Cystic Fibrosis Related Bone Disease: the Role of CFTR: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cystic Fibrosis Related Bone Disease: the Role of CFTR (NCT01549314), a registered phase not stated study. The primary outcome is Bone Microarchitecture and Strength Measures of the Radius and Tibia.

2. Clinical Question

The registry describes an observational comparison rather than a like-for-like controlled treatment comparison. Its allocation field is not stated, and the groups were not described as randomized. Matching can make selected characteristics more comparable, but it does not establish that groups are similar in other factors that may be related to bone measures or treatment use.

3. Trial Design

This completed study, NCT01549314, was sponsored by Massachusetts General Hospital. The registry lists a start date of 2012-04 and a primary completion date of 2018-05, with enrollment of 79. The condition listed is cystic fibrosis related bone disease. These registry entries describe the study record and do not provide a numerical analysis of the primary outcome.

The record describes three groups: subjects with cystic fibrosis taking ivacaftor, subjects with cystic fibrosis not taking ivacaftor, and healthy subjects. The first group was described as including people aged 6 to 75 years who would be starting ivacaftor or had started it within the previous 6 months. The non-ivacaftor group was described as people with cystic fibrosis aged 6 to 75 years who would not take ivacaftor. Healthy subjects were described as having no medical conditions known to affect bone and being between 6 and 75 years old. Age, race, and gender matching was described for the comparisons between groups.

The registry states that the comparison is not randomized and that allocation is not stated. It also cautions that the arms are not a like-for-like control comparison. Thus, group contrasts should be interpreted as observational associations, not as effects established by randomized treatment assignment. The record does not report the matching procedure in enough detail to determine how matching was implemented or accounted for in analyses.

The primary outcome is described as change in cortical volumetric bone mineral density at the radius, measured at baseline and 24 months. The primary outcome title refers to bone microarchitecture and strength measures of the radius and tibia; the outcome description identifies the radius measure. Areal bone mineral density measured by DXA and bone turnover markers are listed as secondary outcomes. Numerical results for these outcomes 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

Analysis population for the primary outcome, as defined in the registry: Subjects who were lost to follow up prior to the 24 month visit were not included in the analyses

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 Bone Microarchitecture and Strength Measures of the Radius and Tibia, measured over Baseline and 24 months.

The primary endpoint is change in cortical volumetric bone mineral density at the radius, with measurements scheduled at baseline and 24 months. The registry gives the unit as mgHA/cm3 and specifies that the outcome is summarized as a mean with standard deviation. It notes that subjects lost to follow-up before the 24 month visit were not included in the analyses. The outcome title refers more broadly to bone microarchitecture and strength measures of the radius and tibia, while the specific primary-outcome description names cortical volumetric bone mineral density at the radius.

As general context, bone is described through different kinds of measurements. Areal bone mineral density, listed as a secondary outcome and measured by DXA, represents a different measurement from volumetric density. Measures of bone microarchitecture and strength can add information about structural properties that a density measure alone may not capture. Those concepts explain why these outcomes can be studied together; they do not establish what this study found.

The registry record does not report numerical baseline or follow-up means, mean changes, between-group contrasts, or confidence intervals for the primary endpoint. Consequently, it is not possible to describe the observed magnitude, direction, or precision of change from the registry record. The reason this particular measure was selected as primary is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measurement, and the registry specifies a mean and standard deviation as its summary. In general, a mean describes the center of a set of measurements, while a standard deviation describes how spread out individual measurements are around that center. A standard deviation is not the same as the uncertainty in the estimated mean or in a comparison between groups. For that uncertainty, analysts commonly report a confidence interval or another inferential measure. Such estimates for this study are not reported in the registry record.

Change from baseline to 24 months can be analyzed in different ways. For example, an analysis might compare each participant’s change over time between groups, or compare follow-up values while accounting for baseline values. These approaches answer related but not identical statistical questions and rely on different modeling choices. The registry record does not report the specific model, the exact contrast used, or whether baseline measurements were incorporated into an adjusted analysis. Therefore, it is not possible to infer the analysis method from the endpoint description alone.

The unit for the primary measure is mgHA/cm3. Keeping the unit attached to an estimate is important because it communicates the scale on which a change or group contrast is expressed. No numerical estimate in this unit is reported in the registry record, so the size of a change cannot be interpreted from this record. The endpoint is summarized as a mean with standard deviation, but no distributional information or model diagnostics are reported.

As general statistical context, matching is a design approach intended to make groups similar on selected characteristics. Here, the record says matching was based on age, race, and gender. Matching does not necessarily make groups comparable on unmeasured or unmatched characteristics. In an observational study, differences between groups may reflect those characteristics as well as treatment exposure. The record does not report whether matching was individual or group-level, whether matched sets were retained in analysis, or whether the analysis accounted for matching. Those design and analysis details are not reported in the registry record.

Likewise, the comparison is described as nonrandomized, and allocation is not stated. Random allocation, in general, can help balance both measured and unmeasured characteristics across treatment groups. Without randomized assignment, the groups may differ for reasons related to treatment use, health status, or other factors. Adjustment can address measured characteristics when they are collected and appropriately modeled, but it cannot guarantee removal of confounding. The covariates included in any adjusted analysis are not reported in the registry record.

The record says that participants lost to follow-up before the 24 month visit were not included in analyses. In general, excluding participants with missing follow-up data can affect an estimate if the probability of missingness is related to outcome values or group membership. Complete-case analysis may be straightforward, but it can reduce the analysis population and may introduce bias under some missing-data patterns. The number with missing data, reasons for loss to follow-up, and any sensitivity analyses are not reported in the registry record. It is therefore not possible to assess the effect of missing follow-up on the study estimate.

For context, a confidence interval describes a range of values compatible with the data and a specified statistical procedure, under that procedure’s assumptions. A narrow interval generally indicates greater precision than a wide interval, but precision is not the same as clinical importance, and an interval does not resolve bias from nonrandomized group differences or missing data. No confidence intervals for the primary or secondary outcomes are reported in the registry record. No p-values or detailed inferential results are reported either.

The registry lists 3 outcome measures and 6 analyses. When multiple outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase if each is assessed separately without an appropriate strategy. In general, multiplicity methods can control or describe this issue, while a prespecified hierarchy can identify which comparisons carry primary emphasis. The multiplicity approach, prespecified analysis hierarchy, and relationship between the listed analyses and outcomes are not reported in the registry record.

The record also describes a sample-size planning illustration based on the observed effect. Its assumptions include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. It specifies that time-to-event illustrations give a total number of events using the Schoenfeld approach, while other illustrations give participants per arm. These are planning assumptions, not evidence of the study’s design justification or observed statistical power. The trial’s own sample-size justification is not reported in the registry record, and numerical planning results are not reported in the registry record.

The registry does not report an interim-analysis plan, stopping rules, or the full statistical analysis plan. These details should not be inferred from the completed status or the outcome listing. The information available describes the endpoint and selected design features, but does not permit a full audit of the analysis methods or reproducibility of the reported outcome estimates.

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("Subjects With CF Taking Ivacaftor", "Subjects With CF Not Taking Ivacaftor", "Healthy Subjects")
n   <- c(23, 21, 24)
m   <- c(44.6, 40.1, 43.7)
sp  <- c(53.9, 44, 53.8)
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  Subjects With CF Taking Ivacaftor  23  44.600  53.900  21.292  67.908
CARM  Subjects With CF Not Taking Ivacaftor  21  40.100  44.000  20.071  60.129
CARM  Healthy Subjects  24  43.700  53.800  20.982  66.418

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 6 analyses. It names the primary outcome as change in cortical volumetric bone mineral density at the radius and identifies areal bone mineral density measured by DXA and bone turnover markers as secondary outcomes. The record does not explain which analyses correspond to which outcome measures, comparisons, or time points. A prespecified testing hierarchy or adjustment for multiple outcomes and analyses is not reported in the registry record.

Multiplicity matters because examining several outcomes or comparisons can increase the likelihood that at least one result appears notable by chance. This general concern does not imply that any particular result is false; it means that interpretation depends in part on the analysis strategy. The record does not report whether multiplicity was addressed, so the statistical meaning of any individual inferential result cannot be fully assessed from the registry record. Numerical outcome results are not reported either.

For missing data, the record states that subjects lost to follow-up before the 24 month visit were not included in the analyses. It does not state how many participants were lost, why they were lost, or how many contributed to each outcome analysis. It also does not describe imputation, sensitivity analyses, or other methods for assessing the effect of missing follow-up. Those details are not reported in the registry record.

The registry’s primary outcome population therefore appears to exclude people lost before the 24 month visit, but the precise analysis population and group-specific denominators are not reported. The record does not describe an intention-to-treat analysis, and the nonrandomized design makes that label especially unhelpful as an assumption about treatment assignment. The analysis population and missing-data strategy cannot be reconstructed from the available record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each listed group, with 26 at risk in each group and 0 serious events in each group. It reports deaths as 0 in all three groups. These are the registry’s group-specific counts; they should not be interpreted as proof that an event is impossible or as a comparison capable of establishing a safety difference.

For other adverse events, the record reports 26 at risk in each group. It lists 0 affected in the group with cystic fibrosis taking ivacaftor, 1 affected in the group with cystic fibrosis not taking ivacaftor, and 0 affected among healthy subjects. The record does not provide further detail about the event counted in the non-ivacaftor group in the registry record for this summary. The top serious adverse event terms list is empty.

These adverse-event counts are distinct from the primary outcome analysis. They do not show how many participants had 24 month bone measurements, and they should not be used as primary-outcome denominators. The safety reporting period, event definitions, ascertainment procedures, and group-level comparisons are not reported in the registry record. With no reported comparative safety analysis, the counts are descriptive only.

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

The record establishes that this completed study examined bone measures in groups of subjects with cystic fibrosis taking or not taking ivacaftor, alongside healthy subjects. It identifies change in cortical volumetric bone mineral density at the radius between baseline and 24 months as the primary outcome. It also lists areal bone mineral density measured by DXA and bone turnover markers as secondary outcomes. These details explain what the study set out to assess, not what the outcome showed.

Numerical primary and secondary outcome results are not reported in the registry record. There is therefore no basis in this record to state the direction or size of any change, whether groups differed, or how precise those estimates were. It also does not support a conclusion that ivacaftor improved or failed to improve bone measures. Outcome estimates, uncertainty measures, and analysis details would be needed to make a quantitative interpretation.

Even if a group difference were reported elsewhere, this study’s nonrandomized design would remain important. The registry says allocation is not stated and that the arms are not a like-for-like control comparison. Matching on age, race, and gender may address those characteristics, but does not rule out differences in other factors related to treatment use or bone outcomes. A group association in this design would not by itself show that treatment caused the difference.

The exclusion of participants lost before the 24 month visit is another interpretive consideration. Without the number lost, reasons for missing follow-up, and analyses of missing data, it is not possible to judge whether exclusion changed the estimate. The presence of a planning illustration based on an observed effect does not resolve this limitation and should not be interpreted as observed power.

The safety figures are limited descriptive counts and do not establish comparative safety. Overall, the registry record is informative about the research question, population, endpoint, and selected safety counts, but it does not report the numerical efficacy outcomes needed to judge the observed result.

14. Why This Trial Matters Statistically

This study is statistically notable because it frames bone health in cystic fibrosis through more than one type of measure. The primary endpoint concerns cortical volumetric bone mineral density at the radius, while the registry also lists areal bone mineral density measured by DXA and bone turnover markers. In general, complementary measures can describe different aspects of a biological process, but analyzing multiple outcomes also makes clear reporting of outcome priorities and analysis methods important.

The three-group structure raises a separate design issue. Subjects with cystic fibrosis taking ivacaftor are compared with subjects with cystic fibrosis not taking it, and healthy subjects provide another reference group. Those comparisons do not answer the same question. In particular, a healthy group is not interchangeable with a non-ivacaftor cystic fibrosis group. The record notes that the arms are not a like-for-like control comparison, which is central to interpreting any contrast.

Matching on age, race, and gender is relevant, but statistical interpretation depends on more than the matching variables. In observational comparisons, treatment use and outcome can both relate to other measured or unmeasured characteristics. A clear account of how matching was performed, what variables were adjusted for, and how missing follow-up was handled would help readers understand the strengths and limitations of any estimate. Those details are not reported in the registry record.

Finally, the registry identifies a primary outcome and reports selected safety counts, yet numerical outcome estimates are not reported. This gap demonstrates why a clear endpoint description cannot replace results with measures of precision. Without those estimates, readers cannot distinguish a small, precise change from a large, uncertain one, or determine whether groups differed on the measured outcome.

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 central limitation of the registry record is that it does not report numerical results for the primary endpoint. Baseline and follow-up means, standard deviations, changes, group contrasts, confidence intervals, and p-values are not reported in the registry record. The direction, magnitude, and statistical precision of the primary outcome therefore cannot be assessed.

The design is nonrandomized, allocation is not stated, and the registry explicitly notes that the arms are not a like-for-like control comparison. Although the groups are described as matched for age, race, and gender, the matching method and its role in analysis are not reported. The registry also does not report adjustment for other potential differences among groups, so residual confounding cannot be evaluated.

Losses to follow-up before the 24 month visit were excluded from analysis. The number lost, reasons for loss, analysis denominators, and missing-data sensitivity analyses are not reported in the registry record. This prevents assessment of whether the analyzed participants were representative of the enrolled groups or whether missing follow-up could have affected the findings.

The record lists 3 outcome measures and 6 analyses, but does not explain the analysis structure or report a multiplicity strategy. The detailed statistical methods, analysis populations, interim analyses, and trial-specific sample-size justification are not reported in the registry record. The planning illustration assumptions do not establish the study’s original design rationale or observed power.

Finally, adverse-event counts are reported without event definitions, ascertainment details, or a comparative safety analysis. The group counts are descriptive and do not resolve the missing efficacy results or the limitations of the observational comparisons.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Cystic Fibrosis Related Bone Disease: the Role of CFTR — NCT01549314.
• Registry record last updated 2020-04-01; status last verified 2020-03.
• Results first posted 2020-03-25.
• 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

NCT01549314 is a completed study sponsored by Massachusetts General Hospital, with enrollment of 79. The record lists cystic fibrosis related bone disease and describes groups of subjects with cystic fibrosis taking ivacaftor, subjects with cystic fibrosis not taking it, and healthy subjects. Age, race, and gender matching is described; the comparison is nonrandomized, allocation is not stated, and the arms are noted not to be a like-for-like control comparison.

The primary outcome is change in cortical volumetric bone mineral density at the radius from baseline to 24 months, expressed in mgHA/cm3 and summarized as a mean with standard deviation. Subjects lost to follow-up before the 24 month visit were excluded from analyses. Areal bone mineral density measured by DXA and bone turnover markers are listed as secondary outcomes.

Numerical outcome results and detailed analysis methods are not reported in the registry record. Serious adverse events and deaths are listed as 0 in each group; one other adverse event is listed in the cystic fibrosis group not taking ivacaftor. These safety counts are descriptive and do not establish comparative treatment effects.