Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency (NCT02019667), a randomized phase 2 study. The primary outcome is Change From Baseline on the Adaptive Behavior Assessment System (ABAS) Test at the End of the Study Drug and Placebo Treatment Periods.

2. Clinical Question

The registry lists safety, tolerability, and efficacy as the trial’s broad objectives. The primary efficacy measure was the ABAS questionnaire, completed by a participant’s parent or caregiver at the end of each six-month treatment period. The registry also identifies neuropsychological testing and responses to a parent questionnaire in its brief description of the planned efficacy assessments. The posted primary result, however, is specifically the ABAS change-from-baseline measure.

The secondary measures included transcranial magnetic stimulation (TMS) assessments of cortical excitation and inhibition, as well as physical examination results. The posted TMS outcomes address motor threshold, intracortical facilitation, and short-interval intracortical inhibition. The registry’s broader description also mentions long-interval intracortical inhibition as a secondary outcome, but a result for that measure is not reported in the registry record.

The question is therefore about the pattern and precision of the measured changes during treatment periods, not about whether SGS-742 should be used. The registry results do not establish a clinical recommendation. They describe a small study with incomplete ABAS outcome availability and estimates whose uncertainty is important to consider.

3. Trial Design

The registry identifies this as a randomized Phase 2 clinical trial with triple masking and a crossover model. The brief description calls the study double-blind. These descriptions differ in their wording; further details about the masking roles are not reported in the registry record. The trial is marked completed and lists the National Institute of Neurological Disorders and Stroke (NINDS) as sponsor.

Participants with SSADH deficiency were assigned to periods of SGS-742 and placebo. Each treatment period is described as lasting six months. The registry also reports safety results for washout periods following each treatment, but the length of those periods and the treatment sequence are not reported in the registry record. A crossover design allows treatment-period observations to be obtained within a study population exposed to both conditions; the details of how the registry’s posted comparisons account for the paired structure are not reported.

The registry records enrollment of 19. Its brief study-population description refers to twenty-two children and adults, so the registry contains both a stated population size and a recorded enrollment that do not match. The reason for that difference is not reported in the registry record. The primary ABAS outcome has 13 observations in each treatment-period group, while the posted TMS outcomes have 16 observations for placebo and 17 for study drug. These outcome-specific counts indicate that not all enrolled participants contributed to every reported measure.

The listed primary outcome is the change from baseline in ABAS score at the end of the study-drug and placebo treatment periods, with baseline and six months named as its timeframe. Safety assessment included clinical examination and neuropsychological testing in the brief description. The registry record does not report the original sample-size justification, detailed allocation sequence, treatment-sequence balance, washout duration, interim analyses, or a full statistical analysis plan. Those omissions limit assessment of how the conduct and planned analysis were intended to address crossover-specific issues.

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: Following a baseline visit, participants were randomized to receive either placebo or study drug for 6 months (Phase 1) followed by 6 months of the alternate treatment (Phase 2). Participants completed a 9-week washout period following each phase of the study.

First Intervention (6 Months)

Reasons for not completing this period:

Washout Period (9 Weeks)

2nd Intervention (6 Months)

Reasons for not completing this period:

Washout Period (9 Weeks)

Analysis population for the primary outcome, as defined in the registry: The ABAS was not able to be completed for all participants.

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 From Baseline on the Adaptive Behavior Assessment System (ABAS) Test at the End of the Study Drug and Placebo Treatment Periods, measured over baseline and six months.

The primary endpoint is change from baseline on the Adaptive Behavior Assessment System (ABAS) at the end of the study-drug and placebo treatment periods. A parent or caregiver completed the questionnaire. The registry describes ABAS as an assessment of adaptive skills across the lifespan, covering conceptual, social, and practical skills. The listed examples include communication, self-direction, leisure, health, safety, and self-care.

The registry says the General Adaptive Composite score ranges from <40 to >160, with lower scores representing lower adaptive behavior. It defines a positive change as improvement compared with baseline and a negative change as decline. The reported treatment-period summaries are averages of the individual baseline-to-period changes, with a standard deviation describing variation among those changes. A comparison of the treatment-period means is intended to give a baseline-adjusted interpretation of the difference between periods.

Adaptive behavior is relevant to this study because it captures everyday skills rather than only a laboratory measurement or a single neurological response. Parent or caregiver reporting can reflect functioning across several domains, though it also depends on questionnaire completion and the reporter’s observations. The registry explicitly notes that ABAS could not be completed for all participants. The primary result is therefore based on 13 observations in each treatment-period group, fewer than the recorded enrollment of 19.

The outcome’s relevance does not remove uncertainty about what a change means for an individual participant. The registry does not report a threshold for a clinically important difference, nor does it provide a participant-level distribution or responder analysis. The mean change summarizes the group but does not show whether individual experiences were similar or varied widely.

7. Results Posted in the Registry

• Study Drug: mean 4.50 versus 5.20 on control; difference -0.70 (95% CI -6.31 to 4.91), standardized effect d = -0.10; z-test p = 0.807.

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.

Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods

• 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:
  • Study Drug: mean -0.50 versus -2.00 on control; difference 1.50 (95% CI -3.25 to 6.25), standardized effect d = 0.22; z-test p = 0.536.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods

• 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:
  • Study Drug: mean 40.50 versus 49.90 on control; difference -9.40 (95% CI -47.99 to 29.19), standardized effect d = -0.17; z-test p = 0.633.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline of TMS Measurement of Short Interval Intracortical Inhibition (Short ICI) at the End of the Study Drug and Placebo Treatment Periods

• 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:
  • Study Drug: mean -11.00 versus 35.50 on control; difference -46.50 (95% CI -112.34 to 19.34), standardized effect d = -0.49; z-test p = 0.166.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover TMS measurements of motor threshold, intracortical facilitation, and short-interval intracortical inhibition. Across these outcomes, the unadjusted estimates do not form a consistent directional pattern: the motor-threshold contrast is positive, while the intracortical facilitation and short-interval inhibition contrasts are negative. Their confidence intervals include zero. This broad pattern does not provide a clear, precise separation between treatment periods.

The secondary outcomes address physiological measurements that differ from the primary ABAS assessment of adaptive behavior. They can add context about cortical excitation and inhibition, but they do not directly answer the primary question about parent- or caregiver-reported adaptive skills. Nor can they resolve uncertainty in the primary result. The registry’s brief description also names long-interval intracortical inhibition and physical examination as secondary measures; a long-interval inhibition result is not reported in the registry record.

The posted secondary estimates are simple unadjusted re-calculations from summary statistics. The registry reports no analyses for these outcomes. The record does not report whether a prespecified order of testing, multiplicity adjustment, or another method was used to control interpretation across outcomes. When several outcomes are examined, isolated findings can occur by chance, so secondary results without a reported analysis plan carry less evidential weight than a clearly prespecified primary result.

The TMS outcome counts also differ from the ABAS counts and between treatment periods. That variation means the secondary summaries do not necessarily describe the same set of participants as the primary result. The reasons for incomplete measurements and the handling of missing values are not reported. The overall secondary pattern should therefore be read as exploratory description rather than confirmation of the primary result or a basis for a definitive claim about treatment-period effects.

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

• Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods
• Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods
• Change From Baseline of TMS Measurement of Short Interval Intracortical Inhibition (Short ICI) at the End of the Study Drug and Placebo Treatment Periods
• Change From Baseline of TMS Measurement of Long Interval Intracortical Inhibition (Long ICI) at the End of the Study Drug and Placebo Treatment Periods
• Results of Physical Examination at the End of the Study Drug and Placebo Treatment Periods

9. Statistical Interpretation

10. Statistical Methods Explained

The registry describes a randomized, triple-masked crossover trial. Randomization is intended to reduce systematic differences in assignment, while masking is intended to limit the influence of expectations on treatment delivery, assessment, or reporting. The registry’s brief description uses the phrase double-blind, whereas the design field says triple masking. Which people were masked, and whether masking was maintained throughout each period, are not reported in the registry record.

What does the crossover structure imply?

In a crossover study, participants receive treatment conditions in periods, so observations under different conditions may come from the same person. This can be useful because each participant can serve as a reference for their own responses, but the statistical analysis needs to represent the within-participant relationship. Outcomes from the same person are generally not independent. A simple comparison of two sets of group means does not show whether that relationship was included in the calculation.

The registry describes six-month placebo and study-drug periods and lists washout periods after each. It does not report the length of washout, the randomized treatment sequences, or whether the reported estimates account for period or sequence effects. In general, crossover interpretation can be affected by changes over time or by effects that persist after a treatment period. Whether those issues occurred or were addressed in this trial is not reported in the registry record.

How should the mean difference be read?

The primary outcome is continuous: each participant has a numeric ABAS change from baseline, and the registry reports the mean and standard deviation for each treatment period. The mean is the arithmetic average of the observed changes. It gives a concise description of the group’s central pattern, but it can conceal variation among participants. The standard deviation describes the spread of participant changes around the group mean; it is not the uncertainty around the mean itself.

The posted primary contrast is the study-drug mean change minus the placebo mean change. Its estimate is -0.7. A negative sign means the study-drug mean change is lower than the placebo mean change in these posted summaries. The estimate alone does not show whether the difference is distinguishable from random variation. The confidence interval and the unadjusted p-value provide additional, but different, information about uncertainty.

What does a confidence interval communicate?

A confidence interval is a range of values compatible with the observed data under the method used to calculate it. A wider interval indicates less precision than a narrower one. It is not a range containing every participant’s response, nor does it assign a probability to the true effect after the data have been observed. For the primary comparison, the interval extends from -6.314 to 4.914 and includes zero. That breadth means the posted estimate is imprecise: values indicating a lower or higher study-drug change relative to placebo remain compatible with the calculation.

The interval’s interpretation also depends on the analysis assumptions. The registry does not report a sponsor analysis for the primary outcome, so the displayed comparison is an unadjusted re-calculation from the posted summaries. In a crossover study, an analysis based on treatment-period means may not represent the precision gained or lost from paired observations. The registry does not provide enough detail to determine whether a paired approach, period adjustment, or another method was used in the trial’s own analysis.

What does the p-value add?

The unadjusted p-value for the primary comparison is 0.807. A p-value describes how unusual data at least as incompatible with a specified null model would be if that model and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of a difference. A large p-value does not prove that treatment periods are equivalent. The confidence interval is more useful for seeing the range of differences that remains compatible with the estimate.

The p-values posted for the secondary outcomes are also unadjusted re-calculations. Without a reported plan for how outcomes were selected and analyzed, these values should not be read as confirmatory evidence. Testing multiple outcomes creates more opportunities for apparently notable findings by chance. Adjustment procedures and a hierarchy of outcomes can help address that concern, but whether the trial used such procedures is not reported in the registry record.

Why do the outcome counts vary?

The primary ABAS summaries include 13 observations for each treatment period. The secondary TMS summaries include 16 observations for placebo and 17 for study drug. The registry explicitly says ABAS was not completed for all participants. It does not report the reasons for missing questionnaires, the patterns of missingness, or how missing data were handled in the trial’s own analysis. Missingness can affect a group estimate if the participants with observed outcomes differ systematically from those without observed outcomes.

In general, analysts may use different methods for incomplete repeated-measures data, and those methods rely on assumptions about why values are missing. No particular method or assumption should be attributed to this trial based on the registry record. The reported counts make clear that the endpoint-specific analysis population is smaller than the recorded enrollment, but they do not explain how the available participants were selected or whether all randomized participants were included in an intended analysis population.

How are the planning illustrations calculated?

The sample-size illustrations use the observed effect as a planning reference and consider the stated fractions of that effect. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For continuous outcomes, the displayed values are participants per arm. The calculations are not the trial’s original design justification, and the original sample-size assumptions are not reported in the registry record. A planning estimate based on an observed effect is sensitive to that estimate, especially when the study has few observed outcomes.

These calculations do not establish that the trial had a particular probability of detecting its observed result. The registry does not report a detailed statistical analysis plan, including the planned primary model, treatment-sequence terms, handling of incomplete data, multiplicity procedures, or interim analyses. Those details would be needed to fully reconstruct the intended analysis and compare it with the posted summaries.

11. Confidence Intervals and Precision

The primary mean difference is -0.7, with a confidence interval from -6.314 to 4.914. The interval spans zero and extends to values on both sides of the point estimate. Its width is a practical reminder that the estimate is not precise enough to pin down the comparative change in ABAS scores. The result does not isolate a single likely treatment-period difference.

Precision depends on more than the total number of observations. In a crossover trial, the relationship between each participant’s responses across periods can affect the uncertainty of a within-person contrast. The registry reports group counts and summary measures but does not report the paired covariance or the method used for a sponsor analysis. The simple unadjusted re-calculation therefore cannot show whether the design’s within-person information was used.

The endpoint also has incomplete availability: the registry says ABAS could not be completed for all participants, and the posted summaries contain 13 observations per treatment period. The reasons and patterns of missingness are not reported. Missing data may affect precision and can also affect the estimated contrast if the observed participants differ from those without a completed questionnaire.

Confidence intervals for the posted TMS re-calculations are also broad relative to their estimates and include zero. These results are not evidence that the effects are exactly zero; rather, the estimates remain uncertain. No clinical-importance threshold is reported for ABAS or the TMS outcomes, so the statistical ranges cannot be translated into a judgment about meaningful benefit or harm.

Overall, the main precision message is uncertainty, not proof of no difference. Larger or more complete data could narrow uncertainty, but the registry record does not establish what a future study would find.

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 illustrations express required sample sizes as participants per arm, not total events. The registry’s stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Each row uses the stated fraction of the observed effect as the effect to detect. These figures are planning illustrations based on the observed effect, not a reconstruction of the trial’s original sample-size justification; that original justification is not reported in the registry record.

The 80% power column gives the estimated participants per arm under the stated assumptions for a design intended to have an 80% chance of detecting the selected effect if that effect were the true one. The 90% power column gives the corresponding per-arm estimate for a design intended to have a 90% chance under those assumptions. Power is a property of a planned design for a specified effect and analysis, not a measure of whether a completed study’s result is true.

As the assumed effect becomes smaller, more participants are needed to distinguish it from random variation with the same stated power and significance level. Thus the rows for 75% and 50% of the observed effect require larger per-arm counts than planning for 100% of the observed effect. The figures may be sensitive to the observed effect estimate, particularly when that estimate comes from a study with limited outcome counts and considerable uncertainty.

This is not observed power. The registry does not report the trial’s original design assumptions, so these calculations should not be read as showing how the trial was planned or as a judgment about its original target enrollment. They are hypothetical planning references, and the assumptions behind them should be considered when interpreting any displayed sample-size curve or values.

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 = -0.700; pooled standard deviation σ = 7.303.
2. n = 2 × (1.96 + 0.842)² × 7.303² / -0.700² = 1,708.5, rounded up to 1,709 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 <- -0.7                      # observed difference in means
sigma <- 7.30273921210391                     # 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(2019667)
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 = 1,709 (80% power), 2,288 (90% power)
 75% of observed effect: n per arm = 3,038 (80% power), 4,067 (90% power)
 50% of observed effect: n per arm = 6,834 (80% power), 9,149 (90% power)
power.t.test: 1709.5 
Simulated power at n = 1,709 per arm: 0.801 (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. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary ABAS outcome and several secondary outcomes, but the statistical plan for managing multiple comparisons is not reported in the registry record. When investigators examine several outcomes, each can generate a result that appears notable by chance even if there is no underlying difference. A prespecified hierarchy or multiplicity adjustment can help govern interpretation, but the registry does not say whether either was used. The secondary p-values are unadjusted re-calculations and should be interpreted accordingly.

The registry reports no sponsor analyses for the posted secondary outcomes. A detailed analysis plan for the primary outcome is also not reported. Therefore, it is not possible to determine from the record which models were prespecified, whether the crossover structure and treatment sequence were incorporated, or which outcomes were intended as confirmatory. The original sample-size justification and interim analyses are also not reported.

Missing outcome data are an important limitation. The registry says the ABAS questionnaire could not be completed for all participants; its primary summaries include 13 observations in each treatment period. The TMS summaries include 16 placebo observations and 17 study-drug observations. The reason for each missing result, whether missingness differed by treatment or period, and how incomplete observations were handled are not reported. In general, missingness can reduce precision and can bias an estimate if the availability of an outcome is related to participants’ responses or other relevant characteristics.

The registry record does not specify the analysis population, such as whether all randomized participants were intended to be included or whether analyses were restricted to participants with complete measurements. The posted counts describe available outcome summaries but do not identify the analysis population or explain exclusions. Nor does the record report a sensitivity analysis to assess the effects of missing data or alternative assumptions.

Together, the lack of a reported multiplicity plan, sponsor analysis details, and missing-data methods limits the strength of conclusions drawn from the set of outcomes. These are reporting limitations; they do not establish that the trial used an inappropriate method. They mean that the registry alone does not permit a full assessment of the intended statistical procedures.

15. 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 non-serious adverse event terms

The registry reports zero serious adverse events in each listed period: placebo, washout following placebo, study drug, and washout following study drug. The corresponding numbers at risk were 18, 16, 19, and 18. No deaths were reported in any of these groups. These counts describe the posted safety record for the periods shown; they do not establish that serious events could not occur.

The registry also reports participants affected by other adverse events: 16 during placebo, 3 during washout following placebo, 18 during study drug, and 6 during washout following study drug. These are separate from the serious adverse event counts. The safety summaries are grouped by treatment and washout periods in a crossover trial, so they should not be read as a simple comparison of independent groups without considering the study structure. The registry record does not provide event-level descriptions in the listed serious-event terms, and the serious-event term list is empty.

These counts are descriptive. They do not establish whether an event was caused by study drug, and they do not provide a complete comparison of safety risks across all possible populations or durations of use.

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

The primary result describes average change in adaptive behavior scores during the placebo and study-drug periods. The registry reports mean changes of 5.2 and 4.5, respectively, and an unadjusted difference of -0.7 for study drug compared with placebo. The confidence interval, from -6.314 to 4.914, includes zero and spans values in both directions. The estimate is therefore uncertain, and the posted summaries do not precisely distinguish the treatment-period changes.

This does not demonstrate that the periods are equivalent. To establish equivalence, a study would need an appropriate design and prespecified bounds defining what differences count as sufficiently similar. Such bounds are not reported in the registry record. Nor does an unadjusted p-value of 0.807 prove that there is no effect. It describes the data under a particular null model and analysis, not the probability that a treatment effect exists or does not exist.

The record also does not establish that the observed change would be clinically important to participants. The registry explains how positive and negative ABAS changes are interpreted relative to baseline but does not report a threshold for a clinically important difference. Group means do not show the full range of individual responses, and the available ABAS summaries exclude participants for whom the questionnaire could not be completed.

The crossover design and outcome-specific counts warrant care in comparing the posted estimates. The registry does not report whether the summary-based re-calculations account for within-participant correlation, treatment sequence, period effects, or missing data. These details matter to both the estimated contrast and its uncertainty. The posted secondary results likewise do not provide a definitive confirmation, because they are unadjusted and the registry reports no analyses for them.

The safety record reports no serious adverse events or deaths in the listed treatment and washout periods, while other adverse events were recorded. These descriptive counts do not determine causation or exclude uncommon risks. Overall, the registry supports a cautious description of the recorded outcomes, not a recommendation about treatment or a conclusion that applies to every person with SSADH deficiency.

17. Why This Trial Matters Statistically

This trial illustrates why a treatment estimate should be read together with its uncertainty. The primary mean difference is close to zero, but its confidence interval covers a range of values on both sides of zero. Reporting the point estimate alone would obscure how little precision the posted summaries provide. Conversely, interpreting the unadjusted p-value as proof of no difference would go beyond what the data establish.

The crossover design makes the distinction between a treatment-period comparison and a simple comparison of independent groups especially important. Participants can contribute observations under both treatment conditions, and the relationship between those observations affects statistical precision. The registry identifies the crossover model but does not report enough analysis detail to determine how that structure was incorporated in the trial’s own analysis.

The study also highlights the practical importance of complete outcome reporting. ABAS was not completed for all participants, and the primary summaries include fewer observations than the recorded enrollment. Without reasons for missingness or details of the analysis population, readers cannot determine whether the available results represent all enrolled participants in a balanced way. Outcome-specific counts also matter when comparing a primary behavioral measure with secondary physiological measures.

Finally, the record shows why secondary outcomes and planning calculations need context. Unadjusted secondary comparisons across several measures are less persuasive than a prespecified primary analysis, while sample-size illustrations based on an observed effect are not the study’s original design assumptions. Careful separation of observed summaries, recalculated comparisons, and hypothetical planning values helps keep conclusions proportional to the evidence.

18. 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 recorded enrollment is 19, while the brief study-population description refers to twenty-two children and adults. The reason for this difference is not reported in the registry record. The primary ABAS summaries contain 13 observations per treatment period, and the registry states that the questionnaire could not be completed for all participants. Reasons for incomplete questionnaires, missingness patterns, and missing-data handling are not reported.

The crossover design is identified, but the registry does not report treatment sequences, the length of washout, or whether statistical analyses accounted for participant-level pairing, period effects, or sequence effects. These details are important for assessing whether the simple unadjusted re-calculations represent the intended analysis and how precisely treatment-period differences are estimated.

The registry does not report the original sample-size justification, a detailed statistical analysis plan, interim analyses, a multiplicity strategy, or the planned analysis population. It also does not report a threshold for a clinically important ABAS difference. Without these details, the results cannot be fully assessed against prespecified design and interpretation criteria.

The registry’s brief description calls the study double-blind, while its design information identifies triple masking. The roles covered by masking are not reported. The listed secondary outcomes include long-interval intracortical inhibition, but a result for that measure is not reported in the registry record. These reporting gaps should not be mistaken for evidence that a particular procedure or outcome was omitted from the trial; they limit what can be concluded from the registry.

Finally, the study is a Phase 2 trial with limited outcome counts. Its summaries do not show individual responses or establish how well the findings generalize beyond the enrolled population. The registry record alone cannot resolve these limitations.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency — NCT02019667.
• Registry record last updated 2020-02-24; status last verified 2018-10.
• Results first posted 2020-02-24.
• 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.

22. Record Summary

NCT02019667 is a completed randomized Phase 2 crossover trial of SGS-742 and placebo in people with SSADH deficiency. The registry records triple masking, while the brief description calls the study double-blind. Treatment periods are described as six months. Recorded enrollment was 19, and the primary outcome was change from baseline on the parent- or caregiver-completed ABAS questionnaire.

The ABAS mean changes were 5.2 during placebo and 4.5 during study drug. The unadjusted mean difference was -0.7, with a confidence interval from -6.314 to 4.914 and an unadjusted p-value of 0.807. ABAS was not completed for all participants. The posted secondary measures concern TMS outcomes, but their unadjusted estimates do not provide a precise or consistent separation between treatment periods.

The registry reports zero serious adverse events and zero deaths in the listed treatment and washout groups. Detailed analysis methods, missing-data handling, multiplicity procedures, and the original sample-size justification are not reported in the registry record. The results are best read as descriptive, uncertain estimates rather than a definitive answer about treatment-period differences.