Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy (NCT01855360), a na phase 1, phase 2 study. The primary outcome is Changes in Strain Echocardiography.

2. Clinical Question

3. Trial Design

This was an open-label, single-group study listed as phase 1 and phase 2. The registry identifies the allocation as not applicable and masking as none. Enrollment was 40. The study status is completed; the recorded start was 2013-06 and primary completion was 2015-05-31.

All participants meeting study criteria were prescribed the combination of TUDCA and doxycycline. The registry describes oral TUDCA at 250 mg three times daily and oral doxycycline at 100 mg twice daily. Because the design had a single group, there was no concurrent randomized comparison between treatment arms. The stated objective was to determine whether the combination would slow progression of familial and senile amyloidosis.

The primary outcome was change in longitudinal echocardiographic strain, expressed as percent LV shortening. The registry describes assessments every 6 months, with a final measurement 18 months after enrollment; change at 12 months was the predefined primary endpoint. The outcome description says the change would be compared with previously determined changes from a cohort not receiving specific therapy for amyloid deposition. The registry does not report the historical cohort’s characteristics or the method used to make that comparison.

The registry lists two outcome measures and identifies number of patients with adverse events as a secondary outcome. It reports no analyses. Details such as the statistical analysis plan, the sample-size justification, and any interim analyses are not reported in the registry record. The completed status therefore describes the trial’s administrative status; it does not by itself establish that primary outcome findings or a full analysis are 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

Analysis population for the primary outcome, as defined in the registry: Patients who completed 18 month visit (primary outcome) and had a technically adequate echocardiogram to analyze strain imaging

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 Changes in Strain Echocardiography, measured over Time Frame: * (FDAAA) outcome measure is assessed every 6 months by serial echocardiography, with final measurement 18 months after enrollment, change at 12 months reported as pre-defined primary endpoint..

The primary endpoint was change in longitudinal echocardiographic strain, measured as percent LV shortening. Strain imaging uses echocardiography to describe the deformation or shortening of heart muscle during the cardiac cycle. In general, a longitudinal strain measure captures change along the long axis of the heart. Such a measure can be used to follow cardiac function over time, but its interpretation depends on consistent image acquisition and analysis.

The registry specifies a mean with standard deviation for this continuous outcome. It describes serial echocardiography every 6 months, a final measurement 18 months after enrollment, and change at 12 months as the predefined primary endpoint. The stated population for the primary outcome consists of patients completing the 18 month visit with an echocardiogram technically adequate for strain analysis. This selection means the endpoint description depends on both follow-up completion and image quality.

The outcome was intended to be compared with previously determined changes in a cohort with TTR cardiac amyloidosis that was not receiving specific therapy for amyloid deposition. That is not a concurrent randomized control group. The registry does not report the primary endpoint’s observed mean change, standard deviation, or comparative result. As a result, the magnitude and precision of any change cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure summarized as a mean and standard deviation. A mean describes the central value of measurements in a group; a standard deviation describes the spread of individual measurements around that mean. In general, both are useful for describing a continuous endpoint, but neither alone establishes whether a treatment caused a change. Interpretation also depends on the baseline and follow-up values, the definition of change, the population analyzed, and the comparison strategy.

What does a change score represent?

In general, a change score compares a participant’s follow-up measurement with that participant’s earlier measurement. A group mean change then summarizes those within-person changes. For this trial, the registry identifies change at 12 months as the predefined primary endpoint and describes serial echocardiography every 6 months, with a final measurement 18 months after enrollment. The registry does not report the actual mean change or standard deviation, or give a statistical estimate comparing the treatment group with the historical cohort.

Change scores can be affected by measurement variability, missing follow-up, and differences in who contributes baseline and follow-up data. Consistent echocardiographic acquisition and strain analysis matter because differences in image quality or measurement procedures can affect the observed values. The registry specifies that the primary outcome population had to complete the 18 month visit and have a technically adequate echocardiogram. It does not report the number meeting those criteria or the handling of measurements that were absent or inadequate.

Why does the study design matter?

In general, a single-group study follows participants who receive the intervention but does not randomly assign them to a concurrent control group. Changes over time may reflect the intervention, the natural course of disease, measurement variation, or other influences. A comparison with a previously observed cohort can provide a reference, but differences between historical and treated groups can complicate interpretation. Here, the outcome description names a previously determined cohort not receiving specific therapy for amyloid deposition. Details about how that cohort was selected, measured, or compared are not reported in the registry record.

Randomized allocation can help balance known and unknown prognostic factors between groups, whereas a historical comparison cannot ensure that balance. This general distinction does not establish that a historical comparison is invalid; it means that its assumptions and methods need to be assessed. The record does not report the historical cohort’s characteristics, an adjustment strategy, or a statistical test for the comparison. Therefore the planned comparator cannot be evaluated as a like-for-like control from the registry information.

How should precision be assessed?

In general, a confidence interval describes a range of values compatible with the data and the specified statistical method. Its width conveys precision: wider intervals indicate more uncertainty about the estimate. A p-value addresses how compatible the data are with a specified null model, under the assumptions of the analysis; it does not measure the size or clinical importance of an effect. Neither a confidence interval nor a p-value is reported for the primary endpoint in the registry record, so precision and statistical evidence for that endpoint cannot be appraised.

The registry lists the endpoint’s summary form as mean and standard deviation, but does not describe a model, covariate adjustment, or approach to repeated measurements. Repeated observations from the same participant are generally correlated, so analyses across multiple visits need to account for that dependence. This is a general statistical consideration, not a statement about the analysis performed in this study; the analysis approach is not reported in the registry record.

What do the planning assumptions mean?

The stated planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect described as a stated fraction of the observed effect. It is an illustration based on an observed effect, not the trial’s own design justification. The registry does not report the trial’s sample-size justification. Planning sample sizes are prospective scenarios under assumptions; they are not observed power and do not supply evidence about the treatment effect in this single-group study.

More generally, over-dispersion occurs when variability is greater than a statistical model assumes. If a model understates variability, standard errors may be too small and intervals too narrow. This concept is relevant when choosing models for some kinds of data, but the primary endpoint is described as continuous and the registry does not report an analysis model or any over-dispersion assessment. No such adjustment should be attributed to this study based on the available 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("TUDCA and Doxycycline")
n   <- c(30)
m   <- c(9.1)
sp  <- c(0.9)
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  TUDCA and Doxycycline  30  9.100  0.900  8.764  9.436

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: changes in strain echocardiography as the primary outcome and number of patients with adverse events as a secondary outcome. It specifies change at 12 months as the predefined primary endpoint, while describing echocardiographic assessments every 6 months and a final measurement 18 months after enrollment. Examining multiple outcomes or time points can raise multiplicity concerns in general, because repeated testing can increase the chance of at least one apparently notable result. The registry does not report a multiplicity strategy or explain whether any other time point was considered confirmatory.

Missing-data handling is also important for a longitudinal endpoint. The primary outcome population is described as participants who completed the 18 month visit and had technically adequate strain imaging. The registry does not report how many participants met that definition, how missing visits or inadequate images were handled, or whether any imputation or sensitivity analysis was used. It also does not describe the analysis population for the adverse event outcome beyond the recorded group at risk.

The registry reports zero analyses and does not provide a statistical analysis plan. Methods for repeated measurements, adjustment for the historical comparator, and treatment of missing data are therefore not reported in the registry record. Interim analyses are also not reported. These omissions limit assessment of how outcome selection, follow-up, and analysis decisions may affect the reported findings; in this case, primary outcome findings themselves are not reported.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute kidney injury (2.5%).

The registry records one patient with a serious adverse event and six with other adverse events in the TUDCA and doxycycline group. The at-risk count is 40 for each of these listed categories. It also records six deaths. Acute kidney injury is the listed serious adverse event term, at 2.5%.

These are descriptive registry counts. They do not establish that an event was caused by the study drugs, and the record does not provide a concurrent control group for comparison. It does not report event timing, individual event histories, or whether patients recorded in one category also appear in another. The death count should therefore be read as a separate recorded count, not assumed to be disjoint from the adverse event counts.

In general, adverse event counts are most interpretable when the definitions, follow-up period, severity criteria, and relationship assessments are clear. The registry does not report those details for these counts. The figures describe what is recorded, but cannot by themselves quantify comparative safety or establish causation.

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

The record establishes that a completed, open-label, single-group study enrolled 40 patients and prescribed TUDCA with doxycycline. It also defines a planned echocardiographic primary endpoint: change in longitudinal strain at 12 months, with serial assessments and an 18 month final measurement. The registry describes a historical cohort as the intended comparator and reports safety counts for the treated group.

Those design details do not amount to a reported primary outcome finding. The registry does not report the primary endpoint’s mean change, standard deviation, comparative estimate, or precision. It therefore does not show whether strain changed, how much it changed, or how the treated group compared with the historical cohort. The study’s completed status is not a substitute for those missing results.

Even if a within-group change were reported, a single-group design would not by itself separate a treatment effect from natural disease progression, measurement variability, or other time-related influences. A historical cohort may help frame the observed course, but the record does not give enough information to evaluate comparability or the analysis used. No causal conclusion about the combination can be drawn from the registry information alone.

The adverse event and death counts are also descriptive rather than comparative. They do not establish causality, and the registry does not report whether categories overlap or provide event timing and attribution. The counts should not be treated as a complete assessment of comparative risk.

In general, interpretation of a clinical trial requires attention to its design, outcome definitions, analysis population, missing data, and uncertainty around estimates. For this study, several of those details and the primary result are not reported in the registry record. The appropriate statistical reading is therefore limited: the registry documents the planned question and some safety counts, but does not permit assessment of the primary endpoint’s result or a treatment effect.

14. Why This Trial Matters Statistically

This study is statistically notable because its central question concerns change over time in an echocardiographic measure, while the design is single group and the intended reference is historical. That distinction matters: repeated measurements can describe how a group’s measurements evolve, but without a concurrent randomized comparator, attributing that evolution to treatment is more difficult. The historical comparison needs its own careful assessment of patient selection and measurement methods.

The endpoint description also makes the analysis population consequential. Primary outcome assessment is tied to completing the 18 month visit and having a technically adequate echocardiogram, even though change at 12 months is specified as the primary endpoint. In general, exclusions based on follow-up or image quality can affect which participants contribute to an estimate. The registry does not report how many participants met the criteria or how missing and inadequate measurements were handled.

The case also illustrates why statistical interpretation requires results as well as a design description. A mean and standard deviation are named, but the primary outcome values and analyses are not reported. Without estimates and a measure of uncertainty, readers cannot evaluate the size or precision of the observed change. Similarly, adverse event counts without a control group and attribution details cannot establish comparative safety.

These features do not negate the value of the study’s stated clinical question. They define what the registry record can support: an account of the intervention, endpoint, and recorded event counts, rather than a causal estimate of treatment effect.

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 endpoint’s result is not reported in the registry record, and the record lists no analyses. This prevents evaluation of the observed mean change, its variability, and its precision. Although the endpoint description identifies a historical comparison, the characteristics of that cohort and the method of comparison are not reported.

The single-group, open-label design has no concurrent randomized control arm. In general, changes observed over time can reflect influences other than the intervention, and a historical reference may differ from the study group in ways that affect the comparison. The registry does not describe methods to address those potential differences.

The primary outcome population is limited by completion of the 18 month visit and technically adequate strain imaging. The registry does not report participant flow, the number with usable measurements, or procedures for missing data and image quality. It also does not report the statistical model for repeated measurements, adjustment methods, or sensitivity analyses.

The record lists two outcome measures but does not report a multiplicity plan. It does not report interim analyses or a statistical analysis plan. The sample-size justification is not reported; the stated planning illustration is based on an observed effect and should not be read as the trial’s design rationale or as observed power.

Safety interpretation is limited by the absence of a concurrent comparison and by missing details on timing, attribution, and overlap among recorded categories. These limitations apply to what can be learned from the registry record and do not establish that unreported analyses or information do not exist elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy — NCT01855360.
• Registry record last updated 2020-12-04; status last verified 2018-11.
• Results first posted 2020-12-04.
• 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

NCT01855360 is a completed, open-label, phase 1 and phase 2, single-group study of TUDCA and doxycycline in patients with transthyretin amyloid cardiomyopathy. The registry reports enrollment of 40 and oral dosing of TUDCA, 250 mg three times daily, with doxycycline, 100 mg twice daily.

The primary outcome was change in longitudinal echocardiographic strain, expressed as percent LV shortening. Change at 12 months was predefined as the primary endpoint, within a schedule of assessments every 6 months and a final measurement at 18 months. The outcome was intended to be compared with previously determined changes in a cohort not receiving specific therapy for amyloid deposition.

The registry reports one patient with a serious adverse event, six with other adverse events, and six deaths; acute kidney injury is listed at 2.5%. Primary outcome results and analyses are not reported in the registry record.