IVIg for Small Fiber Neuropathy With Autoantibodies TS-HDS and FGFR3: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for IVIg for Small Fiber Neuropathy With Autoantibodies TS-HDS and FGFR3 (NCT03401073), a randomized phase 2 study. The primary outcome is The Change in Nerve Fiber Density Between Visits 1 and 8..

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, quadruple-masked, parallel-group trial sponsored by Beth Israel Deaconess Medical Center. The registry lists the study as completed. Its start date was 2018-09-01 and its primary completion date was 2022-02-01. The planned enrollment was 20 individuals, with participants randomized equally to IVIG or 0.9% sodium chloride according to the arm descriptions.

The trial focused on small fiber neuropathy associated with antibodies targeting TS-HDS and FGFR3. The study description says eligibility involved confirmed small fiber neuropathy based on skin biopsy analysis of intra-epidermal nerve fiber density. The registry’s outcome timeframe places visit 8 in a range of 22-27 weeks after visit 1, allowing final follow-up despite travel or holiday conflicts.

The treatment description specifies an initial IVIG dose of 2 grams/kg over 2 days, followed by 1 gram/kg over 1 day every 3 weeks for a total of 6 treatments. The comparator is 0.9% sodium chloride, described as placebo, with a corresponding schedule of administration over 2 days and then over 1 day every 3 weeks for a total of 6 treatments. The placebo-arm description ends before completing its sentence about randomization, so further details are not reported in the registry record.

The primary outcome results include 17 study completers: 9 in the 0.9% sodium chloride group and 8 in the IVIG group. Those numbers describe the analyzed completers, not the planned enrollment. The record lists 10 participants at risk for adverse-event reporting in each group. Details about why the analyzed primary-outcome population differs from planned enrollment, and about the relation between the safety and completer populations, are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: After signing an informed consent, study subjects underwent a detailed history, physical examination, laboratory studies, pain VAS scores, the Short-From 36 question health survey (SF-36), antibody measurement of TS-HDS and FGFR-3 and skin biopsy evaluation of nerve fiber density at the distal leg and proximal thigh using standard methodology. If participants did not meet criteria for the study after screening (based on inclusion and exclusion criteria), they were excluded.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The 17 study completers were analyzed as part of the final results.

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 The Change in Nerve Fiber Density Between Visits 1 and 8., measured over Visit 1 (time zero) and visit 8 (range of visit time 22-27 weeks after visit 1), thus a total of 22-27 weeks for the study (the range is provided to ensure final follow up is completed despite any conflicts with travel or holidays)..

The posted primary endpoint is change in intra-epidermal nerve fiber density between visit 1 and visit 8. The measure is expressed in fibers/mm and is described as the number of nerve fibers per millimeter, assessed by punch skin biopsy. The outcome is calculated as the visit 8 measurement minus the visit 1 measurement. In the registry’s definition, a positive change indicates increased nerve fiber density and a negative change indicates decreased density.

This endpoint is used to quantify a tissue-level feature of small fiber neuropathy rather than relying only on a reported symptom. A biopsy-based density measure can represent structural change over the study’s follow-up period. It does not, by itself, establish how a participant feels or how daily function changes. The study description therefore also identifies neuropathic pain as an outcome of interest.

The posted results report mean change and standard deviation by group. For 0.9% sodium chloride, the mean was 0.5 fibers/mm with a standard deviation of 0.8; for IVIG, the mean was 0.6 fibers/mm with a standard deviation of 0.6. The analyzed populations were 9 and 8 completers, respectively. These group summaries describe the observed changes, but they do not provide a direct estimate of the between-group contrast or its precision.

The registry gives the measurement period as visit 1 and visit 8, with visit 8 occurring 22-27 weeks after visit 1. Further details about biopsy procedures, measurement reliability, or handling of measurements that could not be obtained are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it records a quantity of nerve fibers per millimeter, and the registry reports a mean and standard deviation for each group. General statistical context can help distinguish these summaries from the treatment comparison needed to answer the randomized-trial question.

What does a group mean describe?

General: a mean is the arithmetic average of the observed values in a group. Here, the reported mean changes are 0.5 fibers/mm for 0.9% sodium chloride and 0.6 fibers/mm for IVIG. They summarize change from visit 1 to visit 8 within each analyzed group. A group mean does not say that every participant changed by that amount, nor does it show how much of the change is attributable to the intervention rather than time, measurement variation, or other influences.

In a randomized comparison, the central treatment question is ordinarily expressed as a between-group contrast in outcome. The registry record does not report such a contrast for this endpoint. It is therefore not possible to read the two means as a complete treatment-effect estimate. The record also does not report a confidence interval or hypothesis test for the comparison.

What does the standard deviation describe?

General: a standard deviation describes the spread of individual observations around a group mean. The posted standard deviations are 0.8 fibers/mm for 0.9% sodium chloride and 0.6 fibers/mm for IVIG. They describe variability in the observed changes, not the uncertainty of a treatment contrast. A confidence interval, by contrast, is an interval estimate intended to convey uncertainty about a parameter, such as a mean or group difference, under specified assumptions. No such interval for the between-group difference is reported in the registry record.

With continuous outcomes, analysis choices can depend on the outcome distribution, trial design, and missingness. General methods might compare group means using a model or test, or adjust for baseline outcome values when that approach is specified. The registry record does not report the statistical model, the test used, whether baseline values were included in an adjusted analysis, or assumptions about the outcome distribution. Those details should not be inferred from the reported means and standard deviations.

Why does randomization matter?

General: random assignment is intended to make comparison groups similar on average with respect to factors known and unknown at enrollment. That supports interpretation of a between-group contrast, provided the analysis preserves the randomized comparison and relevant departures from the planned conduct are considered. Randomization does not guarantee identical groups, especially in a small trial, and it does not replace reporting the comparison estimate and its uncertainty. Although the record describes equal randomization, the primary results are reported for 9 and 8 completers. The method used to analyze participants who did not complete the primary outcome is not reported in the registry record.

The study is described as quadruple-masked and parallel-group. Masking can reduce the influence of expectations on care, assessment, or reporting, depending on who is masked and how the procedures are implemented. Which roles were masked and how masking was maintained are not reported in the registry record. The term alone does not demonstrate that masking was successful.

What does the planning illustration mean?

General: a sample-size planning calculation estimates how many participants may be needed to detect a chosen effect under stated assumptions. The planning illustration associated with the results is based on the observed effect, uses a two-sided significance level of 0.05, assumes equal allocation, and uses a normal approximation. It considers an effect defined as a stated portion of the observed effect. Such calculations are planning illustrations, not evidence that the completed trial had a particular probability of detecting an effect. They are not observed power and should not be read as a result of the trial.

The numerical planning outputs and the trial’s own sample-size justification are not reported in the registry record. In particular, the record does not report the effect size anticipated when the trial was designed, the rationale for the planned enrollment, or whether the design incorporated allowance for incomplete follow-up. No conclusion about the trial’s design adequacy can be drawn from the planning assumptions alone.

Why are uncertainty and analysis details important?

General: uncertainty estimates show the range of values compatible with the observed data under a statistical model. They help distinguish a noisy estimate from one measured more precisely. The arm-level standard deviations cannot substitute for an interval around the between-group contrast, especially when the group sizes are small. Because the record does not report comparative inferential results for the primary endpoint, the magnitude and precision of the randomized comparison are not available.

There are no posted analyses listed for the outcome, and the two-arm comparison is identified as missing or not estimable. The reason for that status is not reported in the registry record. It is therefore unclear whether the comparison was not conducted, could not be estimated, or was omitted from the record. Statistical methods beyond the basic descriptive summaries, including any covariate adjustment or sensitivity analysis, are not reported in the registry record.

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("0.9% Sodium Chloride", "Intravenous Immunoglobulin")
n   <- c(9, 8)
m   <- c(0.5, 0.6)
sp  <- c(0.8, 0.6)
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  0.9% Sodium Chloride  9  0.500  0.800  -0.115  1.115
CARM  Intravenous Immunoglobulin  8  0.600  0.600  0.098  1.102

11. Multiplicity, Missing Data and Analysis Populations

The study description identifies change in neuropathic pain and change in intra-epidermal nerve fiber density as co-primary endpoints. The posted outcome list identifies nerve fiber density as the primary outcome and lists neuropathic pain severity and Quantified Utah Early Neuropathy Examination scores as secondary outcomes. The registry record does not report a multiplicity procedure, such as an adjustment to account for testing more than one endpoint, or a hierarchy specifying how outcomes were to be interpreted together. Without that information, the handling of multiple outcome comparisons is not reported in the registry record.

The primary result population is described as 17 study completers, with 9 in the 0.9% sodium chloride group and 8 in the IVIG group. The planned enrollment was 20. The registry record does not report the reasons for noncompletion, whether outcome data were missing for other reasons, or whether the analyzed population was defined in advance. It also does not report how missing measurements were handled, whether any participants were excluded after randomization, or whether sensitivity analyses assessed the effect of missing data.

General: missing-data methods matter because estimates can be affected when the availability of an outcome is related to participant characteristics or observed outcomes. A completer analysis describes the participants with results included, but does not automatically represent every randomized participant. The record does not provide enough detail to judge whether missingness could have affected the reported group means.

The registry does not report an intention-to-treat analysis, a per-protocol definition, or an analysis population beyond the statement that 17 completers were analyzed for the final primary results. The relationship between this outcome population and the participants included in safety reporting is not described. These limitations constrain assessment of analysis populations and missing data.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures report 0 affected participants in each group. Each group lists 10 participants at risk for serious adverse events: 0.9% sodium chloride and IVIG. The registry also reports 0 deaths in each group. These figures describe the entries recorded for this safety reporting and should not be confused with the primary-outcome completer counts, which were 9 and 8.

The registry reports other adverse events in 9 of 10 participants at risk in the 0.9% sodium chloride group and 8 of 10 in the IVIG group. These are listed separately from serious adverse events. The record does not provide event terms for serious adverse events, and it does not report the nature, severity, duration, or attribution of the other adverse events in the registry record. A count of participants with any other adverse event does not indicate how many events each person experienced.

Zero reported serious adverse events in these groups means none were recorded in the registry entries; it does not establish that no adverse events could occur. Safety interpretation is limited by the group sizes and by the absence of further event-level details in the registry record. These figures alone do not support a broader comparison of safety profiles.

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

The posted primary outcome describes mean change in nerve fiber density from visit 1 to visit 8 among study completers. The mean was 0.5 fibers/mm in the 0.9% sodium chloride group and 0.6 fibers/mm in the IVIG group. The corresponding standard deviations were 0.8 and 0.6, with 9 and 8 completers analyzed. Under the registry’s definition, positive values indicate increased density from baseline.

These figures do not establish whether the groups differed. The registry record does not report a between-group estimate, confidence interval, p-value, or other comparative analysis for the primary outcome. Without a comparative estimate and its uncertainty, the group means should be read as descriptive summaries rather than as a definitive estimate of the effect of assignment to IVIG versus placebo.

The results also do not establish what happened to every randomized participant. The final primary results are described as an analysis of 17 completers, while planned enrollment was 20. Reasons for the difference, missing outcome handling, and sensitivity analyses are not reported in the registry record. This leaves uncertainty about how the completer results relate to the full randomized population.

The study description includes neuropathic pain among its co-primary endpoints, and the registry lists pain severity and Quantified Utah Early Neuropathy Examination scores as secondary outcomes. Their results are not reported in the registry information. The nerve-fiber outcome therefore cannot stand in for those other outcomes or establish a broader clinical effect.

More generally, a change in a biopsy-based measure is not by itself evidence about symptoms, function, or longer-term outcomes. The registry record supports a limited reading: it reports positive mean within-group changes in the analyzed completers and gives the associated standard deviations. It does not report the inferential comparison needed to determine the precision of a group difference.

14. Why This Trial Matters Statistically

This trial is statistically notable because it tests a focused question in a small, randomized, masked parallel-group study and uses a quantitative tissue measure as its posted primary outcome. The registry reports mean change in intra-epidermal nerve fiber density, a measure expressed in fibers/mm, and gives within-group standard deviations. Those summaries make the scale and observed variability of the endpoint interpretable.

At the same time, the record illustrates why descriptive results and comparative results are not interchangeable. The two group means are close in their reported values, but a randomized trial’s central comparison requires an estimate of the between-group contrast and its uncertainty. Neither is reported for this endpoint. The posted means and standard deviations cannot, on their own, answer whether the groups differed with useful precision.

The trial also identifies more than one outcome of interest. Its study description names pain and nerve fiber density as co-primary endpoints, while the posted outcome results identify nerve fiber density as primary and list pain and examination scores as secondary. The registry does not report how multiple outcomes were accounted for in the analysis. Clear reporting of outcome roles and multiplicity methods matters because it affects how a set of findings should be interpreted.

Finally, the reported primary analysis includes 17 completers, while planned enrollment was 20. The record does not explain the difference or describe missing-data methods. This makes transparent participant flow and analysis-population reporting particularly relevant. The trial’s posted results offer useful descriptive information, while the missing comparative and analysis details limit how much can be concluded from it.

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 outcome results are based on 17 study completers, with 9 in the 0.9% sodium chloride group and 8 in the IVIG group, despite planned enrollment of 20. The registry record does not explain the difference, report participant flow, or describe reasons for missing outcome measurements. It also does not say whether the primary analysis included all randomized participants or how missing data were handled.

The registry reports group means and standard deviations but no between-group estimate, confidence interval, p-value, or other inferential analysis for the continuous endpoint. It identifies the two-arm comparison as missing or not estimable, without explaining why. Consequently, the size and precision of the randomized comparison cannot be assessed from the posted primary results.

Outcome roles are not fully aligned in the descriptions: the study summary calls pain and nerve fiber density co-primary endpoints, while the posted outcome listing presents nerve fiber density as primary and pain severity among the secondary outcomes. The registry record does not report a multiplicity strategy or explain how this distinction was handled in analysis. Results for the pain and examination-score outcomes are not reported in the registry information.

Details about the biopsy measurement process, assessor procedures, measurement reliability, and handling of unavailable or unusable samples are not reported in the registry record. The placebo-arm description is incomplete, and details about which roles were masked or how masking was maintained are not reported. The record also does not provide the trial’s sample-size justification or additional statistical analysis methods. These gaps limit appraisal of measurement, analysis, and the relation between the planned study and the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: IVIg for Small Fiber Neuropathy With Autoantibodies TS-HDS and FGFR3 — NCT03401073.
• Registry record last updated 2023-09-13; status last verified 2023-08.
• Results first posted 2023-09-13.
• 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

This completed Phase 2 trial was randomized, quadruple-masked, and parallel-group, with planned enrollment of 20. It compared IVIG with 0.9% sodium chloride in small fiber neuropathy associated with TS-HDS and FGFR3 autoantibodies. The posted primary outcome was change in intra-epidermal nerve fiber density between visits 1 and 8, with visit 8 scheduled 22-27 weeks after visit 1.

The primary results describe 17 completers: 9 in the 0.9% sodium chloride group and 8 in the IVIG group. Mean changes were 0.5 and 0.6 fibers/mm, with standard deviations of 0.8 and 0.6, respectively. The registry record does not report a comparative estimate or inferential analysis for this outcome. Serious adverse events and deaths were recorded as 0 in both groups, with 10 participants at risk in each group.

Missing-data handling, the reason for the difference between planned enrollment and analyzed completers, and multiplicity methods are not reported in the registry record.