Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure (NCT03608696), a na phase 1, phase 2 study. The primary outcome is Buprenorphine Pharmacokinetics.

2. Clinical Question

The study addressed a dosing and exposure question rather than a comparative question about buprenorphine versus another treatment. Its registry description presents model-informed dosing as a way to investigate exposure and dose/response in infants receiving treatment. The primary outcome’s timeframe refers to duration of pharmacologic treatment for NAS up to 70 days of age.

The registry summary mentions earlier results in which buprenorphine was associated with a 40% reduction in length of pharmacologic treatment compared with oral morphine. It also says those results used an empirically derived dose. That background statement is not a result of this single-group study, and it does not establish a comparative treatment effect for the current trial.

3. Trial Design

This was a phase 1 and phase 2, open-label, single-group study sponsored by Thomas Jefferson University. The registry lists an enrollment of 10 and marks the study completed. The recorded start date is 2018-08-29, and the primary completion date is 2019-07-11. Allocation is listed as not applicable, and masking is listed as none.

All participants were assigned to the buprenorphine intervention as described in the registry; no control arm is listed. The stated regimen used a 0.075 mg ml sublingual solution. Its initial daily dose was 24 mcg/kg/day, with an initial unit dose of 8 mcg/kg every 8 hours. The maximum daily dose was 75 mcg/kg/day, and the maximum unit dose was 25 mcg/kg every 8 hours. The listed up-titration rate was 33%, with a maximum of 4 up-titrations; the weaning rate was 15%.

Because the study had no control group, it cannot directly compare outcomes under the model-informed regimen with outcomes under another dose or treatment. Open-label status means the registry does not describe masking of treatment assignment. The record does not report the eligibility criteria, how many enrolled participants received treatment, or how many contributed data to each outcome. Enrollment therefore should not be treated as an analysis count.

The registry describes an initial test of a new dosing regimen, with the aim of defining exposure and clarifying the dose/response relationship. It does not report a randomized design, a concurrent comparator, or an analysis plan that would support a causal comparison. Details of treatment adherence, protocol deviations, and the handling of participants who stopped treatment 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: N/A (PK data was not usable as analyzed for this study as most was below the limit of quantification.)

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: Enrolled subjects are those who required pharmacologic therapy for neonatal opioid withdrawal syndrome

6. Primary Endpoint

The registry lists the primary outcome as Buprenorphine Pharmacokinetics, measured over Duration of pharmacologic treatment for neonatal abstinence syndrome up to 70 days of age.

The primary outcome is titled Buprenorphine Pharmacokinetics. It concerns buprenorphine exposure, measured as the area under the plasma concentration versus time curve (AUC), in infants treated with buprenorphine for neonatal abstinence syndrome. The registry gives the timeframe as duration of pharmacologic treatment for NAS up to 70 days of age.

AUC is a pharmacokinetic measure that represents drug exposure across the period in which concentrations are measured. In general, exposure measures can help characterize how a dosing regimen relates to drug concentrations over time. They are not, by themselves, measures of clinical benefit or harm. Interpreting an exposure measure also depends on the concentration measurements being sufficiently informative and on the analysis methods being described.

For this outcome, the registry record says the pharmacokinetic data were not usable as analyzed because most measurements were below the limit of quantification. The population result is listed as N/A. No numerical AUC estimate, variability measure, or dose/exposure relationship is reported in the registry record. Consequently, the stated endpoint and its intended role can be described, but its value cannot be interpreted from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group, open-label study with no allocation to a comparator arm. This design can document what was planned and record outcomes among participants receiving the intervention, but it does not create a concurrent comparison between treatment strategies. Without such a comparison, differences from an external or historical group would require additional information and assumptions; no such analysis is reported in the registry record.

What does AUC represent?

The primary outcome focuses on area under the plasma concentration versus time curve (AUC), a pharmacokinetic summary of drug exposure over a measurement period. In general, pharmacokinetic analyses use measured concentrations over time to characterize how exposure relates to dosing. AUC is not itself a clinical outcome such as treatment duration, and an AUC result alone does not establish a clinical effect. For this study, the registry says most concentration data were below the limit of quantification and were not usable as analyzed. It does not report a usable AUC estimate, its uncertainty, or the analysis method used to derive it.

Why does the limit of quantification matter?

In general, the limit of quantification is the lowest concentration level at which a measurement can be quantified with specified performance. Measurements below that threshold do not provide precise numerical concentration values in the ordinary way. If many observations fall below the limit, the available measurements may not support the planned exposure summaries without an appropriate analysis. Methods for handling such observations can differ, and their suitability depends on the study design and data. The registry record does not report a method for handling values below the limit of quantification, so it is not possible to determine whether any alternative method was considered.

More generally, pharmacokinetic data can have repeated measurements within participants and may require methods that account for the timing and dependence of those measurements. That is a general statistical consideration, not a description of an analysis confirmed for this trial. The analysis population, measurement schedule, model specification, covariates, and diagnostic checks are not reported in the registry record.

What can an open-label, single-group design estimate?

In general, a single-group study can describe outcomes observed in the group receiving an intervention. It cannot by itself separate an intervention effect from other influences that may affect the outcome over time. Open-label status also means that treatment masking is not part of the design as registered. The registry does not report blinded outcome assessment or other steps intended to limit measurement bias. These features do not make descriptive results invalid, but they shape the kinds of claims that can be supported.

The registered design does not list randomization, allocation between arms, or a control group. Therefore, a randomized treatment contrast and its standard error cannot be derived from the design information. Any causal claim comparing the regimen with another treatment would require evidence not reported for this study.

How should planning illustrations be read?

The registry record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that time-to-event planning uses the total number of events under the Schoenfeld approach, while other planning results are expressed as participants per arm. These are planning assumptions, not proof that the trial used those assumptions or conducted a two-arm comparison. The record does not report an observed primary effect for the pharmacokinetic outcome, and no planning value can substitute for a usable outcome estimate.

In general, sample-size calculations estimate the amount of information a future study might need under specified assumptions. A planning illustration based on an observed effect is not observed power, and it does not show that a study’s actual estimate is precise. The record does not report a protocol-based sample-size justification or the effect assumptions used in the trial’s original design.

What analysis details are missing?

The registry lists no analyses. The statistical analysis plan, model details, treatment of missing observations, approach to values below quantification limits, and uncertainty estimates are not reported in the registry record. No multiplicity procedure, interim analysis, or prespecified subgroup analysis is reported. Without those details and a usable primary estimate, the statistical interpretation is necessarily descriptive and limited to the registered design and outcome status.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures, but the details available for the primary outcome concern buprenorphine pharmacokinetics and AUC. Descriptions and analysis results for the other outcome measures are not reported in the registry record. The record lists no analyses, so there is no reported set of outcome-specific estimates to assess for multiplicity.

Multiplicity arises in general when several outcomes, comparisons, time points, or analyses are examined. If many statistical tests are performed, the chance of at least one apparently unusual result can increase unless the analysis plan addresses that issue. This general concern cannot be quantified for this study from the record. A multiplicity strategy, outcome hierarchy beyond the listed primary outcome, and any adjustment method are not reported in the registry record.

The primary outcome is recorded as N/A because most pharmacokinetic data were below the limit of quantification and were not usable as analyzed. The record does not describe the amount or pattern of missing data, the number of participants with usable measurements, imputation, censoring, or sensitivity analyses. It also does not identify an analysis population such as all enrolled participants or participants with evaluable pharmacokinetic data. These missing details prevent assessment of how incomplete or unquantifiable observations may have affected an estimate.

In general, missing-data methods rely on assumptions about why observations are unavailable and how the observed data relate to unobserved values. Those assumptions cannot be evaluated without a description of the missingness and analysis approach. No interim analyses or stopping rules are reported in the registry record. Accordingly, there is no basis in the posted results for assessing multiplicity control, missing-data robustness, or the relationship between the enrolled group and any analyzed population.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: seizure (10.0%).

The registry records 1 participant affected by a serious adverse event among 10 at risk in the buprenorphine group. It lists seizure as a serious adverse-event term at 10.0%. The registry also records 1 participant affected by other adverse events among 10 at risk and 0 deaths. These are the safety counts reported for the single group.

These entries should be read as registry-recorded counts, not as a comparison between treatments. No control group is present, so the counts do not estimate a relative risk or show how event frequency compares with another regimen. The record does not report event timing, duration, severity details beyond the serious-event classification, whether events resolved, or an assessment of causal relationship to treatment.

The record does not clarify whether the serious and other adverse-event categories overlap at the participant level. The counts should therefore not be added together or interpreted as distinct people. The seizure term is listed among serious adverse-event terms, but additional clinical details are not reported in the registry record. These statistics describe recorded safety information and do not establish that buprenorphine caused an event.

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

This study’s registry record documents a completed, open-label, single-group investigation of model-informed buprenorphine dosing for neonatal abstinence syndrome. Its primary question concerned pharmacokinetic exposure, expressed as AUC, during treatment. The record says most pharmacokinetic data were below the limit of quantification and were not usable as analyzed. It does not report a usable exposure estimate or a dose/exposure result.

That finding does not establish that buprenorphine exposure was absent, nor does it show that the regimen was ineffective or effective. It indicates that the registry does not present analyzable primary pharmacokinetic results. The record also does not provide a comparative estimate for treatment duration, despite describing treatment duration in the primary outcome timeframe and discussing earlier comparisons in its background summary.

The background statement about a 40% reduction in length of pharmacologic treatment compared with oral morphine concerns earlier results using an empirically derived dose. It is distinct from the model-informed regimen evaluated in this single-group study. Because this trial has no comparator arm, its design cannot independently establish a treatment difference against oral morphine or another regimen.

The safety entries report serious and other adverse-event counts for the buprenorphine group, including the listed seizure term and no deaths. Without a comparison group and further event details, these entries do not establish comparative safety or causation. They should be interpreted as descriptive registry records.

Overall, the trial’s registered aims are clear, but the posted record does not permit an estimate of the primary pharmacokinetic outcome. It also does not provide enough analysis detail to assess precision, missing-data handling, or the population contributing to the outcome. Conclusions should therefore remain limited to the study design, the stated data usability problem, and the safety counts recorded.

13. Why This Trial Matters Statistically

This trial is statistically notable because its primary objective depends on measurable drug concentrations, yet the registry reports that most pharmacokinetic data were below the limit of quantification and were not usable as analyzed. That makes measurement quality central to interpretation: an intended endpoint can be well defined while still yielding no interpretable estimate in the posted record.

The study also illustrates the distinction between a dosing rationale and evidence about a dosing regimen. Model-informed dosing was intended to clarify exposure and the dose/response relationship. To evaluate that aim statistically, readers would need interpretable exposure measurements, an analysis method, and an estimate with uncertainty. Those results are not reported in the registry record.

The single-group, open-label design is another important feature. It can support descriptive observation of the group’s experience, but it does not provide a randomized comparison or a concurrent control. The background reference to earlier results using an empirically derived dose should not be mistaken for a comparative result from this study. The design and the primary-outcome data status limit the claims that can be drawn from the registry.

Finally, registry entries for enrollment and adverse events are not substitutes for a complete statistical report. The record lists enrollment of 10, but does not say how many participants contributed usable primary-outcome data. It records adverse-event counts but does not report detailed event narratives or comparative safety estimates. The case highlights why readers need endpoint results, analysis populations, methods for handling measurements below quantification limits, and uncertainty estimates alongside study aims and design descriptions.

14. 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 principal limitation specific to this trial is that the registry describes the primary pharmacokinetic data as unusable as analyzed because most measurements were below the limit of quantification. The primary outcome population is listed as N/A, and no AUC estimate or uncertainty measure is reported. The extent of usable data and any alternative handling of unquantifiable measurements are not reported in the registry record.

The study is single group and open label, with no comparator arm. It therefore does not provide a controlled comparison of the model-informed regimen with another dose or treatment. The record does not report randomization, masking, or a comparative analysis. The earlier oral morphine comparison in the registry summary is background information and is not an outcome from this trial.

Although the registry lists enrollment of 10, it does not report how many participants received treatment, completed the regimen, or contributed data to each outcome. Eligibility criteria and the analysis population are not reported. Details about the timing and frequency of pharmacokinetic measurements, data completeness, protocol deviations, and participant withdrawals are also not reported in the registry record.

The statistical analysis plan, model specification, uncertainty estimation, missing-data methods, and any sensitivity analyses are not reported. The record lists 3 outcome measures but does not provide their full results in the registry record for this analysis. Safety entries lack event timing, outcome, and causality details. These limitations mean that neither a precise exposure result nor a comparative clinical or safety effect can be evaluated from the posted record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure — NCT03608696.
• Registry record last updated 2022-02-11; status last verified 2022-01.
• Results first posted 2022-02-11.
• 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.

18. Record Summary

The registry identifies NCT03608696 as a completed phase 1 and phase 2 study sponsored by Thomas Jefferson University. It lists a start date of 2018-08-29, a primary completion date of 2019-07-11, and enrollment of 10. The design is open label and single group, with allocation listed as not applicable and no masking.

The intervention was sublingual buprenorphine using a model-informed dosing regimen. The primary outcome concerned buprenorphine pharmacokinetics, particularly AUC, in infants treated for neonatal abstinence syndrome up to 70 days of age. The registry states that most pharmacokinetic data were below the limit of quantification and were not usable as analyzed; the primary outcome population is listed as N/A.

The safety record lists 1 participant affected by a serious adverse event among 10 at risk, seizure as a serious-event term at 10.0%, 1 participant affected by other adverse events among 10 at risk, and 0 deaths. The registry lists no analyses. It does not report a usable primary pharmacokinetic estimate or a controlled treatment comparison.