Dose Escalation Study of QR-010 in Homozygous ΔF508 Cystic Fibrosis Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Escalation Study of QR-010 in Homozygous ΔF508 Cystic Fibrosis Patients (NCT02532764), a randomized phase 1, phase 2 study. The primary outcome is Incidence of Subjects Experiencing Treatment Emergent Adverse Events From Baseline Through End of Study.

2. Clinical Question

This is an early-phase safety, tolerability, and pharmacokinetic study, rather than a trial whose primary question is whether QR-010 improves a clinical outcome. The registered primary endpoint counts participants experiencing at least one treatment-emergent adverse event. The registry gives separate counts across dose cohorts and placebo cohorts, with different observation periods for single-dose and multiple-dose cohorts.

The posted results can describe the number of participants with events in each cohort, but they do not, on their own, establish whether differences between cohorts are attributable to treatment. The groups are small, the study evaluates multiple doses and dosing schedules, and the registry does not report a comparative effect estimate or uncertainty interval for the primary endpoint. The registry record also does not report a formal statistical plan explaining how the dose groups were intended to be compared.

3. Trial Design

The registry describes a Phase 1b, randomized, double-blind, placebo-controlled, dose-escalation study of QR-010 in people with homozygous ΔF508 cystic fibrosis. The record lists Phase 1 and Phase 2, and describes the study as completed. It records an enrollment of 70. The listed start is 2015-06 and the primary completion date is 2017-09-14.

QR-010 and placebo were administered by inhalation. The single-ascending-dose cohorts are labelled SAD, and the multiple-ascending-dose cohorts are labelled MAD. The QR-010 dose groups are 6.25 mg, 12.5 mg, 25 mg, and 50 mg for both schedules. Placebo is listed separately for SAD and MAD. The registry describes multiple dosing as three times weekly for four weeks; the single-dose cohorts received a single dose. It does not give further details about how participants were assigned among dose cohorts.

The study is described as randomized, double-blind, and placebo-controlled, but the registry also labels its model as single group. Those entries do not provide a clear account of the intended analysis structure. The posted arm-level results nevertheless show separate QR-010 dose cohorts and placebo cohorts. The registry does not explain the single-group classification or reconcile it with the randomized, placebo-controlled description.

The primary endpoint observation period differs by schedule: 8 Days for Single-dose cohorts and 8 weeks for Multiple-dose cohorts. This difference matters when reading event counts, because the periods over which events could be observed are not the same across those sets of cohorts. The registry lists pharmacokinetic outcomes including maximum serum concentration, time to maximum serum concentration, terminal half-life, area under the curve, and serum clearance. Numerical results for those outcomes are not included in the 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.

Only the first 6 of 10 groups are shown.

Single Ascending Dose (SAD) Cohorts

Multiple Ascending Dose (MAD) Cohorst

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All subjects who received either QR-010 or placebo

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.

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Subjects Experiencing Treatment Emergent Adverse Events From Baseline Through End of Study, measured over 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts.

The primary endpoint is the number of participants who experienced at least one treatment-emergent adverse event from baseline through the end of study. The registry defines the outcome as a count of participants, not a count of all separate event episodes. A participant with more than one event is therefore represented once in this endpoint if they experienced at least one event.

Safety and tolerability are central questions in an early-phase dose-escalation study. Counting participants with at least one treatment-emergent event gives a direct descriptive summary of how many participants in each cohort had an event during the specified observation period. It can help readers see the observed event burden across dose and schedule groups. It does not describe the severity, duration, or clinical importance of every event, and the endpoint alone does not establish that an event was caused by study treatment.

The endpoint uses different timeframes for the single-dose and multiple-dose cohorts: 8 Days for Single-dose cohorts and 8 weeks for Multiple-dose cohorts. Counts should therefore be read in the context of their respective follow-up periods. The registry gives arm-level counts but does not report a comparative statistical analysis, uncertainty intervals, or a definition of how treatment-emergent status was determined beyond the endpoint description.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count show?

A count of participants with at least one event is a binary-outcome summary at the participant level: each person either experienced an event meeting the endpoint definition or did not. This differs from counting every event episode, because a participant with multiple events is not counted multiple times in this endpoint. The posted results show these counts separately by cohort. They are useful for describing what was observed, but counts alone do not quantify the uncertainty around the underlying event frequency or a difference between groups.

Why are comparison estimates and confidence intervals useful?

In general, an estimate of the difference between groups puts the observed contrast on a scale that can be interpreted directly. A confidence interval describes the range of values reasonably compatible with the data under the statistical method used. A wide interval indicates substantial uncertainty; an interval that includes no difference does not establish equivalence. These are general principles, not reported analyses for this trial. Comparative estimates, confidence intervals, and inferential tests for the primary endpoint are not reported in the registry record.

How should dose cohorts be handled?

A dose-escalation study has more than one treatment dose and may also have distinct dosing schedules. An analysis could compare each dose with placebo, examine a dose-response pattern, or use another prespecified approach. Those choices answer different questions and affect interpretation. The registry record does not report which comparative strategy, if any, was prespecified for these cohorts. It also does not report a statistical model for the primary endpoint. Consequently, the arm-level counts should not be treated as evidence of a formal dose-response relationship.

Small cohort sizes make descriptive results sensitive to the outcome of individual participants. General statistical reasoning also cautions that a non-significant result, if one had been reported, would not by itself show that treatments are equivalent. Establishing similarity requires a suitable design and analysis, including a defined margin and sufficiently precise estimates. Such details are not reported in the registry record.

What does the planning section mean?

The accompanying sample-size section is a planning illustration based on an observed effect, not a report of the trial’s design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These are assumptions for illustrative planning, not evidence that the trial was designed or powered in that way. The sample-size values are not observed power, and they do not show the probability that the completed trial detected a true effect.

In general, sample-size planning asks how many participants would be needed for a chosen analysis to detect a specified effect under stated assumptions. Changing the effect size or assumptions changes the planning result. Since the registry record does not report the trial’s own sample-size justification, the illustrative calculations should not be read as a reconstruction of the sponsor’s rationale. Any sample-size figures in the accompanying section are planning quantities, not trial outcomes.

Why does follow-up matter?

The primary endpoint has an observation period of 8 Days for Single-dose cohorts and 8 weeks for Multiple-dose cohorts. Longer observation creates more opportunity to record an event, all else being equal. This does not mean that follow-up alone explains the observed counts, but it does mean that raw counts across schedules are not directly comparable without attention to exposure time and the analysis used. The registry record does not report an adjustment that places the different schedules on a common time scale.

The registry lists 18 outcome measures and 16 analyses, and names seven secondary outcomes, including safety assessments and pharmacokinetic measures. In general, examining multiple outcomes or comparisons raises a multiplicity issue: the chance of at least one apparently notable result can increase as the number of analyses grows. Methods such as adjustment or a prespecified hierarchy may address this, but no multiplicity procedure is reported in the registry record. The number of listed outcomes does not tell us which analyses were confirmatory or how results were prioritized.

The primary endpoint population is described as all subjects who received either QR-010 or placebo. This is a treatment-received description. The registry record does not report whether an intention-to-treat population was used for other analyses, how missing outcome data were handled, or how participants with incomplete follow-up were treated. Those omissions limit assessment of the analysis population and possible bias from missing observations.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("QR-010 SAD 6.25 mg", "QR-010 SAD 12.5 mg", "QR-010 SAD 25 mg", "QR-010 SAD 50 mg", "Placebo SAD", "QR-010 MAD 6.25 mg")
n      <- c(6, 6, 9, 6, 9, 6)
events <- c(3, 2, 7, 4, 2, 5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  QR-010 SAD 6.25 mg  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6
ARM  QR-010 SAD 12.5 mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  QR-010 SAD 25 mg  9  7  77.8  40.0  97.2  45.3  93.7  44.4  93.3
ARM  QR-010 SAD 50 mg  6  4  66.7  22.3  95.7  30.0  90.3  29.0  90.1
ARM  Placebo SAD  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6
ARM  QR-010 MAD 6.25 mg  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures and 16 analyses, and identifies seven secondary outcomes. The secondary outcomes include abnormalities in laboratory parameters, vital signs, ECG, spirometry, and physical findings, along with pharmacokinetic measures such as maximum serum concentration, time to maximum serum concentration, terminal half-life, area under the curve, and serum clearance. The presence of multiple outcomes and several dose cohorts creates the general possibility of multiple comparisons. In such settings, a prespecified strategy can clarify which questions are primary and whether statistical error is controlled across comparisons.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or which secondary analyses were designated as confirmatory. It also does not report an interim-analysis plan. These procedures should not be inferred from the existence of the listed analyses.

The primary endpoint population is described as all subjects who received either QR-010 or placebo. The record does not describe a separate intention-to-treat analysis population or give enough information to determine how participants were handled if they did not complete follow-up. A missing-data method, imputation approach, or sensitivity analysis is not reported in the registry record. The record also does not state how missing endpoint information affected the arm-level counts.

These omissions do not mean that no methods were used; they mean that the registry record does not provide them. As a result, readers cannot assess from this record how multiplicity or missing observations may have affected the reported findings.

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: respiratory tract infection (16.7%), calculus urinary (16.7%), abdominal pain (11.1%).

The serious-adverse-event data are shown by cohort. The registry lists no serious events in the QR-010 SAD cohorts or Placebo SAD, and none in QR-010 MAD 6.25 mg, 12.5 mg, or 25 mg. It lists one affected participant in QR-010 MAD 50 mg and one in Placebo MAD. The death count is zero in each listed group.

The registry also names Respiratory Tract Infection and Calculus Urinary at 16.7% each, and Abdominal Pain at 11.1%, among the top serious-event terms. These percentages are reported as term-level figures; the record excerpt does not specify their cohort distribution. They should not be assigned to a particular treatment group based on the arm-level serious-event counts.

Serious-event counts are descriptive, especially when the cohorts are small. The figures do not establish that an event was caused by QR-010, and they do not provide a precise estimate of comparative risk. The listed event counts should also be distinguished from the primary endpoint, which counts participants with any treatment-emergent adverse event, not only serious events.

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

The posted results show that participants experiencing at least one treatment-emergent adverse event were recorded in every dose and placebo cohort. The registry gives the counts separately for single-dose and multiple-dose schedules. It also reports serious-event counts by cohort and records no deaths in the listed groups. These are useful descriptive observations about the participants included in the reported results.

They do not establish that QR-010 caused the events, nor do they show that QR-010 has a higher or lower event risk than placebo. A randomized, blinded, placebo-controlled design can support comparative inference when the analysis and results are reported, but the registry excerpt does not provide a comparative effect estimate, confidence interval, or test for the primary endpoint. The cohort counts alone do not show the precision of a treatment contrast.

The results also do not answer whether QR-010 improves cystic fibrosis outcomes. The primary endpoint concerns treatment-emergent adverse events, while the registry lists pharmacokinetic outcomes as secondary measures. Numerical pharmacokinetic results and clinical efficacy findings are not reported in the record. Their absence from this account should not be interpreted as a null result.

Finally, the different follow-up periods for single-dose and multiple-dose cohorts limit direct comparisons of their raw event counts. The record’s classification as single group is not reconciled with its randomized, placebo-controlled description, and the statistical plan and handling of missing observations are not reported. These constraints make the arm-level counts best read as a descriptive summary rather than a definitive estimate of treatment differences.

14. Why This Trial Matters Statistically

This trial illustrates how a dose-escalation study can generate several distinct safety summaries: one for each dose, one for each dosing schedule, and separate summaries for placebo. The primary endpoint is a participant-level event count, which is straightforward to read descriptively but cannot, on its own, express the uncertainty in a comparison. Readers need to distinguish the visible cohort counts from a statistical estimate of treatment effect.

It also highlights why design details matter to interpretation. The study includes single-dose and multiple-dose cohorts with different follow-up periods. A raw count across those schedules does not put observations on a common time basis. The record also lists a single-group model alongside a randomized, placebo-controlled design, leaving the analysis structure unclear in the registry description.

There are multiple dose groups and several listed outcomes, yet the registry record does not report a multiplicity strategy or a complete analysis plan. This is relevant to any attempt to interpret apparent patterns across doses or outcomes. The sample-size illustration must also be separated from trial planning: it is not evidence of the original design justification and does not describe observed power.

For biostatistical reading, the central lesson is to keep three things distinct: what was observed in each cohort, what comparison was estimated, and how uncertain that estimate is. Here the registry provides the first, but does not report the second or third for the primary endpoint. That distinction prevents descriptive counts from being mistaken for a conclusive comparative result.

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 registry record does not report comparative estimates or confidence intervals for the primary endpoint. As a result, the precision of between-group differences cannot be assessed from the posted counts. The record also does not report a statistical analysis plan, sample-size justification, multiplicity procedure, or interim-analysis plan.

The cohort sizes shown are small, and the study includes multiple dose levels and two dosing schedules. Counts from small cohorts can be sensitive to individual participant outcomes. The follow-up periods differ between the single-dose and multiple-dose cohorts, which limits direct comparison of their raw event counts. No time-adjusted analysis is reported in the registry record.

The registry’s single-group model label is not explained alongside its randomized, double-blind, placebo-controlled description and separate treatment arms. The record does not clarify how allocation among dose cohorts occurred or how comparisons were intended to be conducted. The stated primary population consists of subjects who received either QR-010 or placebo, but the handling of missing data, withdrawals, and incomplete follow-up is not reported.

The primary outcome provides a count of participants with at least one treatment-emergent event, not a complete account of event frequency, severity, timing, or attribution. The serious-event terms are listed with percentages, but their cohort distribution is not specified. Numerical results for the listed pharmacokinetic outcomes are also not reported in this record summary. These limitations narrow what can be concluded from the available registry results; they do not establish that further analyses or information do not exist elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose Escalation Study of QR-010 in Homozygous ΔF508 Cystic Fibrosis Patients — NCT02532764.
• Registry record last updated 2019-02-06; status last verified 2019-01.
• Results first posted 2019-02-06.
• 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

NCT02532764 is a completed, randomized, double-blind, placebo-controlled dose-escalation study of inhaled QR-010 in adults with homozygous ΔF508 cystic fibrosis. The registry describes Phase 1b and lists Phase 1 and Phase 2. Enrollment is recorded as 70. The listed start is 2015-06, and primary completion is dated 2017-09-14.

The primary endpoint counts participants with at least one treatment-emergent adverse event through the end of study. The registry reports arm-level counts across single-dose and multiple-dose QR-010 cohorts and corresponding placebo cohorts, with different endpoint timeframes for the two schedules. Serious adverse events and deaths are also listed by cohort.

The record does not report comparative estimates or uncertainty intervals for the primary endpoint, nor does it describe the statistical plan, multiplicity handling, or missing-data methods. Its reported counts therefore support descriptive reading, but not a precise estimate of comparative treatment effects.