L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1 (NCT01733407), a randomized phase 1, phase 2 study. The primary outcome is Charcot Marie Tooth Neuropathy Score.

2. Clinical Question

The stated clinical rationale concerns HSAN1 and the accumulation of two neurotoxic sphingolipids. The registry summary says the investigators planned a two-year study to examine whether L-serine supplementation could correct biochemical and neurological features, and also planned to examine correlations between a neurological rating scale and intraepidermal nerve fiber density. That stated rationale and those aims describe the study question; they are not themselves findings. The outcome results available for interpretation are the CMTNS summaries at 48 weeks, along with listed secondary outcomes and safety counts. The registry does not report the CMTNS change from baseline or an adjusted comparison, so the posted means cannot establish how the groups changed over time.

3. Trial Design

The study is listed as randomized and quadruple-masked, with Phase 1 and Phase 2 designations. Massachusetts General Hospital is the sponsor, and the registry status is completed. The listed start was 2013-09 and the primary completion was 2016-05. Enrollment was 18. The arms listed for the primary outcome are Sugar Pill and L-serine, with nine participants in each arm. These design details indicate a placebo-controlled comparison with masking, while the small enrollment means the reported arm summaries should be read with attention to their limited precision.

There is a registry classification inconsistency: the study is described as randomized and lists two intervention arms, but its model is recorded as single group. The record does not resolve this inconsistency. The posted results nevertheless present outcome summaries for the two arms; that does not establish what analysis model the investigators used. The masking designation is quadruple, but the registry record does not identify which groups of people were masked or describe how masking was maintained.

The brief summary describes a planned two-year study, whereas the primary outcome timeframe is 48 Weeks. These are distinct descriptions in the registry; the record does not explain their relationship. Dose, adherence, treatment discontinuation, allocation concealment, randomization method, and the detailed study schedule are not reported in the registry record. Nor is the protocol or a statistical analysis plan described in the available record. The phase designation does not by itself supply those missing design details.

Several secondary outcomes are named: Intraepidermal Nerve Fiber Density (IENFD), Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS), Nerve Conduction Testing, 1-deoxy-sphinganine, and 1-deoxy-sphingosine. The registry indicates six outcome measures, while five secondary outcome names are listed. The reason for that difference is not reported in the registry record. The design summary is therefore useful for describing the registered comparison, but it cannot replace details about implementation or analysis that are not available.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

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 Charcot Marie Tooth Neuropathy Score, measured over 48 Weeks.

The primary endpoint is the Charcot Marie Tooth Neuropathy Score (CMTNS) at 48 Weeks. The registry describes it as a composite score used to assess disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. It includes nine items covering sensory and motor symptoms, pinprick and vibration sensation, leg and arm strength, and nerve conduction tests. Each item is scored from 0 to 4, and the items are totaled to form a global score from 0 to 36. Lower scores represent less severe symptoms; higher scores represent more severe symptoms. The registry says subscores were not used in this study.

A composite endpoint can bring different aspects of a condition into one measure, which can be useful when disease features span symptoms, examination findings, and nerve testing. Its meaning depends on the components and scoring rules, so the total score should be interpreted as the measure defined in the registry rather than as a direct measurement of any single symptom or biological process. The registry does not report a threshold for a clinically important change or explain how much change would be meaningful to participants.

The posted primary results are arm-level means and standard deviations at 48 weeks. They are not baseline-to-follow-up changes. The registry does not report baseline CMTNS values, an analysis of change, or the number of participants contributing to an analysis beyond the listed arm counts. Consequently, these summaries describe the endpoint values at the stated follow-up time, but do not show the trajectory of scores or quantify a between-arm treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What do the mean and standard deviation describe?

The primary outcome is continuous: each participant’s CMTNS is a numeric score, and the registry reports the mean and standard deviation by arm. The mean is a measure of the center of the scores. The standard deviation describes how dispersed individual scores are around that center. These summaries answer different questions. A mean describes the average observed score, while a standard deviation describes variation among participants. Neither one alone quantifies uncertainty in the difference between randomized arms.

For the Sugar Pill arm, the posted mean is 25.67 and the standard deviation is 6.69. For the L-serine arm, the mean is 20.22 and the standard deviation is 10.1. The registry identifies nine participants in each arm for these summaries. Because the endpoint is a severity score, the direction of the scale matters: a lower score corresponds to less severe symptoms, and a higher score corresponds to more severe symptoms. However, an endpoint score at one time point is not equivalent to a change score. Without baseline values, these summaries cannot show whether the groups started at similar levels or how scores changed during follow-up.

What would an inferential comparison add?

A treatment-effect estimate would express the between-arm contrast under a specified analysis. A confidence interval would convey the uncertainty around that estimate, while a statistical test could assess compatibility with a null hypothesis under its assumptions. The registry record does not report a confidence interval, p-value, or treatment-effect estimate for the primary endpoint. The posted means and standard deviations therefore support descriptive interpretation but not a formal conclusion about the randomized comparison.

In general, randomization makes an arm comparison meaningful when the analysis respects the assignment process and the participants included in the analysis are clearly defined. An analysis may also adjust for baseline outcome values or other prespecified factors, but such adjustment should be described rather than assumed. The registry does not report the primary analysis model, baseline adjustment, analysis population, or handling of protocol deviations. The single-group model label also conflicts with the randomized two-arm description. This uncertainty about the registered analysis classification is another reason not to infer an unreported analysis from the outcome summaries.

Why can variation and distribution matter?

General statistical interpretation of a mean often relies on how the outcome values are distributed and on the appropriateness of the model used to compare groups. A composite score is bounded by its scoring range, and observed scores may not necessarily follow a symmetric distribution. A standard deviation gives a useful measure of spread but does not reveal the full distribution, outliers, or concentration near the scale limits. The registry does not provide participant-level observations or a distributional description, so those features cannot be assessed from the posted summaries.

In general, over-dispersion means that observed variability is greater than a statistical model expects. If present, it can make standard errors too small and confidence intervals too narrow when the model does not account for it. The registry does not report an over-dispersion assessment, and the available summaries are not enough to establish whether it is relevant to this endpoint. This is a general methodological consideration, not a finding about this study.

What does masking contribute?

The registry records quadruple masking. In general, masking can reduce the influence of expectations on care, outcome assessment, and reporting, depending on which people are masked and how the masking is maintained. The record does not identify the masked parties or explain procedures for maintaining masking. The designation alone therefore does not allow an assessment of how masking operated in practice.

What are planning illustrations?

General sample-size calculations estimate how many participants may be needed under chosen assumptions about the target effect, variability, significance level, allocation, and statistical model. The planning description associated with this study uses a two-sided significance level of 0.05, equal allocation, and a normal approximation; it describes the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial had a particular probability of detecting an effect. Sample-size illustrations should not be called observed power, and they cannot replace an outcome analysis or a confidence interval.

The record does not report the trial’s own sample-size justification or establish that its design was based on the observed endpoint effect. The posted illustrations are therefore best understood as conditional planning scenarios. Their meaning depends on their assumptions and does not establish that the selected enrollment was adequate for the primary comparison. The registry also does not report a prespecified interim analysis or stopping rule. These methods details remain uncertain, so interpretation should stay close to the descriptive results that are actually posted.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Sugar Pill", "L-serine")
n   <- c(9, 9)
m   <- c(25.67, 20.22)
sp  <- c(6.69, 10.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Sugar Pill  9  25.670  6.690  20.528  30.812
CARM  L-serine  9  20.220  10.100  12.456  27.984

11. Multiplicity, Missing Data and Analysis Populations

The registry names five secondary outcomes: Intraepidermal Nerve Fiber Density (IENFD), Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS), Nerve Conduction Testing, 1-deoxy-sphinganine, and 1-deoxy-sphingosine. It also indicates six outcome measures. The explanation for the difference between the number of listed secondary outcome names and the reported measure count is not reported in the registry record. The number of analyses is listed as zero.

When several outcomes or analyses are considered, the chance of at least one apparently unusual result can increase. General approaches to multiplicity include identifying a primary endpoint in advance, adjusting tests, or interpreting secondary findings as exploratory. The registry identifies a primary endpoint, but does not report a multiplicity strategy, hierarchy among secondary outcomes, or which secondary analyses were planned. No secondary outcome results are included in the registry record for interpretation. The record therefore does not support conclusions about those outcomes or the degree to which multiplicity was addressed.

Missing-data handling is also not reported in the registry record. The listed primary-outcome arm counts total the stated enrollment, but these counts do not establish whether all randomized participants had complete follow-up, whether any values were imputed, or how participants with incomplete outcome data were handled. The analysis population—such as all randomized participants or a subset—is not reported in the registry record. Reasons for missing observations, if any, are also not reported.

These omissions matter because missingness can affect the meaning of an estimate, and different analysis populations can produce different interpretations. Without a documented analysis population and missing-data method, the posted arm summaries cannot be assumed to represent a particular prespecified estimand. The record also does not describe protocol deviations or adherence. These are reporting limitations, not evidence that data were missing or that a particular analysis was used.

12. 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: esophageal cancer (11.1%), mrsa staff infection (11.1%).

The registry reports serious adverse event figures separately for the Sugar Pill and L-serine groups. For each group, nine participants were listed as at risk and one participant was listed as affected by a serious adverse event. The death count was one in the Sugar Pill group and zero in the L-serine group. These are counts in a small study; they should be read as the registry’s reported observations, not as evidence about the cause of an event or a comparative safety effect.

The registry also lists nine participants at risk and nine affected by other adverse events in each group. These other adverse event counts are not interchangeable with the serious adverse event counts. The record lists Esophageal Cancer and MRSA Staff Infection as top serious adverse event terms, each at 11.1%. It does not assign these terms to an arm in the information, nor does it report whether events were considered related to treatment. No conclusion about causation, severity beyond the registry classification, timing, or comparative risk can be drawn from these entries alone.

In general, adverse event counts require context about how events were defined, collected, coded, and attributed. The registry record does not report those details, exposure time, event timing, or a statistical comparison of safety outcomes. A count of affected participants is not the same as a count of all events, since one participant may experience more than one event. The posted figures are therefore descriptive and should not be interpreted as demonstrating that either intervention caused or prevented an event.

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

The registry supports a limited descriptive statement about the primary outcome: at 48 weeks, the L-serine arm had a mean CMTNS of 20.22 with a standard deviation of 10.1, and the Sugar Pill arm had a mean of 25.67 with a standard deviation of 6.69. Because higher CMTNS scores represent more severe symptoms, the arm means differ in their numerical position on the scale. The record does not report an inferential comparison, so this description should not be converted into a claim that the groups differed statistically or that assignment caused the observed pattern.

The endpoint summaries do not show change over time. No baseline CMTNS values or change-from-baseline results are reported. They also do not show how the scores were distributed among individuals, how many participants completed the 48-week assessment, or how missing data were managed. Standard deviations describe within-arm variability, but they are not confidence intervals and do not quantify the uncertainty of the between-arm contrast. The registry’s lack of a reported analysis means that the strength and precision of any comparative interpretation remain unknown.

The record also does not establish whether the displayed means represent a prespecified analysis population or an adjusted model. The study is labeled randomized and lists two arms, but its model field is single group. The registry does not explain the inconsistency. Its design labels and posted outcome summaries should therefore be distinguished from evidence about the actual analysis procedures.

The safety entries are counts, not a determination of causation. The registry lists serious events and deaths in each group, along with other adverse events, but does not report event attribution or a safety comparison. Likewise, the listed secondary outcomes are not accompanied by results in the information available for interpretation. The planned biochemical and neurological aims in the study summary should not be mistaken for reported findings.

In general, a completed randomized trial can contribute evidence even when its registry results are incomplete, but a conclusion requires an estimate, uncertainty, and transparent analysis details. In this case, the posted information supports a description of endpoint values and safety counts. It does not establish efficacy, lack of efficacy, clinical importance, or comparative safety. Those questions cannot be resolved from the reported summaries alone.

14. Why This Trial Matters Statistically

This trial is statistically notable because it pairs a randomized, masked, placebo-controlled description with a small enrollment of 18 and an incompletely reported primary comparison. The registry lists nine participants in each arm for the 48-week CMTNS summaries. Such a design can generate useful descriptive information, but the precision of a group comparison depends on the amount of information in the data and on how the analysis is conducted. The record does not report a confidence interval or test result that would show that precision directly.

Another important issue is the difference between a group mean at follow-up and a treatment effect. Readers may be drawn to compare the two posted means, but the primary outcome values are not reported as changes from baseline, and no adjusted analysis is described. Baseline balance cannot be assessed from the posted summaries. A descriptive difference at one time point does not, by itself, identify the effect of treatment assignment.

The registry’s single-group model classification sits alongside a randomized two-arm description. This highlights why registry design fields and results need to be interpreted together rather than treated as a complete analysis report. The record does not reconcile the inconsistency, and does not report the analysis population, missing-data approach, or multiplicity plan. These details affect how findings should be understood, particularly when several secondary outcomes were planned or named.

Finally, the listed planning assumptions serve a different purpose from an observed trial result. Sample-size illustrations can clarify how design choices depend on assumptions, but they are not observed power and do not compensate for missing inferential statistics. The key statistical lesson is the distinction between what can be described—the arm means, variation, and safety counts—and what requires an explicit comparative analysis. The registry supports the former and does not report the latter for the primary endpoint.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation for interpretation is the absence of a reported two-arm analysis for the continuous endpoint. The registry explicitly indicates that values are missing or not estimable for such a comparison, and lists zero analyses. No effect estimate, confidence interval, or p-value is reported. The two arm means therefore provide a descriptive snapshot, not a complete estimate of the randomized treatment contrast.

The record gives endpoint values at 48 weeks but no baseline values or changes from baseline. It does not report the number analyzed separately from the listed arm counts, the analysis population, or whether all randomized participants contributed outcome data. Missing-data methods and reasons for missingness are not reported. The registry also does not describe adherence, treatment discontinuation, or protocol deviations, all of which could help explain the relation between assignment and observed scores.

Key design and analysis details are absent: the dose and schedule, randomization method, allocation concealment, exact masking procedures, prespecified model, baseline adjustment, and sample-size justification are not reported in the registry record. The study is classified as single group even though it is described as randomized and lists two arms; no explanation is given. A two-year study is described in the summary, while the primary endpoint timeframe is 48 Weeks, and the relationship between those periods is not reported.

The scale’s component structure and direction are described, but no threshold for clinically meaningful change is given. The registry does not provide participant-level data or a distributional account, so score patterns and unusual observations cannot be assessed. It lists secondary outcomes but does not provide their results, and does not report how multiplicity was handled. These reporting limitations restrict both statistical and clinical interpretation; they should not be mistaken for proof that a particular design or analysis procedure was absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1 — NCT01733407.
• Registry record last updated 2018-09-12; status last verified 2018-08.
• Results first posted 2018-09-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01733407 is a completed Phase 1 and Phase 2 randomized, quadruple-masked study sponsored by Massachusetts General Hospital. It lists enrollment of 18 participants and compares L-serine supplementation with placebo for hereditary sensory and autonomic neuropathy type 1. The listed start was 2013-09, and primary completion was 2016-05.

The primary outcome is CMTNS at 48 Weeks, a composite neuropathy severity score for which higher values indicate more severe symptoms. The Sugar Pill arm has a posted mean of 25.67 and standard deviation of 6.69; the L-serine arm has a mean of 20.22 and standard deviation of 10.1. The registry does not report a formal two-arm analysis, confidence interval, or p-value for this endpoint. It lists secondary outcomes and adverse event counts, but the available record does not provide inferential results for the primary comparison or detailed methods for missing data, multiplicity, and analysis populations.