A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users. (NCT05587998), a randomized phase 1 study. The primary outcome is Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1.

2. Clinical Question

The study’s stated overall aim was to assess respiratory drive when morphine was administered after multiple doses of AZD4041, compared with morphine administered alone, in healthy recreational opioid users. The registry’s listed primary endpoint, however, is specifically the number of participants meeting the EtCO2 threshold on Day 1. The arm schedules place the AZD4041 or placebo dosing after the Day 1 morphine dose, so this primary endpoint is not a Day 15 comparison of morphine given after the multiple-dose sequence.

The posted primary results show no participants meeting the threshold in either arm on Day 1. The registry also posts Day 15 summaries for oxygen saturation, EtCO2 and respiratory rate. Those later measurements provide additional descriptive context, but they are distinct from the primary Day 1 event count. The available record does not report an analysis connecting the Day 1 count to the Day 15 measurements.

3. Trial Design

This was a Phase 1, single-centre, randomized, double-blind, placebo-controlled study with two fixed sequences. The registry lists a parallel model and an enrollment of 45. The brief description says participants would be randomized to AZD4041 and morphine or placebo and morphine, and planned to ensure completion of at least 36 participants on Day 15. These are design statements; they do not establish how many participants completed each sequence or contributed to every endpoint.

The two sequences began with a single intravenous dose of morphine on Day 1. From Day 2 to Day 15, one sequence received oral AZD4041 once daily and the other received matching oral placebo once daily. The brief description identifies planned morphine coadministration on Day 15. The exact dose levels are not reported in the registry record. The listed safety population includes participants who received at least 1 dose of morphine.

The primary endpoint is a Day 1 count, while the posted continuous secondary outcomes highlighted are Day 15 measurements. The primary endpoint therefore describes the threshold event on the first day of the sequence, and the later measurements describe different outcomes at a later time. The record lists 52 outcome measures and 48 posted secondary outcomes; the secondary results are a subset.

The registry lists the study as completed. It records a start date of 2022-08-31 and primary completion date of 2023-05-25. The total study duration was described as up to 54 days per participant, including screening. The record does not report the randomization procedure, allocation concealment details, or the protocol’s statistical analysis plan.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety population included all participants who received at least 1 dose of morphine.

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.

Population: The safety population included all participants who received at least 1 dose of morphine.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1, measured over Day 1.

The primary endpoint counts participants with an increased EtCO2 on Day 1. The registry defines an event as an increase of at least 10 mmHg compared with baseline or a value > 50 mmHg, sustained for at least 30 seconds. EtCO2 is carbon dioxide measured in exhaled gas. The record describes measurement using a standardized capnography configuration with a nasal cannula and bedside monitor.

The endpoint is used as a threshold-based indicator of a change in respiratory drive in this clinical pharmacology setting. A participant either meets the stated event definition or does not, so the primary result is a count rather than a mean EtCO2 value. That distinction matters: a count of participants crossing a threshold does not describe the size, timing, or duration of all EtCO2 changes.

The registry describes expected baseline values for spontaneously breathing healthy volunteers, but the posted primary endpoint is the event count, not a comparison of baseline averages. The Day 1 timeframe is also important. In the listed sequence, morphine is given on Day 1 and AZD4041 or placebo dosing follows from Day 2. Thus, the primary endpoint as posted does not directly measure the Day 15 response after multiple days of AZD4041 or placebo. The record does not report a separate primary endpoint for the Day 15 threshold event.

7. Results Posted in the Registry

• Morphine Then AZD4041 Then Morphine + AZD4041: 0.0% (0/26) versus 0.0% (0/15) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

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.

Post-dose SpO2

• 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:
  • Morphine Then AZD4041 Then Morphine + AZD4041: mean 96.99 versus 97.90 on control; difference -0.91 (95% CI -1.82 to 0.00), standardized effect d = -0.61; z-test p = 0.051.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Morphine Then AZD4041 Then Morphine + AZD4041 and the control. The interval gives the range of effects that remain compatible with the data.

Post-dose EtCO2

• 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:
  • Morphine Then AZD4041 Then Morphine + AZD4041: mean 41.87 versus 40.92 on control; difference 0.95 (95% CI -0.78 to 2.67), standardized effect d = 0.35; z-test p = 0.282.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Morphine Then AZD4041 Then Morphine + AZD4041 and the control. The interval gives the range of effects that remain compatible with the data.

Post-dose RR

• 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:
  • Morphine Then AZD4041 Then Morphine + AZD4041: mean 13.58 versus 13.48 on control; difference 0.10 (95% CI -1.57 to 1.77), standardized effect d = 0.04; z-test p = 0.907.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Morphine Then AZD4041 Then Morphine + AZD4041 and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes span oxygen saturation, carbon dioxide, and respiratory rate. The posted Day 15 means and contrasts offer several views of respiratory measurements, but they are not the same endpoint as the primary Day 1 participant count. In particular, a group mean at Day 15 does not reveal how many participants crossed the primary EtCO2 threshold, nor does the primary count describe the full distribution of the later measurements.

Across the three posted continuous comparisons, the confidence intervals include zero and the unadjusted p-values do not fall below 0.05. This overall pattern is consistent with uncertainty in the estimated group differences. It should not be translated into a conclusion that all respiratory measures were the same, because the intervals allow for differences in either direction and the registry does not report an equivalence design or margin.

The secondary outcomes are numerous: 48 are posted, with three continuous Day 15 comparisons highlighted. Testing multiple outcomes can produce apparently notable results by chance when no adjustment is made. The posted comparisons are unadjusted, and no multiplicity strategy is reported in the registry record. They therefore carry less confirmatory weight than a prespecified primary analysis with a documented analysis plan. The record does not state whether these particular secondary outcomes were prioritized in advance.

These secondary summaries are useful for understanding what was measured and for identifying uncertainty in later respiratory measurements. They do not resolve the timing distinction between the primary Day 1 endpoint and the overall question about morphine after multiple doses of AZD4041. Nor do the posted means establish how individual responses varied, beyond the reported group standard deviations. Read them as descriptive and exploratory evidence alongside, not in place of, the primary endpoint.

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

• Time to Reduction in SpO2 to < 92%
• Duration of Reduction in SpO2 to < 92%
• Post-dose Reduction of SpO2 Adjusted for Baseline
• Post-dose SpO2
• Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
• Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
• Post-dose Increase in EtCO2 Adjusted for Baseline
• Post-dose EtCO2

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: the event definition is either met or not met. The registry reports the number of participants with an event in each arm. For a binary outcome, a risk difference compares the event proportions between groups. Here, the posted proportions are both 0.0 and the posted risk difference is 0.0. A zero observed difference is a description of these data, not proof that the underlying event risks are equal.

What does a confidence interval describe?

In general, a confidence interval expresses the uncertainty around an estimate under the assumptions of the method used to construct it. Wider intervals usually indicate less precision, while narrower intervals indicate greater precision. For a difference, an interval that includes zero is compatible with no difference as well as with some differences in either direction, within the limits shown. An interval does not assign a probability to a particular true value, and it does not by itself establish equivalence.

The primary result has interval limits of 0.0 and 0.0 in the posted comparison. With no observed events in either group, the displayed estimate contains no observed difference. The record does not describe how the interval was calculated or whether a special method was used for the zero-event situation. It is therefore not possible to assess from the record whether that displayed interval captures all relevant uncertainty for the underlying risks.

How should the continuous outcomes be read?

The Day 15 secondary outcomes are reported as group means with standard deviations. The posted comparisons express the mean in the AZD4041 sequence minus the mean in the placebo sequence. A positive mean difference indicates a higher observed group mean in the AZD4041 sequence; a negative value indicates a lower observed group mean. Standard deviation describes spread among observations within a group, whereas the confidence interval around a mean difference describes uncertainty about the contrast between group means. These are related but distinct quantities.

The reported unadjusted p-values assess how compatible the observed comparison is with a null value of zero under the calculation used. They do not measure the probability that the null hypothesis is true, nor do they convey the magnitude or practical importance of a difference. The registry does not report a full model specification for these comparisons. The posted analyses field is empty for the secondary outcomes, so the methods behind the comparisons are not described there.

What do the sample-size illustrations mean?

The sample-size section is a planning illustration based on the observed effect, not the trial’s own design justification. It assumes a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect to detect set to a stated fraction of the observed effect. The accompanying rows show planning for 100%, 75% and 50% of the observed effect, with participants per arm for 80% and 90% power. These are hypothetical planning quantities, not observed power and not evidence that the trial was designed around those assumptions. The protocol’s sample-size justification is not reported in the registry record.

Such illustrations are especially sensitive to the effect estimate used. Estimates from small groups can be uncertain, so planning around the observed effect may not reflect a future study’s true effect. Smaller assumed effects generally require larger samples to detect under otherwise similar assumptions. The values in the posted planning section should be read as scenario-based planning figures, not as a forecast of what a new study would necessarily need.

Why can multiplicity matter?

When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase if each is evaluated separately without adjustment. The registry lists 52 outcome measures and 48 posted secondary outcomes. It does not report a multiplicity adjustment or explain how outcome families were prioritized. The Day 15 p-values are explicitly unadjusted, so they should be treated as exploratory evidence rather than as a collection of independently confirmatory tests.

The record also does not report interim analyses, an analysis population for each secondary endpoint, or a missing-data method. Those omissions limit how fully a reader can evaluate the analysis. The safety population is defined for the primary outcome as participants who received at least 1 dose of morphine, but the record does not provide a complete account of inclusion and exclusions for every endpoint.

11. Confidence Intervals and Precision

The precision of an estimate is reflected partly by its confidence interval, not just by whether a p-value crosses a threshold. The primary count comparison is reported as a risk difference of 0.0, with interval limits of 0.0 and 0.0. Both groups had zero observed events, with 26 participants in the AZD4041 sequence and 15 in the placebo sequence. The registry does not describe the interval method. With no observed events, the displayed interval should not be read as proof that the underlying event risks are known without uncertainty.

The Day 15 continuous comparisons have broader intervals relative to their point estimates. For SpO2, the interval is -1.822 to 0.002 percentage points around a mean difference of -0.91. For EtCO2, it is -0.780 to 2.674 mmHg around a mean difference of 0.947. For respiratory rate, it is -1.571 to 1.771 breaths per minute around a mean difference of 0.1. Each interval includes zero, so the posted summaries are compatible with no group difference as well as with differences in either direction within the interval.

The Day 15 sample sizes are 25 and 13 for each of these measures. The groups are therefore modest in size, and the intervals remain important context for interpreting the point estimates. The results do not establish that the outcomes are equivalent: an equivalence conclusion would require a prespecified margin and an analysis designed to assess it, neither of which is reported in the registry record.

The displayed interval and p-value are not substitutes for one another. The interval shows a range of effect estimates compatible with the data under the method, while the unadjusted p-value summarizes a test against zero under its assumptions. As the exact interval procedure and model are not reported, the posted values should be interpreted as reported summaries rather than as a fully documented inferential analysis.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 52 outcome measures and 48 posted secondary outcomes. Evaluating many outcomes creates a multiplicity issue: even when there is no underlying effect, separate tests can yield a seemingly unusual result by chance. The three Day 15 continuous comparisons are accompanied by unadjusted p-values. The registry record does not report a correction for multiple testing, a hierarchy of outcomes, or a plan describing which comparisons were intended to be confirmatory.

Consequently, the secondary p-values should not be treated as if each came from a single isolated primary hypothesis. Their interpretation is exploratory, especially when considered alongside the many other posted outcomes. The record also does not report interim analyses, so it is not possible to establish from the registry whether interim looks were planned or conducted.

The primary endpoint identifies its safety population as all participants who received at least 1 dose of morphine. The posted primary group counts are 26 and 15. For the Day 15 continuous outcomes, the posted counts are 25 and 13 in the two sequences. The registry does not explain why the available counts differ across those outcomes or describe the handling of missing measurements. It does not report a missing-data strategy, imputation method, or sensitivity analysis.

These omissions matter because the interpretation of group summaries can depend on which participants contributed data and why others did not. The posted values remain informative descriptions of the observed participants, but the record does not permit a complete assessment of missingness or of the robustness of the results to it. The full statistical analysis plan and detailed analysis populations are not reported in the registry record.

13. 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 posted serious adverse event counts are zero in both sequences: 0 of 26 participants in the AZD4041 sequence and 0 of 15 in the placebo sequence. The record also lists 0 deaths in both groups. These are observed counts during the reported safety accounting; they do not establish that serious events cannot occur or that the groups have identical underlying safety risks.

The registry lists other adverse events for 26 of 26 participants in the AZD4041 sequence and 14 of 15 in the placebo sequence. These counts are distinct from serious adverse events. The record does not provide the terms for serious events because none are listed, and the serious-event term list is empty. The counts alone do not describe event severity beyond the serious/non-serious classification, timing, duration, or causal attribution.

The safety population is described as participants who received at least 1 dose of morphine. The modest group sizes and the study’s Phase 1 setting limit what can be inferred about uncommon harms. These results are a summary of what was recorded in this study, not a comprehensive estimate of safety in broader populations.

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

The primary result means that no participants in either posted arm met the registry’s Day 1 EtCO2 event definition. The observed risk difference was 0.0. This is a statement about the recorded threshold event among the participants represented in the posted counts, at the specified timepoint. It does not establish that there is no respiratory effect, that all measurements were unchanged, or that the two sequences are equivalent.

The overall study question concerns morphine administered after multiple doses of AZD4041 compared with morphine administered alone. The primary outcome shown in the registry is on Day 1, before the listed AZD4041 or placebo dosing schedule. The Day 15 secondary results provide later measurements, but they are continuous group summaries rather than the primary threshold count. The record does not report a Day 15 primary analysis of that event definition.

The confidence intervals for the Day 15 means include zero, but this does not prove that the group means are identical. Instead, the estimates are uncertain and the displayed ranges include both no difference and possible differences in either direction. The unadjusted p-values should not be used alone to claim absence or presence of an effect, particularly among numerous secondary outcomes.

These findings do not establish how the results would apply beyond the study’s healthy recreational opioid-user population, or under other doses, settings, or schedules. The registry record does not report all details needed to reconstruct the analysis or assess missing data. The statistical summaries describe the posted observations; clinical interpretation requires context beyond these results, and no treatment recommendation follows from them.

15. Why This Trial Matters Statistically

This trial is statistically notable because its stated scientific question and its posted primary endpoint do not line up neatly in time. The study aims to assess morphine after multiple doses of AZD4041, but the primary endpoint is a threshold event on Day 1, when the listed sequence has not yet begun the AZD4041 or placebo dosing schedule. That distinction is central to interpreting what the primary result can answer.

It also illustrates why counts and continuous measurements should not be conflated. The primary result records whether participants crossed a threshold. The secondary outcomes summarize group means on Day 15. Each type of summary answers a different question, and one cannot be substituted for the other without an appropriate analysis.

The record further shows how statistical precision and multiplicity shape interpretation. The Day 15 estimates have intervals that include zero, and their p-values are unadjusted amid many posted outcomes. A small p-value threshold alone would not convey the size or precision of an effect, and a result that does not meet such a threshold is not evidence of exact equality. The confidence intervals and the reporting context matter.

Finally, the study’s enrollment and outcome-specific participant counts emphasize that the information available for a comparison depends on who contributed data to that endpoint. The registry does not explain all count differences or report a missing-data plan. For biostatistical readers, this makes clear why a complete protocol, analysis plan, and transparent population accounting are valuable for interpreting a completed clinical study.

16. 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 Day 1 timeframe is a key limitation for interpreting the study’s stated overall question about morphine following multiple doses of AZD4041. The posted Day 1 result occurs before the AZD4041 or matching placebo schedule described in the arm sequences. The record does not post a primary Day 15 analysis of the same threshold event, so the central intended comparison cannot be evaluated from this primary result alone.

The registry lists 45 enrolled participants, while the brief description states plans to randomize up to 44. The primary safety population counts are 26 and 15, and the Day 15 continuous outcome counts are 25 and 13. The record does not explain these differences, provide a participant-flow account, or state why some measurements are unavailable. It is therefore difficult to assess the extent or potential effect of missing outcome data.

The secondary outcome list is extensive, while the posted continuous comparisons are unadjusted and no multiplicity plan is reported. These results are consequently less suitable for confirmatory interpretation. The record also does not report the analysis model, detailed randomization procedure, allocation concealment, endpoint-specific analysis populations, or protocol sample-size justification. It does not describe interim analyses or a missing-data method.

The primary result has no observed events in either group, and the registry does not explain the interval calculation for this zero-event comparison. The posted Day 15 group sizes are limited, and their intervals reflect uncertainty. Finally, the study is Phase 1 and concerns healthy recreational opioid users at one centre; the registry does not establish how the findings generalize beyond this study population and setting.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users. — NCT05587998.
• Registry record last updated 2024-11-15; status last verified 2024-09.
• Results first posted 2024-11-15.
• 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.

20. Record Summary

This completed Phase 1 study was randomized, double-blind, placebo-controlled, and conducted at a single centre in healthy recreational opioid users. The registry records enrollment of 45, a start date of 2022-08-31, and primary completion on 2023-05-25. Participants followed a morphine sequence with subsequent AZD4041 or matching placebo dosing.

The primary endpoint was the number of participants with an EtCO2 increase of at least 10 mmHg compared with baseline or > 50 mmHg on Day 1. The posted count was zero in both groups, with a risk difference of 0.0. Day 15 secondary summaries cover SpO2, EtCO2, and respiratory rate; their posted intervals include zero.

The registry lists 52 outcome measures and 48 posted secondary outcomes. It does not report the full statistical analysis plan, multiplicity approach, or missing-data method. The posted findings should be interpreted as summaries of the recorded outcomes at their stated timepoints.