an adjustment was used, or whether only selected analyses were intended to be confirmatory, is not reported in the registry record. The unadjusted recalculated p-values should therefore be treated as descriptive rather than as a set of independently confirmatory tests.

Missing-data handling is also not described in enough detail to assess its effect. The registry notes that 1 participant with FAOD withdrew after completing the glycerol clamp. It also says that 2 control participants completed the protocol to establish study procedures but were not included in statistical analysis, and that 1 control participant withdrew and 1 was discontinued. The primary population description is truncated after stating that 18 participants had data for the intr...; the rest of that text is not reported in the registry record. The reasons for the control withdrawal and discontinuation, the handling of incomplete crossover measurements, and any imputation or sensitivity analyses are not reported in the registry record.

In general, missing observations can affect a crossover analysis if the measurements available differ systematically from those that are missing, or if incomplete participation changes which within-person comparisons can be made. The registry does not report whether the mixed model used all available observations under a missing-at-random assumption or whether other approaches were considered. The analysis population and assumptions about missingness therefore cannot be independently assessed.

These reporting gaps do not establish that the analysis was inappropriate. They mean that readers cannot verify the full analysis plan, determine the impact of missing observations, or establish whether the reported tests were adjusted for all relevant comparisons.

16. 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: urinary tract infection/kidney infection (5.6%), vomiting (5.6%), rhabdomyolysis (5.3%).

The registry lists serious adverse events and other adverse events by group-condition category. Serious adverse events affected 1 participant in Glycerol/Saline FAOD, 2 in Intralipid FAOD, none in Glycerol/Saline Control, and 1 in Intralipid Control. The corresponding numbers at risk were 19, 18, 20, and 21. The record lists zero deaths in each group.

Other adverse events affected 13 participants in Glycerol/Saline FAOD, 12 in Intralipid FAOD, 11 in Glycerol/Saline Control, and 13 in Intralipid Control. These are participant counts, not event counts, and the groups have different at-risk totals. The registry also lists Urinary Tract Infection/Kidney Infection and Vomiting at 5.6% each, and Rhabdomyolysis at 5.3%, among the top serious adverse event terms.

These descriptive registry counts do not establish that an event was caused by a particular infusion or distinguish risks between conditions. The record does not provide event-level timing, severity detail beyond the serious/non-serious categories, or a causal assessment. Small group counts and the crossover design also mean that these figures should be read as safety reporting, not as a stand-alone comparative safety analysis.

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

The posted results concern short-term physiological responses measured during hyperinsulinemic euglycemic clamps. They do not establish long-term effects on blood glucose, health outcomes, or daily functioning. The primary endpoint measures glucose disposal during the clamp, and the secondary endpoint measures endogenous glucose production during the same experimental setting.

The registry's group means show that glucose disposal was lower during Intralipid co-infusion than during Glycerol/Saline in both FAOD participants and matched controls. That pattern is consistent with the study's stated experimental purpose. The sponsor-reported mixed-model p-value for the primary endpoint is 0.136, but the registry does not post the model estimate or its confidence interval. Consequently, the size and precision of the model's result cannot be judged fully from the reported analysis.

The simple recalculated contrasts show differences relative to the Glycerol/Saline Control group, not a direct estimate of whether the Intralipid-related change differs between participants with FAOD and controls. They are useful for understanding the posted means but cannot establish the main interaction question by themselves. The secondary endpoint adds a separate view of glucose production, but its mixed-model estimate and uncertainty are also not posted.

These findings should not be generalized beyond the experimental groups and conditions described in the registry. The listed diagnoses are varied, and the record does not provide subgroup estimates by disorder. The study also does not report enough detail to assess the randomization process, crossover sequence, missing-data assumptions, or full analysis plan.

In general, a registry result describes what was measured and analyzed in a particular study; it is not a treatment recommendation. The evidence is best understood as a small experimental investigation of insulin-related physiology, with reported group summaries and limited detail on the sponsor's model-based estimates.

18. Why This Trial Matters Statistically

This trial is statistically informative because it combines a crossover model with a comparison between diagnostic groups. That structure makes the principal question more specific than whether one group has a higher or lower mean: it asks whether the response across infusion conditions differs between people with FAOD and matched controls. Answering that question depends on comparing changes across conditions, while accounting for the study's repeated-measure structure.

The registry reports a mixed-model analysis, which is relevant to the stated crossover design, but it provides only an overall p-value and not the modeled contrasts or their confidence intervals. The unadjusted recalculations make the posted group means easier to interpret, yet they do not recover the direct interaction estimate. This distinction illustrates why descriptive contrasts and the primary design-based analysis answer different questions.

The example also shows why statistical significance in individual comparisons is not equivalent to evidence that two groups respond differently. A contrast against a shared reference can be precise while the direct difference between responses remains uncertain or unreported. The model estimate and its interval would be needed to assess the central comparison directly.

Finally, the record contains incomplete reporting about the analysis population, missing data, multiplicity, and model specification. These details matter because they shape both the validity and interpretation of the estimates. The study is a useful illustration of how a physiological endpoint, crossover structure, group comparisons, and reporting completeness jointly affect what can be concluded from trial results.

19. 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 limitation for interpreting the central question is that the registry does not report the mixed-model estimate or confidence interval. The overall p-value alone does not show the magnitude or precision of the modeled group-by-condition response, and the exact hypothesis associated with that result is not detailed.

The recalculated contrasts are unadjusted comparisons against the Glycerol/Saline Control mean. They are not direct estimates of the difference between the two groups' responses to Intralipid, and they do not account for the crossover structure in the way a participant-level model may. The registry labels the study as crossover, but does not report the condition sequence, period effects, washout details, or covariance structure.

The primary population description is truncated. The registry does identify withdrawals, a discontinuation, and control participants excluded because they completed procedures to establish study methods, but it does not fully describe the analysis population or explain all missing measurements. The treatment of incomplete crossover data and any sensitivity analyses are not reported in the registry record.

Matching criteria, randomization details, the original sample-size justification, and the full statistical analysis plan are not reported in the registry record. The diagnoses are heterogeneous, yet subgroup results by specific disorder are not posted. The number of participants in the outcome groups is limited, and confidence intervals for the recalculated comparisons indicate uncertainty for at least some contrasts.

Multiplicity procedures and a hierarchy for primary and secondary analyses are also not reported. These limitations constrain reproducibility and the strength of inferences that can be drawn from the posted results; they do not, by themselves, prove that the study's analysis was invalid.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Fatty Acid Oxidation Defects and Insulin Sensitivity — NCT02517307.
• Registry record last updated 2024-01-30; status last verified 2023-12.
• Results first posted 2024-01-30.
• 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.

23. Record Summary

NCT02517307, titled “Fatty Acid Oxidation Defects and Insulin Sensitivity,” is a completed randomized, unmasked crossover study sponsored by Oregon Health and Science University. It enrolled 41 participants and examined clamp-based glucose disposal in participants with fatty acid oxidation disorders and normal matched controls.

The primary endpoint was glucose disposal rate (Rd) during the last 30 minutes of a 300 minute hyperinsulinemic euglycemic clamp. The registry reports group means and standard deviations, along with a Mixed Models Analysis p-value of 0.136 for the primary endpoint. One secondary outcome, endogenous glucose production (Ra), is also posted, with a mixed-model p-value of 0.011.

Unadjusted recalculations offer simple contrasts based on posted group summaries, but the sponsor's mixed-model analysis takes precedence. Model estimates, confidence intervals, full analysis details, and key information about missing-data handling and multiplicity are not reported in the registry record.