Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis (NCT00409175), a randomized 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 18.

2. Clinical Question

The clinical question is about a measured neurological impairment outcome over the treatment period, not about every aspect of FAP or every possible consequence of treatment. The study also listed quality-of-life, nerve-fiber, body-mass-index, and transthyretin-related secondary outcomes, but numerical results for those measures are not reported in the registry record. The primary outcome therefore provides a focused comparison of response status at the specified assessment time.

3. Trial Design

The registry describes a randomized, parallel-group trial with placebo control and quadruple masking. The official title calls it a randomized, double-blind study. These descriptions both indicate masking, but the record does not identify the people or roles covered by the quadruple-masking designation, or explain why the title uses a different description.

The trial is listed as Phase 2 and Phase 3, and the brief summary describes it as a Phase 2/3 study. Enrollment was 128. The record lists the start as 2007-01, primary completion as 2009-05, and status as completed. Pfizer is listed as sponsor. Participants were assigned to Fx-1006A or placebo. The brief describes once-daily dosing over eighteen months, while the main posted endpoint is assessed at month 18.

The population in the brief consisted of male and female patients with FAP and a documented V30M TTR mutation, at an early to mid-stage of disease. The registry outcome display uses the group label Tafamidis for the active-treatment arm, while the trial title and intervention listing use Fx-1006A. The record does not explain this labeling difference, so both labels should be understood as they appear in their respective registry descriptions rather than treated as evidence of a separate treatment group.

The primary endpoint is the percentage of participants classified as having a response on NIS-LL at month 18. The stated response definition combines improvement and stabilization, so it does not represent improvement alone. Additional outcomes were listed at several follow-up times, but the registry record does not report their numerical analyses. Details of the randomization procedure, allocation concealment, dose strength, treatment adherence, and the trial's original sample-size rationale 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITTset:randomized participants received atleast(\>=)1 dose of study drug, had \>=1 post-baseline efficacy assessment for NIS-LL,Norfolk Quality of Life-Diabetic Neuropathy(QOL-DN) or discontinued study due to death/liver transplant(LT).Last-observation-carried-forward(LOCF) used;participant who discontinued due to death/LT was set non-responder.

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 18, measured over Month 18.

The primary endpoint is the percentage of participants with a response to treatment, measured using the Neuropathy Impairment Score–Lower Limb (NIS-LL) at month 18. NIS-LL assesses muscle weakness, reflexes, and sensation in the lower limbs. The registry description states that components are scored separately for the left and right limbs; higher scores indicate greater impairment. The response assessment is based on the mean of 2 scores obtained during a 1 week period.

A participant was classified as responding if the NIS-LL score improved from baseline, meaning a decrease, or if it was stabilized, defined as a change from baseline of 0 to <2. Because the endpoint includes either improvement or stabilization, the response percentage does not tell how many participants improved versus remained stable. Separate counts for those response subtypes are not reported in the registry record.

A binary response endpoint reduces a score trajectory to a participant-level category. That can make a group comparison easier to interpret as the proportion meeting a defined criterion, but it also discards information about the size and pattern of score changes within each category. The endpoint is relevant to the trial's stated question about progression of lower-limb impairment, but it is not a complete measure of neurological function, quality of life, or the broader clinical course of FAP.

7. Results Posted in the Registry

• Tafamidis: 45.3% (29/64) versus 29.5% (18/61) on control; risk difference 15.8 percentage points (95% CI -0.9 to 32.5), risk ratio 1.54 (0.96–2.46); unadjusted two-proportion z-test p = 0.068.

8. Statistical Interpretation

9. Statistical Methods Explained

The main outcome is binary at the participant level: each person either met the registry's response definition or did not. For a binary outcome, a group percentage expresses the proportion classified as having the event of interest, here response. The posted values are 45.3% for Tafamidis and 29.5% for placebo. This summary is straightforward to read, but it depends on the chosen response definition and does not preserve all of the information in the original NIS-LL scores.

What does a risk difference describe?

A risk difference compares the response proportion in one group with the response proportion in the other group by subtraction. The posted unadjusted risk difference is 0.158. Its sign and size represent the direction and magnitude of the group contrast on the proportion scale. The registry also gives a confidence interval for this comparison, which includes zero. An interval that includes zero is compatible with no difference under the model used to construct it, while also allowing a range of nonzero differences. It is not proof that the groups are identical.

The group-level confidence intervals are separate estimates of uncertainty for each response percentage. They should not be substituted for the interval around the difference: the comparative interval uses uncertainty in both groups and addresses a different statistical quantity. The posted unadjusted p-value is 0.068. A p-value describes how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor does it measure the clinical importance of the observed contrast.

Why can binary outcomes be useful?

A binary endpoint can make a prespecified clinical criterion easier to communicate, particularly when the criterion has an explicit interpretation such as improvement or stabilization. In this study, however, the response category combines those two outcomes. The reported percentage cannot distinguish the participants whose scores decreased from those whose scores remained within the stabilization range. It also treats participants close to the response boundary differently from those just on the other side, even if their underlying scores are similar. A score-based analysis could retain more detail, but the registry record does not report a numerical primary analysis of that kind.

What does masking contribute?

Masking is intended to reduce the risk that knowledge of assigned treatment influences participant experience, clinical assessment, or other trial processes. The registry describes quadruple masking, and the official title says double-blind. The identities of the masked roles and the procedures used to maintain masking are not reported in the registry record. Random allocation supports a comparative design by assigning participants to groups rather than allowing treatment choice to determine assignment; the specific randomization method and allocation-concealment procedures are not reported.

How does the missing-data approach matter?

The primary outcome description says LOCF was used. In general, LOCF replaces a missing later measurement with the participant's last observed measurement. This produces a value for the planned time point, but it assumes that carrying the earlier value forward is an acceptable representation of the missing value. If participants who leave the study differ in their subsequent outcomes from those who remain, this approach can affect the estimated response proportion. The registry record does not report the amount or reasons for missing outcome data, or sensitivity analyses examining alternative assumptions.

What analysis details are not available?

The registry record does not report the sponsor's full statistical analysis plan, the specific test behind the primary comparison, covariate adjustment, subgroup methods, or a multiplicity strategy. It lists 8 secondary outcome measures, including repeated assessments of NIS-LL and other measures, but does not post their numerical analyses. Without those details, the primary result can be described and its uncertainty discussed, but the broader analytic context and the handling of all planned comparisons cannot be assessed from the registry record.

The distinction between an unadjusted recalculation and a sponsor analysis also matters when both are available. The reported comparison in this record is identified as unadjusted, and no discrepancy between posted and recalculated results is flagged. No sponsor-adjusted primary analysis is reported in the registry record. Accordingly, the unadjusted estimate and p-value should not be represented as a fully adjusted or multiplicity-controlled result.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimate. The registry reports a 95% confidence interval for the Tafamidis response percentage of 33.1% to 57.5%, and for the placebo response percentage of 18.1% to 41.0%. Both intervals span a range of plausible values for the corresponding group proportion under the assumptions of the interval method. Their width reflects uncertainty; it does not indicate that the observed percentage is wrong, nor does it assign a 95% probability to the fixed true value after the data have been observed.

The confidence interval for the unadjusted risk difference is also reported in the comparative results. It includes zero, so the posted data do not pin down the direction of the underlying difference with the same clarity as a narrow interval wholly on one side of zero would. The associated unadjusted p-value is 0.068. Together, the interval and p-value indicate uncertainty in the comparison; neither proves the absence of a group difference.

The interval for each group percentage answers a different question from the interval for the group contrast. Overlap between separate group intervals is not a substitute for examining the confidence interval of the difference. For the comparative question, the risk-difference interval is the relevant interval to interpret. The registry record does not report additional precision measures for the secondary outcomes.

Confidence intervals depend on statistical assumptions and the data used to construct them. The registry record does not report every detail of the interval calculation or the effects of missing data on precision. The results should therefore be read as estimates with meaningful uncertainty, rather than as exact values for the underlying response rates.

11. 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 sample-size display is a planning illustration based on the observed risk difference, not the trial's original design rationale. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The planning rows consider detecting 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The figures are participants per arm, not total events.

For 100% of the observed effect, the display gives 146 participants per arm for 80% power and 195 participants per arm for 90% power. For 75% of the observed effect, it gives 255 participants per arm for 80% power and 341 participants per arm for 90% power. For 50% of the observed effect, it gives 559 participants per arm for 80% power and 748 participants per arm for 90% power.

The 80% power column illustrates a planning target under which a study of the stated size would have an 80% chance of detecting the specified effect if that effect were the true one and the planning assumptions held. The 90% column uses a higher chance target. These are not guarantees for a future study, and the figures are not observed power for this completed trial. The curve presents the same planning relationship graphically: smaller effects require more participants to maintain a given power target.

The registry record does not report the trial's original sample-size assumptions or justification. The planning illustration should therefore not be used to infer what the investigators expected when designing the trial, or to treat the posted trial enrollment as evidence that a particular effect was adequately powered.

12. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.295; treatment proportion p₁ = 0.453; average p̄ = 0.374.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6843 = 1.3413.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6751 = 0.5682.
4. n = (1.3413 + 0.5682)² / (0.1580)² = 146.0, rounded up to 146 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
p0 <- 0.295081967213115                          # control proportion
p1 <- 0.453125                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(409175)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 146 (80% power), 195 (90% power)
 75% of observed effect: n per arm = 255 (80% power), 341 (90% power)
 50% of observed effect: n per arm = 559 (80% power), 748 (90% power)
power.prop.test: 146 
Simulated power at n = 146 per arm: 0.797 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 secondary outcome measures, including NIS-LL response at earlier assessments, changes in NIS-LL and quality-of-life scores, nerve-fiber function, modified body mass index, and TTR stabilization. Several outcomes are assessed at more than one time point. Considering multiple outcomes and time points creates multiple opportunities for an apparently notable result to arise by chance. Statistical methods can address this through prespecified testing hierarchies or adjustment procedures, but the registry record does not report a multiplicity plan.

The primary comparison is described as unadjusted, and its p-value is 0.068. The record does not report whether the primary comparison was part of a broader testing strategy, whether any adjustment was applied elsewhere, or whether interim analyses were planned. Interim analyses and the statistical plan are not reported in the registry record. The unadjusted p-value should therefore be read as the result for the reported comparison, without assuming control of the error rate across all listed outcomes.

The registry identifies LOCF as the approach used for the primary endpoint. It also gives a partial description of the ITT set: randomized participants received at least 1 dose and had at least 1 post-baseline efficacy assessment for specified measures, or discontinued study because of death or liver transplant. The population definition is truncated in the registry record, so its complete eligibility rules and the treatment of all other missing observations are not reported.

The registry record does not report the number of missing primary assessments, reasons for missingness, sensitivity analyses, or whether alternative imputation methods were used. These omissions matter because missing outcome data can affect both the estimated response percentages and their uncertainty, especially when the primary outcome is classified using a threshold. Numerical results for the listed secondary outcomes are also not reported in the registry record. These limits restrict assessment of the full analysis population, robustness to missingness, and evidence across the other outcomes.

14. 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: urinary tract infection (3.1%), anaemia (1.6%), cardiac amyloidosis (1.6%), nausea (1.6%), vomiting (1.6%).

The serious adverse event display reports 6 affected participants among 65 at risk in the Tafamidis group and 5 among 63 at risk in the placebo group. The other adverse event figures are 57 among 65 at risk and 56 among 63 at risk, respectively. These are participant counts and their listed group denominators; they should not be confused with the efficacy population counts, which use a different displayed denominator.

The registry lists urinary tract infection at 3.1% among the most frequent serious-event terms. Anaemia, cardiac amyloidosis, nausea, vomiting, and catheter site phlebitis are each listed at 1.6%. These entries describe terms in the posted safety record; they do not by themselves show that an event was caused by the assigned treatment. The display does not provide event-level timing or a comparative statistical analysis for these terms.

Deaths are not reported in the registry record. The safety counts should be interpreted descriptively, with attention to the group denominators and the limited information available about event definitions and follow-up.

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

The posted results describe the proportion of participants meeting the registry's combined improvement-or-stabilization definition for NIS-LL at month 18. The response percentage was higher in the Tafamidis-labeled group than in the placebo group, and the unadjusted risk difference was 0.158. The confidence interval for the comparison includes zero, and the unadjusted p-value is 0.068. These findings indicate that the estimated contrast is uncertain; they do not prove either that the groups differ or that they are the same.

The endpoint has a specific scope. It measures a response category based on lower-limb impairment scores, not all aspects of FAP. Because response includes stabilization as well as improvement, the overall percentage cannot tell how many participants improved, how many remained stable, or how much scores changed within each category. The registry lists other outcomes that could describe quality of life, nerve function, body mass index, and TTR stabilization, but their numerical analyses are not reported in the registry record.

The comparison also depends on the analysis choices recorded for the endpoint, including LOCF for missing values. The amount and pattern of missing data are not reported, and the primary population definition is incomplete in the registry record. The posted results therefore cannot fully show how robust the response estimate is to alternative assumptions about missing outcomes.

Statistical uncertainty is not the same as clinical importance. The registry result alone does not establish how meaningful the observed group contrast is to patients, nor does the p-value measure the size or importance of the difference. The study description states that the trial examined whether Fx-1006A could halt FAP progression, but the posted month 18 response comparison should be interpreted only as evidence about the defined outcome and analysis. It should not be extended to a claim about every treatment effect, every patient group, or the disease course beyond the recorded study.

16. Why This Trial Matters Statistically

This trial presents several statistical issues that are common in clinical research. Its primary outcome converts a continuous impairment score into a binary response category. That makes a group percentage accessible, but the interpretation depends on the threshold and on combining improvement with stabilization. A reader needs to distinguish the response rate from a direct description of the score change.

The study also illustrates why the comparative estimate and its uncertainty matter more than a pair of percentages alone. The posted risk difference estimates the contrast between groups, while its confidence interval conveys how imprecise that estimate is. Here, the interval includes zero and the unadjusted p-value is 0.068. The data therefore leave room for a range of possible underlying group contrasts. A point estimate alone would obscure that uncertainty.

Repeated outcomes and assessment times raise the question of multiplicity. Eight secondary measures are listed, with some outcomes measured at several time points, but the registry record does not report a strategy for interpreting the full set of comparisons. This makes it important to keep the primary result distinct from any broader claim based on multiple outcomes.

Missing-data handling is another key issue. The stated use of LOCF makes an assumption about unobserved later scores, while the registry record does not provide the extent or pattern of missingness or sensitivity analyses. Such details help readers judge whether a result depends on how incomplete follow-up is treated.

Finally, the study descriptions use different active-arm labels and different masking terminology. The registry record does not reconcile those differences. This does not change the reported numerical comparison, but it is a reminder that careful interpretation depends on understanding how registry labels and outcome definitions map to the trial conduct.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record leaves several trial-specific questions unresolved. The primary outcome population description is truncated after the stated inclusion criteria, so the full analysis-set definition is not available. Although the record reports LOCF, it does not report how many outcome observations were missing, why they were missing, or whether alternative missing-data assumptions were examined.

The record lists 8 secondary outcomes but provides no numerical analyses for them. It does not report the trial's full statistical analysis plan, multiplicity handling, subgroup analyses, interim analyses, or the sponsor's original sample-size justification. The sample-size illustration is based on the observed effect and cannot replace those original design details.

There is also a naming difference: the study title and intervention listing use Fx-1006A, whereas the active outcome group is labeled Tafamidis. The official title describes double-blind masking, while the design field indicates quadruple masking. Explanations for these differences are not reported in the registry record. The description of response combines improvement and stabilization and does not provide separate counts for those components.

The safety display is descriptive, and deaths are not reported in the registry record. The available information does not establish the timing, attribution, or full clinical context of each adverse event. These limitations do not invalidate the posted estimates, but they narrow the conclusions that can be drawn from the registry record alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis — NCT00409175.
• 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.

21. Record Summary

The registry record describes a completed randomized, parallel-group, placebo-controlled study of Fx-1006A in familial amyloid polyneuropathy. It lists Phase 2 and Phase 3, enrollment of 128, start in 2007-01, primary completion in 2009-05, and Pfizer as sponsor. The primary outcome is the month 18 percentage meeting a combined improvement-or-stabilization definition on NIS-LL.

The posted response percentages are 45.3% for the Tafamidis-labeled group and 29.5% for placebo. The unadjusted risk difference is 0.158, with an unadjusted p-value of 0.068; its confidence interval includes zero. The record reports LOCF for the primary endpoint, lists 8 secondary outcomes without numerical analyses, and does not report the full analysis plan or complete missing-data information.