An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy (NCT00791492), a na phase 2, phase 3 study. The primary outcome is Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6.

2. Clinical Question

3. Trial Design

This was an open-label extension study of Fx-1006A in people with transthyretin amyloid polyneuropathy. The registry identifies it as Phase 2 and Phase 3, with a single-group model, no masking, and allocation listed as not applicable. Enrollment was 86. The record lists the study as completed, with a start date of 2008-07 and primary completion in 2008-08.

All participants entering the extension were to receive once-daily oral 20 mg Fx-1006A for 12 months. Participants assigned to placebo in Study Fx-005 crossed over to active drug. Participants and their families, investigators, and site staff were to remain blinded to the original Fx-005 treatment assignment, even though the extension itself was open-label. The plan intended no interruption in study medication between the studies.

The registry describes two treatment sequences: tafamidis-tafamidis and placebo-tafamidis. These labels distinguish prior treatment history; they do not establish a randomized comparison within the extension. Both groups received tafamidis during the extension, so differences between their outcomes could reflect prior treatment, participant characteristics, or other factors rather than an extension treatment contrast.

Most safety and clinical outcome assessments were intended to match those in Fx-005. The extension added 24-hour Holter monitoring and skin biopsy for intraepidermal nerve fiber density (IENF), with written informed consent required for these procedures. Values from the Month 18 visit of Fx-005 were to serve as extension baseline, and the additional baseline assessments were to occur before the first extension dose. The registry record does not report further operational detail for the visit schedule in the available description.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

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 Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6, measured over Month 6.

The primary endpoint is the percentage of participants with a response to treatment on the NIS-LL at Month 6. Response was defined as either improvement, meaning a decrease from baseline, or stabilization, defined as a change from baseline of 0 to less than 2. The score was based on the mean of two assessments within a 1 week period.

NIS-LL assesses muscle weakness, reflexes, and sensation in the lower limbs. Its total score ranges from 0 to 88, with higher scores indicating more impairment. Muscle weakness items are scored from normal to paralysis; reflex and sensation items distinguish normal, decreased, or absent function. The registry notes that for the tafamidis-tafamidis sequence, the baseline from the previous study FX-005 was used as the reference.

A responder percentage is a binary summary: each evaluable participant is classified as meeting or not meeting the stated response rule, and the result expresses the share classified as responders. In general, this can be easier to interpret than a mean score change, but it depends on the selected threshold and does not show how far an individual’s score changed. The registry record does not report the Month 6 responder percentage, the number evaluable, or the confidence interval. The endpoint definition alone therefore describes what was intended to be measured, not the observed outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary measure summarize?

The primary measure is a participant-level binary outcome: response or no response according to the NIS-LL rule at Month 6. The registry defines response as improvement from baseline or stabilization, with stabilization specified as a change from baseline of 0 to less than 2. The percentage is the proportion of evaluable participants classified as responders. The record says the analysis population included participants who received at least one dose and had no more than 2 months of interruption between Fx-005 and Fx-006; it also specifies that the N for this measure means participants evaluable for the endpoint.

In general, a binary summary is useful when a clinical question is framed around meeting a prespecified condition. It is also sensitive to the cutoff: people with changes near the boundary can be classified differently despite having similar score changes. A responder percentage does not convey the range or distribution of score changes. Those features would require additional results, which are not reported in the registry record for this primary endpoint.

How should a confidence interval be understood?

The endpoint lists a 95% confidence interval as its dispersion measure, but the interval itself is not reported in the registry record. In general, a confidence interval describes the statistical uncertainty around an estimate under the assumptions of the method used. It is not a guarantee that the true value lies within the particular interval, nor does it address all sources of bias. A narrower interval generally indicates greater precision for the estimate, while a wider interval indicates more uncertainty. Without the estimated response percentage, its interval, and the evaluable count, precision cannot be judged for this endpoint.

For a binary percentage, the interval depends in part on the number of evaluable participants and the observed proportion. In general, the estimate can be imprecise when the number of observations is limited, especially when the outcome is uncommon or very common. The registry record does not state which interval procedure was used, so the exact statistical construction cannot be assessed.

What does the study design imply?

The extension is described as a single-group, open-label study with allocation not applicable. There is no concurrent untreated or placebo group in the extension. In general, a within-group change can describe what happened over time among participants, but it cannot by itself distinguish treatment-associated change from natural disease course, prior treatment, changes in measurement, or other influences. The crossover from placebo in Fx-005 means those participants received active drug in the extension; it does not create a placebo control during the extension.

The two listed sequences reflect prior treatment history. Because both sequences received tafamidis in the extension, their comparison would not have the interpretation of a randomized contrast between active treatment and placebo. The registry expressly cautions that the arms are not a like-for-like control comparison. This limits any causal interpretation of differences between their outcomes.

How do planning illustrations differ from trial results?

The registry describes sample-size planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The intended effect to detect is expressed as a fraction of the observed effect. Those assumptions describe planning calculations, not the design of this single-group extension. They should not be interpreted as evidence that the extension had a particular probability of detecting an effect or that any result was statistically significant.

In general, power is a design-stage probability defined for a particular assumed effect, variability, sample size, and analysis. It is not a measure of the probability that a reported finding is true. Planning illustrations based on observed effects can also be optimistic if the observed effect is uncertain. The registry does not report a trial-specific sample-size justification, and no observed primary endpoint estimate is available to evaluate against a planning target.

What can the listed analyses establish?

The registry describes multiple clinical outcomes, including NIS-LL, quality-of-life domain scores, nerve fiber function scores, modified body mass index, biomarkers, and IENF density. It lists 19 outcome measures, but no analyses are listed in the record. General statistical practice recognizes that assessing multiple outcomes can raise the chance of at least one apparently unusual result when many hypotheses are tested. The registry record does not report a multiplicity strategy, so it is not possible to determine whether or how that issue was addressed.

The record also does not describe the statistical model for continuous outcomes, adjustment for baseline values, handling of repeated measurements, or the method used for missing observations. Those choices can affect estimates and uncertainty. The available endpoint description supports explaining the response definition and intended population, but not reconstructing the analysis or evaluating its assumptions.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Tafamidis-Tafamidis", "Placebo-Tafamidis")
n      <- c(37, 32)
events <- c(23, 22)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Tafamidis-Tafamidis  37  23  62.2  44.8  77.5  46.1  75.9  46.0  76.0
ARM  Placebo-Tafamidis  32  22  68.8  50.0  83.9  51.4  82.0  51.3  82.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including the primary Month 6 NIS-LL response and secondary measures at several follow-up times. It does not report a multiplicity strategy, such as a hierarchy for testing outcomes or an adjustment to account for multiple statistical tests. In general, when multiple outcomes or time points are examined, the chance of at least one apparently positive result can increase. Without a stated plan, the role of any individual result in a broader testing program would be difficult to judge.

The primary endpoint population is described as participants who received at least one dose and had no more than 2 months interruption between Fx-005 and Fx-006. The record says the N for this measure represents participants evaluable for it. However, it does not report the evaluable count, exclusions from that population, or the extent and pattern of missing endpoint data. It also does not report imputation methods, sensitivity analyses, or other missing-data procedures.

These omissions matter because an analysis restricted to evaluable participants may differ from one that includes all eligible participants under another missing-data assumption. In general, the consequences depend on why measurements are missing and how missingness relates to outcomes. The registry record does not provide enough information to assess those factors. It also does not report whether interim analyses were planned or conducted, nor does it give a statistical analysis plan. Those matters are not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: vomiting (4.5%), anaemia (2.4%), nausea (2.4%), infection (2.4%), meningitis (2.4%).

The registry reports serious adverse events for the two prior-treatment sequences. In the tafamidis-tafamidis group, 5 of 44 participants had a serious adverse event; in the placebo-tafamidis group, 4 of 41 did. Other adverse events are listed for 24 of 44 and 24 of 41 participants, respectively. The record does not report deaths.

These figures describe events recorded within the extension groups. They are not a like-for-like comparison: both groups received tafamidis during the extension, and the groups differed by prior treatment history. The registry also does not provide the timing or duration of exposure needed to interpret the counts as exposure-adjusted rates.

The listed serious event terms include vomiting at 4.5%, and anaemia, nausea, infection, meningitis, and osteomyelitis at 2.4% each. These are registry-listed percentages; the record does not give further detail about the event-level attribution or context. In general, an event occurring during a study does not by itself establish that the study drug caused it. The counts should be read as safety observations, not as proof of causation or as a controlled estimate of comparative risk.

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

The registry record explains the clinical question and the intended primary endpoint: the percentage of evaluable participants meeting the Month 6 NIS-LL response definition. It does not report the observed percentage, the evaluable count, or the confidence interval. As a result, the primary outcome cannot be quantified or assessed for statistical precision from the posted information.

The record does describe treatment exposure and some adverse event counts. Those safety counts provide a factual account of events recorded in the two prior-treatment sequences, but the design does not support treating the sequences as randomized comparison groups. Both received tafamidis during the extension, and the registry cautions that they are not like-for-like controls. The counts alone do not establish a treatment effect or a causal link between treatment and an event.

In general, an open-label extension can describe longer-term experience among people who continue into it, but selection into an extension and lack of a concurrent control can limit interpretation. A change from baseline is not automatically attributable to treatment. It can also reflect disease course, previous treatment, measurement variability, or other factors. The registry does not report enough outcome data or analysis detail to assess those possibilities for this study.

The endpoint’s response threshold is a useful operational definition, but a responder percentage would not describe the magnitude of score changes for individual participants. A confidence interval would be needed to understand sampling precision, and additional analysis details would be needed to understand missing data and multiplicity. Neither the primary estimate nor those details are reported in the registry record.

Accordingly, the posted record supports describing the study design, treatment sequence, endpoint definition, and reported safety counts. It does not support a conclusion about the size or certainty of the primary clinical outcome, nor does it establish that treatment caused any observed change or event.

14. Why This Trial Matters Statistically

This study illustrates why an extension’s design needs to be kept distinct from the randomized study that preceded it. The record describes an intended transition from Fx-005 into open-label treatment, including crossover of participants previously assigned to placebo. The extension’s single-group structure means that the earlier treatment histories do not create a concurrent control contrast. Treating those sequences as equivalent to randomized extension arms would overstate what the design can establish.

It also illustrates how endpoint definitions and endpoint results are different kinds of information. The registry gives a detailed operational definition for NIS-LL response, including improvement or a specified degree of stabilization. But without the response percentage, evaluable count, and confidence interval, the definition cannot answer how participants actually fared or how precisely the outcome was estimated.

The safety record further shows why event counts require context. Counts and listed percentages can describe what was recorded, but the two sequences are not a like-for-like control comparison, and event occurrence does not establish causation. The absence of a reported death count and additional detail limits further interpretation.

Finally, the record lists numerous outcomes but does not report analyses or a multiplicity approach. Statistical interpretation depends not only on what was measured, but on which analyses were planned, how missing observations were handled, and how uncertainty was quantified. These methodological details are not reported in the registry record. The example therefore highlights the importance of pairing a clear outcome definition with transparent analysis and complete numerical results.

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.

Several limitations are specific to the information available for this extension. It is open-label and described as a single-group study, with no concurrent control group. The listed treatment sequences differ by prior treatment, while both received tafamidis during the extension. The registry itself cautions against treating the groups as a like-for-like control comparison. Any difference between them would therefore be difficult to attribute to treatment during the extension.

The primary endpoint definition is available, but its result is not reported in the registry record. The record gives no Month 6 responder percentage, confidence interval, or evaluable count. Without those values, neither the observed outcome nor its precision can be assessed. The registry also does not report score distributions or individual changes that would show what the binary response classification leaves out.

The analysis population is described, but the record does not report how many participants met the endpoint-specific evaluability criteria, how many were excluded, or what happened to missing measurements. Missing-data methods and sensitivity analyses are not reported. These gaps prevent assessment of whether the reported endpoint, if available elsewhere, would be sensitive to assumptions about missingness.

The record lists 19 outcome measures but no analyses. It does not report a multiplicity plan, trial-specific sample-size justification, interim analyses, or a statistical analysis plan. Further safety detail, including deaths, is not reported in the registry record. These limitations concern the interpretability of the posted record and should not be mistaken for evidence that the unreported analyses or procedures did not occur.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy — NCT00791492.
• Registry record last updated 2012-12-17; status last verified 2012-11.
• Results first posted 2012-12-17.
• 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 open-label extension evaluated once-daily oral 20 mg Fx-1006A for 12 months in people with transthyretin amyloid polyneuropathy. The registry lists Phase 2 and Phase 3, a single-group model, no masking, allocation not applicable, and enrollment of 86. Participants previously assigned to placebo in Fx-005 crossed over to active treatment.

The primary endpoint was the percentage with NIS-LL improvement or stabilization at Month 6. Its definition and analysis-population criteria are reported, but the endpoint result, evaluable count, and confidence interval are not reported in the registry record. Serious adverse event counts are listed for the two prior-treatment sequences, but they are not a like-for-like comparison. The record does not report deaths, analysis results, missing-data methods, or a multiplicity plan.