A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) -Experienced Subjects With Cystic Fibrosis (CF): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) -Experienced Subjects With Cystic Fibrosis (CF) (NCT03150719), a randomized phase 3 study. The primary outcome is Incidence of Respiratory Adverse Events of Special Interest (RAESIs).

2. Clinical Question

The study also reported secondary outcomes concerning lung function, respiratory symptoms measured by the CFQ-R, treatment discontinuation, and adverse events. These outcomes provide different kinds of information: some describe changes from baseline, while others count participants with events. They do not replace the prespecified primary safety question.

3. Trial Design

This was a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group study. The registry lists quadruple masking and describes the study as multicenter. Enrollment was 98, and the registry record lists the study as completed. The recorded start date was 2017-05-24, and the primary completion date was 2018-08-09.

The target population was specific: participants were aged 12 years and older, had cystic fibrosis, were homozygous for the F508del mutation, and had stopped Orkambi because of respiratory symptoms considered related to treatment. The results therefore describe this selected study population; the registry record does not establish how well they generalize to other people with cystic fibrosis or other treatment histories.

Participants were assigned to TEZ/IVA or matching placebo. Both regimens were taken orally in the morning and evening for 56 days. The primary outcome covered Day 1 up to Day 84, so its observation window was not limited to the stated treatment period. The registry record does not report the reason for that follow-up window.

The safety set included participants who received at least one dose of study drug. The registry record lists 47 participants in the placebo arm and 50 in the TEZ/IVA arm for the primary outcome. The overall enrollment figure and these analysis-group sizes describe different aspects of the record and should not be added to infer a participant total. The registry record does not report further details about the randomization procedure, concealment, or the original design assumptions.

4. Participant Flow and Accounting

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

Before assignment: A total of 98 participants were randomized: 47 in placebo group and 51 in tezacaftor (TEZ)/ivacaftor (IVA) group. One participant in TEZ/IVA group did not receive any study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety set included all participants who received at least 1 dose of study drug.

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 Incidence of Respiratory Adverse Events of Special Interest (RAESIs), measured over Day 1 up to Day 84.

The primary endpoint was the incidence of respiratory adverse events of special interest (RAESIs), expressed as the number of participants with such events. The registry defines these events as chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing. The outcome timeframe was Day 1 up to Day 84.

This endpoint is a safety measure: it counts participants who experienced at least one event in the specified group of respiratory events during the stated timeframe. The safety set consisted of participants who received at least one dose of study drug. A participant count is not the same as an event count; a participant could have more than one event, but the endpoint is reported as participants with an event.

Grouping events of particular clinical interest can help focus safety monitoring on symptoms relevant to the treatment context. In this study, the selected events concern respiratory symptoms and conditions, which were also relevant to the population’s prior discontinuation of Orkambi. The endpoint does not, by itself, establish that an event was caused by study treatment. The registry record does not report event-level timing, severity breakdowns for RAESIs, or an adjudication method for deciding whether an event met the definition.

7. Results Posted in the Registry

• TEZ/IVA: 14.0% (7/50) versus 21.3% (10/47) on control; risk difference -7.3 percentage points (95% CI -22.4 to 7.9), risk ratio 0.66 (0.27–1.59); unadjusted two-proportion z-test p = 0.346.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • TEZ/IVA: mean 2.20 versus -0.60 on control; difference 2.80 (95% CI 1.15 to 4.45), standardized effect d = 0.67; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for TEZ/IVA than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • TEZ/IVA: mean 5.20 versus -1.50 on control; difference 6.70 (95% CI 2.65 to 10.75), standardized effect d = 0.65; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for TEZ/IVA than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • TEZ/IVA: mean 5.70 versus 4.70 on control; difference 1.00 (95% CI -4.91 to 6.91), standardized effect d = 0.07; z-test p = 0.740.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TEZ/IVA and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover several domains rather than repeating the primary safety question. The two ppFEV1 outcomes describe lung-function change, the CFQ-R respiratory-domain score concerns reported respiratory symptoms, and other listed outcomes address discontinuation and adverse events. Across the posted continuous results, the reported mean differences for both ppFEV1 measures have confidence intervals that exclude zero, while the CFQ-R interval includes zero. The results therefore do not form a uniform pattern across every secondary domain.

These findings are related to, but separate from, the primary outcome. The primary endpoint counts participants with a defined set of respiratory safety events during Day 1 up to Day 84. The secondary endpoints measure changes in lung function or questionnaire scores, or describe other safety and tolerability outcomes. A difference in one domain does not establish a difference in another, and the secondary measurements do not negate or resolve uncertainty in the primary safety comparison.

The registry record lists 5 secondary outcomes, but only 3 secondary continuous outcomes have detailed group results and comparisons in the posted results. The record does not report results for the secondary treatment-discontinuation and treatment-emergent adverse-event outcomes in the same detailed form. Their absence from the reported results should not be interpreted as a finding of no events or no difference.

Unadjusted secondary results carry less weight as confirmatory evidence because several outcomes are examined and no multiplicity adjustment is reported in the registry record. The observed pattern may be useful for describing the trial and motivating further study, but it should not be read as a set of independent, definitive tests. The reported sponsor analyses take precedence over recalculated summary-statistic comparisons for describing the sponsor’s own analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements
• Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements
• Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements
• Tolerability as Assessed by Number of Participants Who Discontinued Treatment
• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

9. Statistical Interpretation

10. Statistical Methods Explained

For the primary outcome, the data are binary at the participant level: each participant either was or was not counted as having a respiratory adverse event of special interest during the defined period. The posted counts are 10 among the 47 participants in the placebo group and 7 among the 50 in the TEZ/IVA group. The recalculated comparison uses the risk difference, which expresses the difference between the proportions with an event in the two arms. A risk difference of zero represents equal observed risks under that measure. The posted confidence interval includes zero, and the unadjusted p-value is 0.346.

A confidence interval describes a range of values compatible with the observed data under the assumptions of the method. It conveys uncertainty around an estimate; it is not a guarantee that the true value lies in the interval, nor does it represent the range of individual participant outcomes. For a risk difference, an interval that includes zero means that the data do not rule out equal risks at the interval’s confidence level. The width also matters: a wide interval indicates less precision about the magnitude and direction of the difference.

The registry record does not report the method used for the trial’s primary comparison, and the posted primary results do not include a sponsor-reported analysis with a confidence interval or p-value. The numerical comparison and p-value described in the statistical display are unadjusted recalculations from the posted summary counts. They should be distinguished from trial-level analyses described by the sponsor. The record does not report an adjustment for baseline factors or other covariates for the primary outcome.

The secondary ppFEV1 and CFQ-R outcomes are continuous measures, reported as mean changes from baseline and standard deviations. For these outcomes, a mean difference compares the average change in one group with the average change in the other. The standard deviation describes variation among individual observations around the group mean; it is not the uncertainty of the mean difference itself. The confidence interval for the mean difference expresses uncertainty in the group comparison.

For the absolute change in ppFEV1, the posted sponsor analysis reports a mean difference of 2.7 with a 95% confidence interval from 1.0 to 4.4. For relative change in ppFEV1, the reported difference is 6.7, with a 95% confidence interval from 2.5 to 10.9. For the CFQ-R respiratory-domain score, the reported mean difference is 1.1, with a 95% confidence interval from -4.9 to 7.0. These sponsor-reported analyses take precedence over simple unadjusted recalculations when describing the sponsor’s own analysis. The registry record does not report the methods used to estimate these trial analyses.

General statistical explanation: standard deviations summarize the spread of participant measurements, whereas standard errors and confidence intervals describe uncertainty in estimated means or contrasts. A smaller standard error generally produces a narrower interval, all else equal. For binary outcomes, the amount of information depends on the number of participants and how often events occur; sparse events can make comparative estimates uncertain. No additional model or correction should be inferred when the registry record does not identify one.

What does an unadjusted result mean?

An unadjusted comparison uses the posted group summaries without accounting for other variables. Randomization is intended to support fair comparisons between assigned groups, but random assignment does not guarantee that every measured or unmeasured characteristic is balanced in a particular study. An adjusted analysis can account for specified factors, but the factors and analysis method need to be reported to evaluate that approach. For the primary comparison, such details are not reported in the registry record.

The p-values attached to recalculated secondary comparisons are unadjusted. When multiple outcomes are examined, the chance of seeing at least one apparently notable result can increase, even if no corresponding underlying differences exist. A prespecified multiplicity strategy can address this issue, but one is not reported in the registry record. Therefore, the secondary p-values should not be read as though each were a single, isolated confirmatory test.

Why can over-dispersion matter?

General statistical explanation: a count model may assume that the variability in counts follows a particular relationship to the average count. Over-dispersion occurs when the observed variability is greater than that assumption allows. If not accounted for, uncertainty can be understated and intervals may be too narrow. The primary outcome in this study is reported as participants with an event rather than a recurring event rate, and the registry record does not report a count model or an over-dispersion adjustment. There is no basis to infer that such a model was used.

For the primary safety endpoint, the analysis population is explicitly identified as the safety set. The registry record does not report the analysis population definitions for every secondary endpoint, the approach to missing measurements, or whether any imputation was used. Those omissions limit the ability to reproduce or fully assess the analysis from registry information alone.

11. Confidence Intervals and Precision

The primary outcome has limited precision: the observed counts were 10 participants with a respiratory adverse event of special interest in the placebo group and 7 in the TEZ/IVA group, and the unadjusted p-value was 0.346. The confidence interval for the recalculated risk difference includes zero. It therefore does not isolate a single direction or magnitude of difference. The interval should be read as expressing uncertainty around the group contrast, not as showing that the groups are equivalent.

For the secondary ppFEV1 analysis, the sponsor-reported mean difference was 2.7 and the 95% confidence interval ranged from 1.0 to 4.4. For relative change in ppFEV1, the reported mean difference was 6.7, with an interval from 2.5 to 10.9. Both intervals exclude zero, but the estimates remain subject to the outcome definitions, analysis methods, and multiplicity considerations described elsewhere. For the CFQ-R respiratory-domain score, the reported mean difference was 1.1 and the interval ranged from -4.9 to 7.0, spanning zero.

In general, narrower confidence intervals indicate greater precision, while wider intervals leave more uncertainty about the true value. Precision depends on the amount and variability of information as well as the analysis method. A confidence interval does not measure clinical importance; interpreting importance requires context about the outcome scale and what differences matter, and that context is not reported in the registry record. The posted intervals are estimates, not guarantees about the results of other studies.

12. 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 planning figures are expressed as participants per arm. They are illustrations based on an effect size set to the stated fraction of the observed effect, not a reconstruction of the study’s original sample-size calculation. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For these outcomes, the figures refer to participants per arm, not total events.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the assumed effect under those assumptions, if that effect were the true one. The 90% column uses a higher target chance of detecting that effect and consequently generally requires more participants. These are planning concepts, not guarantees about what a future trial would find. This is not observed power.

The rows use the observed effect and smaller fractions of it as planning targets. A smaller effect is harder to distinguish from random variation, so detecting it generally requires more participants. The entries therefore grow as the assumed target effect becomes smaller. The illustrations use the observed effect as a planning reference, but an observed effect can be imprecise and may not be a reliable estimate of the effect in a future study.

The registry record does not report the assumptions used for the original trial design, including its original target effect, power target, or sample-size justification. The planning illustrations should not be mistaken for evidence that the trial was designed to detect the effects shown, or for a claim about the probability that its results are correct.

13. 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 = 0.213; treatment proportion p₁ = 0.140; average p̄ = 0.176.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5390 = 1.0565.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5366 = 0.4516.
4. n = (1.0565 + 0.4516)² / (-0.0728)² = 429.5, rounded up to 430 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 <- 0.212765957446809                          # control proportion
p1 <- 0.14                          # 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(3150719)
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 = 430 (80% power), 575 (90% power)
 75% of observed effect: n per arm = 796 (80% power), 1,064 (90% power)
 50% of observed effect: n per arm = 1,858 (80% power), 2,486 (90% power)
power.prop.test: 429.5 
Simulated power at n = 430 per arm: 0.799 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and several secondary outcomes, but it does not report a multiplicity strategy. In a study that examines more than one outcome, repeated testing can increase the chance of obtaining at least one result that appears statistically notable by chance. Approaches such as defining a testing hierarchy or adjusting significance thresholds can address this issue, but no such approach should be assumed.

The reported secondary analyses should therefore be interpreted with caution, particularly where their p-values are unadjusted. A result that appears notable on one secondary measure is not automatically confirmatory, and a result that is not notable does not prove the absence of a meaningful difference. The registry record does not report whether any secondary outcomes were designated as confirmatory or how their analysis related to the primary endpoint.

The record also does not report whether interim analyses were planned or conducted, nor does it provide a detailed statistical analysis plan in the information summarized. The method for the primary comparison, covariate adjustment, handling of missing data, and analysis populations for the secondary outcomes are not reported in the registry record. These details matter because they influence which participants contribute to each estimate and how uncertainty is calculated.

The primary population is specified as the safety set, defined as all participants who received at least one dose of study drug. That definition is appropriate to describe the population included in the posted primary safety result, but it is not the same as an intention-to-treat definition unless the record establishes that equivalence. The registry record does not report enough detail to characterize missing outcome data, reasons for missingness, imputation, or sensitivity analyses. As a result, the effect of missing data on the reported estimates cannot be assessed from the registry record alone.

15. 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: infective pulmonary exacerbation of cystic fibrosis (14.9%), lower respiratory tract infection (2.1%), pericardial effusion (2.1%), musculoskeletal chest pain (2.1%), pleuritic pain (2.1%).

The serious adverse event summary reports 9 participants at risk and affected in the placebo group and 5 in the TEZ/IVA group. The registry lists 47 participants at risk in the placebo group and 50 in the TEZ/IVA group. These are participant-level figures; they do not show the total number of serious adverse event episodes or their duration. The record also reports 0 deaths in the placebo group and 1 in the TEZ/IVA group.

The listed serious-event terms include infective pulmonary exacerbation of cystic fibrosis at 14.9%, followed by lower respiratory tract infection, pericardial effusion, musculoskeletal chest pain, and pleuritic pain at 2.1%, and sepsis at 2.0%. The registry record does not provide arm-specific attribution alongside these listed terms, so they should not be assigned to a particular group based on this summary.

These descriptive safety counts do not establish that treatment caused or prevented an event. The registry record does not report a comparative statistical analysis for the serious adverse event summary, nor does it provide the detail needed to compare severity, timing, or recurrence. The single reported death is a serious safety observation, but the registry summary does not provide its cause or a treatment attribution.

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

The posted results describe outcomes in a randomized, placebo-controlled study among people with cystic fibrosis who were homozygous for the F508del mutation and had stopped Orkambi because of respiratory symptoms considered related to treatment. For the primary safety endpoint, the observed participant counts were 10 in the placebo group and 7 in the TEZ/IVA group. The unadjusted comparison is imprecise, with a confidence interval that includes zero and a p-value of 0.346.

This result does not demonstrate that the groups had identical risks, and it does not establish that one regimen caused fewer respiratory events. The study’s estimate is compatible with a range of possible differences. The counts also refer to a defined group of respiratory adverse events during a defined period, not to every possible safety outcome or to all events experienced by participants.

The secondary results describe other outcomes, including changes in ppFEV1 and CFQ-R respiratory-domain scores. They add information about the observed groups, but they cannot be substituted for the primary endpoint. The lack of a reported multiplicity adjustment also means that secondary findings deserve cautious, exploratory interpretation. The registry record does not report enough information about missing data and analysis methods to resolve all potential sources of uncertainty.

The results apply most directly to the study population and treatment schedule recorded in the registry. They should not be generalized automatically to people with different mutation status, treatment history, age, or clinical characteristics. The record does not establish long-term outcomes beyond the reported observation period, nor does it answer questions about treatments or outcomes not studied. Statistical interpretation describes evidence and uncertainty; it does not provide individual medical guidance.

17. Why This Trial Matters Statistically

This trial raises a useful statistical question because it studies a population defined partly by a prior treatment experience: participants had discontinued Orkambi because of respiratory symptoms considered related to treatment. That context makes the distinction between a safety endpoint and other measures especially important. The primary endpoint counts participants with a specified set of respiratory events, while lung-function and questionnaire outcomes address different aspects of the study.

The primary comparison also illustrates why event counts alone are not enough to judge certainty. The groups had 10 and 7 participants with a respiratory adverse event of special interest, but the unadjusted confidence interval includes zero. The observed difference is therefore not a precise estimate of how risks might differ beyond this study. The p-value alone cannot convey that uncertainty or determine whether the possible differences matter clinically.

The range of secondary outcomes illustrates the value of looking across related but distinct measures. The posted ppFEV1 comparisons and the CFQ-R comparison do not have the same uncertainty pattern. That variation cautions against treating a single secondary result as a complete account of respiratory status, or treating several unadjusted outcomes as independent confirmations.

Finally, the registry record makes some essential aspects of interpretation explicit, including the primary safety population and event definition, while leaving other details unreported, including the primary comparison method and missing-data handling. Recognizing what is documented and what is not is part of sound statistical reading. The study is informative as a record of observed outcomes in a specific randomized comparison, but the limits of precision and reporting constrain the strength and reach of conclusions.

18. 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 is reported as the number of participants with a respiratory adverse event of special interest, rather than as event frequency, duration, severity, or time to first event. Participants with repeated events are not distinguished in the participant count. The registry record does not provide a breakdown of primary-endpoint events by individual term, making it difficult to see whether the group pattern was driven by one particular event type.

The primary comparison is imprecise, and the registry record does not report a sponsor analysis method or adjusted estimate for it. The detailed methods for secondary analyses are also not reported. The record does not describe missing-data handling, sensitivity analyses, or the analysis populations for all secondary outcomes. These gaps limit independent assessment of the robustness of the reported estimates.

The study population is narrowly described by age, mutation status, cystic fibrosis diagnosis, and prior discontinuation of Orkambi for respiratory symptoms considered treatment-related. Results may not apply in the same way to people outside this group. The stated treatment period was 56 days, and the primary outcome timeframe was Day 1 up to Day 84; longer-term outcomes are not reported in the record.

The registry record does not report a multiplicity adjustment for secondary outcomes or a detailed original sample-size rationale. The planning illustrations are based on observed effects and are not evidence about the original design. The listed serious adverse-event terms are not attributed by arm in the summary, and the record does not report the cause or treatment attribution of the reported death.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) -Experienced Subjects With Cystic Fibrosis (CF) — NCT03150719.
• Registry record last updated 2019-09-12; status last verified 2019-09.
• Results first posted 2019-09-12.
• 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.

22. Record Summary

The registry record describes a completed Phase 3b randomized, double-blind, placebo-controlled, parallel-group study of TEZ/IVA in people aged 12 years and older with cystic fibrosis who were homozygous for the F508del mutation and had stopped Orkambi because of respiratory symptoms considered related to treatment. Enrollment was 98; the recorded study start was 2017-05-24 and primary completion was 2018-08-09.

The primary endpoint was the incidence of respiratory adverse events of special interest from Day 1 up to Day 84 in the safety set. The posted counts were 10 in the placebo group and 7 in the TEZ/IVA group. The unadjusted comparison was imprecise. Secondary results included lung-function and CFQ-R changes, while several statistical and missing-data details are not reported in the registry record.