A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD) (NCT05107128), a randomized phase 2 study. The primary outcome is Change From Baseline in the SDMT.

2. Clinical Question

The question is framed as a comparison between randomized groups, not as a before-and-after assessment of SAGE-718 alone. The registry record describes the study’s primary purpose as evaluating cognitive performance and functioning in participants with Huntington’s disease. The SDMT was the primary outcome measure. Its score reflects the number of correct pairings completed within the test’s time limit, with higher scores indicating better cognitive performance.

The posted primary analysis reports a difference in least-squares means for SAGE-718 compared with placebo. That estimate is negative, and its confidence interval includes zero. The interval therefore remains compatible with no difference as well as with differences in either direction. The posted result does not establish a clear group difference on this outcome; it also does not establish that the groups were equivalent.

3. Trial Design

This was a randomized, placebo-controlled, double-blind, parallel-group phase 2 study. The registry record lists triple masking. It reports enrollment of 189 participants with Huntington’s disease and a completed study. The recorded start date is 2022-01-26, and the primary completion date is 2024-09-04.

Participants were assigned to SAGE-718 or a matching placebo. SAGE-718 was taken orally once daily at 1.2 mg for Days 1 to 27, followed by 0.9 mg for the remainder of the treatment period up to Day 84. Participants in the placebo group received matching placebo orally once daily for up to Day 84. The registry record does not identify which specific groups of people were masked despite listing triple masking.

The primary outcome was change from baseline in SDMT score, assessed at baseline and Day 84. The primary analysis included participants who initiated investigational product and had both a baseline and at least 1 post-baseline efficacy evaluation. The overall analyzed counts indicate the number with data available for the analysis: 90 participants in the placebo group and 93 in the SAGE-718 group.

The registry record identifies a randomized parallel comparison, but details of the randomization procedure, allocation concealment, stratification factors, and the original sample-size justification are not reported in the registry record. The original statistical analysis plan, including any planned interim analyses, is also not reported in the registry record. The posted analysis method for the primary outcome is MMRM, with results expressed as a difference in least-squares means.

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: A total of 309 participants with Huntington's disease (HD) were screened, of which 189 participants were randomized to receive either SAGE-718 or placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The FAS included all participants who initiated IP and had baseline and at least 1 post-baseline efficacy evaluation. The overall number of participants analyzed indicates the number of participants with data available for this analysis.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The Full Analysis Set (FAS) included all participants who initiated investigational product (IP) and had baseline and at least 1 post-baseline efficacy evaluation.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in the SDMT, measured over Baseline, Day 84.

The primary endpoint was change from baseline in the Symbol Digit Modalities Test (SDMT) score, assessed at baseline and Day 84. The registry describes the SDMT as a way to track cognitive function over time and to support early detection of cognitive impairment. It assesses sustained attention, processing speed, visual scanning, and psychomotor speed.

During the test, participants complete as many correct symbol-number pairings as possible within 90 seconds. The total score is the number of correct pairings, out of 110 possible. Scores range from 0 to 110, and higher scores indicate better cognitive performance. Change from baseline focuses the comparison on how scores differed over the study period rather than on Day 84 scores alone.

A continuous outcome such as SDMT score can preserve information across the score range instead of reducing results to categories. In general, a group mean estimates the average change, while uncertainty measures describe how precisely that average is estimated. Here, the posted primary results are least-squares means from an MMRM analysis, rather than simple raw averages. The registry record does not describe why SDMT was selected over other cognitive measures or specify a threshold for a change considered meaningful to participants.

7. Results Posted in the Registry

• SAGE-718: mean 0.80 versus 2.00 on control; difference -1.20 (95% CI -2.79 to 0.39), standardized effect d = -0.22; z-test p = 0.140.

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 in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale

• 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 errors.
• Result:
  • SAGE-718: mean -1.50 versus -0.80 on control; difference -0.70 (95% CI -2.46 to 1.06), standardized effect d = -0.11; z-test p = 0.436.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SAGE-718 and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in the Trail Making Test Part B

• 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 errors.
• Result:
  • SAGE-718: mean -10.70 versus -5.70 on control; difference -5.00 (95% CI -16.82 to 6.82), standardized effect d = -0.14; z-test p = 0.407.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SAGE-718 and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response)

• 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 errors.
• Result:
  • SAGE-718: mean -3.85 versus -4.56 on control; difference 0.71 (95% CI -1.76 to 3.18), standardized effect d = 0.08; z-test p = 0.573.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SAGE-718 and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes spanning independence, cognitive task performance, everyday functioning, clinical severity, and treatment-emergent adverse events. The posted continuous secondary comparisons cover more than one type of performance measure. Their estimates do not all point in the same direction, and their uncertainty intervals include zero. This broad pattern does not offer a consistent secondary signal that would override or resolve the uncertainty in the primary SDMT result.

Secondary outcomes can help describe whether findings are consistent across related aspects of function, but they are not interchangeable with the primary outcome. A change on one task may reflect different abilities or measurement properties than a change on another. The registry record does not report thresholds for clinically meaningful change across these measures, so the practical significance of the observed estimates cannot be established from the posted results alone.

Unadjusted secondary results carry less weight when several outcomes are examined because the chance of seeing at least one apparently unusual result can increase with the number of comparisons. In general, multiplicity procedures control the overall error rate across a family of tests, while unadjusted p-values treat each comparison separately. Whether the trial used a prespecified hierarchy or multiplicity adjustment is not reported in the registry record. The secondary findings should therefore be read as supportive or exploratory descriptions rather than as independent confirmation of the primary result.

The overall secondary pattern is best considered alongside the primary analysis, the uncertainty intervals, the study population, and the limitations in the registry record. It does not establish a treatment effect or its absence. Outcomes without a posted quantitative comparison should not be inferred from the presence of an outcome name in the registry listing.

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

• Change From Baseline in the Unified Huntington's Disease Rating Scale (UHDRS) - Independence Scale
• Change From Baseline in the Trail Making Test Part B
• Change From Baseline in the One Touch Stockings of Cambridge (OTS-Mean Latency Until Correct Response)
• Change From Baseline in the Paced Tapping Test (PTAP)
• Change From Baseline in the Huntington's Disease Everyday Functioning (Hi-DEF) Home Subdomain Score
• Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Cognitive Status Subdomain Score
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a score that can take values across a numerical range. The registry reports least-squares means and standard errors for the change from baseline, then reports a difference in least-squares means between the groups. A least-squares mean is a model-based estimate of a group mean. It can reflect the fitted statistical model rather than being identical to a direct arithmetic average of all observed scores.

What does MMRM mean?

MMRM stands for mixed model for repeated measures. In general, this kind of model analyzes repeated observations from participants over time and accounts for the fact that measurements from the same person are related. It can estimate group differences at particular time points while using the repeated-measure structure. The registry names MMRM as the method for the reported primary analysis, but the model’s detailed specification is not reported in the registry record. For example, the exact fixed effects, covariance structure, and any covariate adjustments are not reported in the registry record.

What is the estimated difference?

The reported difference in least-squares means is -1.1 for SAGE-718 compared with placebo. It summarizes the estimated contrast between the groups on change in SDMT score. A negative value is in the direction of a lower estimated change for SAGE-718 under that contrast. Interpreting the estimate requires the accompanying confidence interval; the point estimate alone does not convey how uncertain the comparison is.

What does a confidence interval communicate?

A confidence interval gives a range of values compatible with the data and the analysis, under the model’s assumptions. In general, a 95% confidence interval is produced by a procedure that would cover the true value in 95% of repeated samples under those assumptions. It is not a statement that there is a 95% probability that this particular interval contains the true value. For the primary analysis, the interval from -2.7 to 0.5 includes zero, so the data do not distinguish the estimated group contrast from zero at the usual two-sided 0.05 threshold.

Why are the recalculated results different?

The simple recalculation uses the posted arm-level summary estimates and standard errors to form an unadjusted group comparison. It is an approximate calculation, not a reproduction of the MMRM model. In general, a model-based analysis can account for repeated observations and other specified model terms, whereas a simple comparison of summary statistics does not. The recalculated estimate is -1.2, with a 95% interval from -2.794 to 0.394. The sponsor’s MMRM analysis is the registry-reported result and takes precedence over this unadjusted recalculation.

What do standard errors describe?

A standard error describes the sampling uncertainty of an estimate. It is not the same as the spread of individual participant scores. Smaller standard errors generally indicate a more precise estimate, although precision also depends on the analysis and the data. The registry reports standard errors of 0.58 for placebo and 0.57 for SAGE-718 at the arm level. The posted summary does not give standard deviations for these outcomes; the recalculation uses an approximate pooled standard deviation derived for its unadjusted comparison. That approximation should not be confused with a sponsor-reported model estimate.

Why can extra variability matter?

In general, over-dispersion means that observed variability is greater than a model assumes. If variability is understated, standard errors can be too small and confidence intervals too narrow, which can make results appear more precise than they are. The registry record does not report an over-dispersion assessment for this outcome. The recalculation uses the posted summary statistics and should be read as an illustration rather than a replacement for the trial analysis.

What does the FAS definition imply?

The registry defines the FAS as participants who initiated investigational product and had baseline and at least 1 post-baseline efficacy evaluation. This is the stated population for the primary efficacy outcome. It is not identical to a definition that automatically includes every randomized participant regardless of post-baseline data. The precise handling of missing repeated measurements in the MMRM, additional analysis populations, and sensitivity analyses are not reported in the registry record.

Statistical significance and clinical importance are distinct ideas. A p-value evaluates how compatible the observed data are with a specified null model, given the analysis assumptions; it does not measure the size or importance of an effect. Clinical importance requires context about meaningful changes in SDMT and participant experience. A threshold for meaningful change is not reported in the registry record.

11. Confidence Intervals and Precision

The primary MMRM estimate is -1.1, and its 95% confidence interval extends from -2.7 to 0.5. The interval includes zero and spans estimates in both directions. Thus, the analysis leaves uncertainty about whether the group contrast is negative, close to zero, or positive. Its width is a reason to avoid treating the point estimate as a precise description of a single underlying effect.

In general, confidence intervals communicate both the estimated direction and the range of values compatible with the analysis. An interval that includes zero does not prove that the true difference is zero. Conversely, an interval that excludes zero would not by itself establish that a difference is large or important to participants. The registry record does not report a minimum clinically important difference for SDMT, so the clinical meaning of values within the interval cannot be determined from this record alone.

The simple unadjusted recalculation gives an estimate of -1.2 and a 95% interval from -2.794 to 0.394. Its interval also includes zero. It is based on posted summary statistics and an approximate calculation, while the sponsor’s reported analysis uses MMRM. Differences between the estimates and interval endpoints reflect the distinct analyses and rounding; the recalculation should not be used to replace the sponsor’s analysis.

Precision is affected by the amount and variability of available data and by the analysis method. The primary analysis included 90 placebo participants and 93 SAGE-718 participants with data available for that analysis. The registry record does not report detailed missing-data patterns or sensitivity analyses that would show how robust the interval is to alternative assumptions. The interval therefore describes uncertainty under the reported analysis, not every possible source of uncertainty.

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 events. They are illustrations computed from the observed effect, not the original trial’s design calculation. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

For each effect size considered, the 80% power column gives the approximate number of participants per arm that the planning calculation says would be needed for an 80% chance of detecting that assumed effect under its assumptions. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning probabilities conditional on the assumed effect and model; they are not probabilities that the observed study result is correct.

The planning illustration uses three assumptions about the effect: 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The corresponding requirements increase as the assumed effect becomes smaller. This is expected in general: smaller differences are harder to distinguish from random variation, so more participants are needed to detect them at the same significance level and target power.

These figures are not observed power. They do not report the probability that this completed trial detected an effect after seeing its results. They are hypothetical planning calculations based on the observed effect and the stated assumptions. In particular, estimates based on an observed effect can be unstable, so the planning values should be interpreted as illustrations rather than as evidence about the study’s actual design adequacy.

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 = -1.200; pooled standard deviation σ = 5.500.
2. n = 2 × (1.96 + 0.842)² × 5.500² / -1.200² = 329.7, rounded up to 330 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 <- -1.2                      # observed difference in means
sigma <- 5.49957728159566                     # 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(5107128)
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 = 330 (80% power), 442 (90% power)
 75% of observed effect: n per arm = 587 (80% power), 785 (90% power)
 50% of observed effect: n per arm = 1,319 (80% power), 1,766 (90% power)
power.t.test: 330.7 
Simulated power at n = 330 per arm: 0.798 (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-reported primary comparison is the sponsor’s MMRM analysis: a difference in least-squares means of -1.1, with a 95% confidence interval from -2.7 to 0.5. It is the analysis to use when describing the sponsor’s reported trial result. Its interval includes zero, so the result does not establish a statistically clear difference between groups.

The unadjusted recalculation from the posted arm-level summary statistics gives a mean difference of -1.2, with a 95% interval from -2.794 to 0.394. This is close to, but not identical to, the MMRM result. The recalculation uses a simple comparison of summary values and an approximate standard deviation; it does not reproduce the repeated-measures model or any model terms that may have been used in the sponsor analysis.

The registry record does not report enough detail to reproduce the MMRM specification independently. The distinction is therefore between the sponsor’s reported model-based result and an approximate, unadjusted check based on the posted summaries. The recalculation is useful for understanding the direction and approximate scale of the contrast, but it should not be treated as an alternative primary analysis. There is no discrepancy flag in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The study evaluates a primary SDMT outcome and multiple secondary outcomes. When several hypotheses are tested, the chance of at least one nominally positive result can rise unless the analysis accounts for multiplicity. Common approaches include adjusting significance thresholds, controlling a family-wise error rate, or defining an ordered testing hierarchy. These are general statistical methods; which approach, if any, was planned for this trial is not reported in the registry record.

The registry identifies MMRM for the reported primary analysis and gives results for secondary analyses, but does not report whether secondary p-values were adjusted, whether outcomes were grouped into testing families, or whether a hierarchical testing strategy was used. The posted secondary results should consequently be interpreted with caution and should not be treated as if each were a separately confirmed primary finding.

The registry’s primary efficacy population is the FAS: participants who initiated investigational product and had baseline and at least 1 post-baseline efficacy evaluation. The stated overall analysis counts indicate participants with available data for each analysis. This population definition means that the primary efficacy analysis is not described simply as including every randomized participant. The registry record does not report the number of randomized participants excluded from the primary analysis or the reasons for any exclusions.

Repeated-measures models can use available outcome measurements under their modeling assumptions, but the method name alone does not explain how missing data were handled. The assumptions about why data are missing, the amount and pattern of missingness, any imputation procedures, and sensitivity analyses are not reported in the registry record. The record also does not report a detailed analysis plan or interim analyses. These omissions limit assessment of whether the reported estimate would change under different missing-data assumptions or analysis choices.

These reporting gaps do not show that a particular procedure was or was not used; they mean the registry record does not make it possible to assess those details. The primary result can be interpreted as the posted MMRM estimate for the stated analysis population, with the reported uncertainty, while recognizing that multiplicity and missing-data handling remain unclear.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (2.1%), humerus fracture (1.1%), thoracic vertebral fracture (1.1%), suicidal ideation (1.1%), suicide attempt (1.1%).

The adverse-event figures describe participants at risk and participants affected, not the total number of separate events. For serious adverse events, 94 placebo participants were at risk and 6 were affected; in the SAGE-718 group, 95 were at risk and 3 were affected. The registry also reports other adverse events affecting 29 of 94 participants in the placebo group and 18 of 95 in the SAGE-718 group. No deaths were reported in either group.

The serious-event terms listed include Fall at 2.1%, Humerus fracture at 1.1%, Thoracic vertebral fracture at 1.1%, Suicidal ideation at 1.1%, Suicide attempt at 1.1%, and Pneumonia at 1.1%. The registry listing does not provide an arm-specific breakdown for these terms in the information, so the percentages should not be assigned to a particular treatment group.

These counts describe events recorded during the trial; they do not by themselves establish that treatment caused or prevented an event. The registry record does not provide detailed event timing, severity beyond the serious classification, relatedness assessments, or exposure-adjusted rates. Comparisons should therefore remain descriptive and be read in the context of the study’s size and follow-up period.

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

The posted primary analysis estimates a difference between SAGE-718 and placebo in change from baseline to Day 84 on SDMT. The MMRM estimate is -1.1, and the 95% confidence interval from -2.7 to 0.5 includes zero. The result therefore does not establish a statistically clear group difference on the primary outcome. The interval also does not prove that there was no difference or that the groups were equivalent.

The estimate concerns an average group contrast in the analyzed population, not the outcome for any one participant. It does not show how an individual’s score would change, and it should not be translated into a prediction for an individual. The registry record does not report a threshold for meaningful change in SDMT or enough contextual information to determine the clinical importance of the estimates within the interval.

The primary result also does not settle the interpretation of every cognitive or functional measure. Secondary outcomes assess different domains and carry additional uncertainty when multiple comparisons are considered. Their posted estimates do not change the primary analysis’s interval or resolve its uncertainty. The registry record does not report whether secondary tests were adjusted for multiplicity.

These findings are limited to the recorded comparison, assessment period, outcome definitions, and analysis population. They do not establish effects beyond Day 84, and the record does not report long-term follow-up results in the information. The safety counts are descriptive and do not establish causation. The study’s completed status and enrollment do not, by themselves, determine whether its estimates are precise enough to answer every clinical or scientific question.

In statistical terms, the result is an uncertain estimate rather than a conclusive positive or negative finding. It should be interpreted with the reported confidence interval, the analysis method, the defined population, and the registry’s limits on reporting in view.

18. Why This Trial Matters Statistically

This trial illustrates why a point estimate should not be interpreted without its uncertainty interval. The primary difference in least-squares means is negative, but its 95% confidence interval extends across zero. Looking only at the point estimate could suggest more certainty about direction than the analysis supports; considering the interval shows that multiple underlying values remain compatible with the posted result.

It also illustrates the distinction between a sponsor-reported model analysis and a simple recalculation from summary statistics. The recalculation is close to the reported estimate but is not the same analysis. A model that handles repeated measures may include structure not recoverable from arm-level summaries. Transparent distinction between the two helps readers avoid treating an approximate check as a substitute for the trial’s stated analysis.

The study is also a useful example of how outcome multiplicity and analysis-population definitions affect interpretation. Several secondary domains are listed, while the primary population requires post-baseline efficacy data. Without details on adjustment for multiple testing, missing-data assumptions, and sensitivity analyses, readers cannot fully assess the robustness of all comparisons.

Finally, the registry makes clear that planning calculations based on an observed effect are not the same as a trial’s original design justification or the power actually observed after completion. Keeping those concepts separate supports a more careful reading of both the trial’s estimates and any planning illustrations associated with them.

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 registry record does not report the original sample-size justification, the assumptions used in the trial’s design, or whether interim analyses were planned or conducted. It also does not provide the detailed MMRM specification, including its covariates and covariance structure. Those omissions limit independent reproduction of the sponsor’s primary analysis.

The stated FAS definition requires participants to have initiated investigational product and to have baseline and at least 1 post-baseline efficacy evaluation. The record does not report detailed exclusion counts, reasons for missing data, or the pattern of missing observations. It does not describe imputation, sensitivity analyses, or the assumptions used to address missing repeated measurements. These details matter when interpreting a model-based analysis over time.

Multiplicity handling for the secondary outcomes is not reported in the registry record. Nor is a clinically meaningful threshold for change in SDMT or the secondary scales. As a result, statistical uncertainty can be described, but the practical importance of estimates cannot be determined from the registry entries alone.

The follow-up described for the treatment period extends up to Day 84. The results therefore do not address longer-term outcomes. The safety record gives participant counts for serious and other adverse events, but the information does not provide detailed timing, causality assessments, or an arm-specific breakdown for each listed serious-event term. These limits call for descriptive interpretation rather than causal conclusions from the counts.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD) — NCT05107128.
• Registry record last updated 2025-09-15; status last verified 2025-09.
• Results first posted 2025-09-05.
• 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

NCT05107128 is a completed randomized, placebo-controlled, double-blind, parallel-group phase 2 study of SAGE-718 in participants with Huntington’s disease. The registry lists triple masking and enrollment of 189 participants. Treatment was oral once daily through Day 84, with the SAGE-718 regimen beginning at 1.2 mg and then continuing at 0.9 mg.

The primary endpoint was change from baseline in SDMT score at Day 84. The sponsor’s MMRM analysis estimated a difference in least-squares means of -1.1, with a 95% confidence interval from -2.7 to 0.5. The interval includes zero, leaving uncertainty about the direction and size of the group difference. Detailed information on multiplicity, missing-data methods, the original sample-size justification, and the MMRM specification is not reported in the registry record.