This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045) (NCT02715700), a na phase 1 study. The primary outcome is Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02715700 |
| Phase | Phase 1 |
| Condition | Human Immunodeficiency Virus (HIV) Infection |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 14 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Merck Sharp & Dohme LLC |
| Results posted | Yes |
2. Clinical Question
Population
Participants maintained on a stable methadone regimen. The registry record lists HIV infection as the study condition and reports enrollment of 14 participants. It does not give further demographic or clinical details.
Intervention
Doravirine 100 mg once daily from Day 2 through Day 6, alongside the participants’ maintenance methadone regimen.
Comparator
Methadone alone on Day 1, compared with methadone plus doravirine on Day 6 in the same study sequence. This is not a randomized comparison between separate groups.
Primary question
How does the 24-hour exposure to R-methadone, measured as AUC0-24, compare between methadone alone and methadone given with multiple doses of doravirine?
The study’s stated primary hypothesis is that R-methadone AUC0-24 is similar when maintenance methadone is taken with or without multiple daily doses of doravirine. The endpoint is measured on Day 1, when participants receive methadone alone, and on Day 6, when they receive methadone with doravirine. This repeated measurement creates a within-participant comparison: each participant’s two measurement occasions correspond to the two treatment conditions.
The design can describe pharmacokinetic measurements under these conditions, but the registry record does not report the endpoint estimates, their confidence intervals, or a numerical comparison between days. It therefore does not show how close the measured exposures were, or how precisely any difference or ratio was estimated. The registry record also does not report a prespecified numerical boundary for deciding whether exposures count as similar. The clinical question is clear, but the posted information is not enough to determine whether the data support the stated hypothesis.
3. Trial Design
This was a Phase 1, completed, single-group study with enrollment of 14 participants. The registry record identifies allocation as not applicable and masking as none. Participants were maintained on a stable methadone regimen of 20 to 200 mg once daily for at least 14 days before Day 1. They continued methadone once daily on Days 1 through 7. Doravirine 100 mg once daily was added from Day 2 through Day 6.
The primary pharmacokinetic measurements were scheduled on Day 1 and Day 6. Day 1 represents methadone alone; Day 6 represents methadone with doravirine. These measurements are taken at different points in a fixed treatment sequence, rather than in randomized order. The same participants are therefore assessed under both conditions, but the comparison is not a randomized parallel-group comparison. The registry record does not report a washout period or a second randomized treatment sequence.
The primary outcome population is described as all treated participants. The registry record reports 12 outcome measures and 9 analyses, but does not include details about all of their methods or results. The primary endpoint is the geometric mean of R-methadone AUC0-24, with a 95% confidence interval specified as the measure of dispersion. Numerical endpoint results are not reported in the registry record.
The registry record states that the study is completed. It does not report a sample-size justification, the planned target beyond the enrollment figure, or details of interim analyses or a statistical analysis plan. The sample-size section elsewhere on the page should be read as planning illustration, not as observed power or as evidence that the trial was designed around a particular effect. The design and endpoint are described, but the available record does not supply enough numerical results to assess the primary pharmacokinetic comparison.
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
| Stage | Maintenance Methadone + Doravirine |
|---|---|
| STARTED | 14 |
| COMPLETED | 14 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: All treated participants are included.
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.
| Characteristic | Unit | Maintenance Methadone + Doravirine |
|---|---|---|
| Participants analysed | 14 | |
| Age, Continuous | Years | 36.7 (SD 10.7) |
| Sex: Female, Male: Female | Participants | 7 |
| Sex: Female, Male: Male | Participants | 7 |
6. Primary Endpoint
The registry lists the primary outcome as Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone, measured over Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | ng*hr/mL/mg |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the area under the plasma concentration-time curve from zero to 24 hours after dosing for R-methadone, reported in ng*hr/mL/mg. AUC summarizes measured drug concentrations across the specified time interval. In general, it is used as a measure of overall drug exposure during that interval, rather than relying on a single concentration at one sampling time. The endpoint is normalized per milligram in its stated unit.
R-methadone is one of the two methadone enantiomers described in the assay information; the registry record says samples were analyzed for both R- and S-methadone. The primary endpoint concerns R-methadone specifically. Sampling for the primary measure was scheduled predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6. The listed times provide observations over the dosing interval from which the AUC is determined.
In general, comparing AUC under methadone-alone and combination conditions can characterize whether total measured exposure differs in this study setting. The registry record describes the endpoint as a geometric mean with a 95% confidence interval. A confidence interval conveys uncertainty around an estimate; it is not itself a guarantee that the true value lies within the interval. Here, however, the numerical geometric means and confidence intervals are not reported in the registry record. Nor is a numerical similarity margin reported. The endpoint definition therefore explains what was to be measured, but the posted record does not show the estimated exposure or the precision of its comparison.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The design focuses on a pharmacokinetic question: whether the 24-hour exposure to R-methadone measured on Day 6 with doravirine is similar to the exposure measured on Day 1 with methadone alone. Because the same group is measured under both conditions, the intended contrast is within participants. This can reduce the influence of stable differences between people when measurements are compared, although the registry record does not report the specific statistical model used for the comparison.
The central limitation for interpreting the posted result is that the registry record does not report the primary endpoint’s numerical results. It gives the measure, unit, assessment days, summary type, and confidence-interval level, but no geometric means, estimated contrast, or confidence interval for the comparison. Without those values, readers cannot judge the direction or size of the observed difference, or how precisely the contrast was estimated. The stated hypothesis of similarity is not, by itself, evidence that similarity was demonstrated.
In general, a confidence interval helps distinguish a precise estimate from one that leaves substantial uncertainty. For a similarity question, interpretation also depends on the comparison scale and on a prespecified range regarded as acceptably similar. The registry record does not report a numerical similarity boundary or provide the primary comparison interval. It is therefore not possible from this record to determine whether an interval would fall within such a boundary. A non-significant test, even if one were reported, would not by itself establish similarity; the relevant estimates and decision criteria would matter.
The fixed sequence also matters. All participants received methadone alone on Day 1 and methadone with doravirine on Day 6. The comparison therefore combines treatment condition with assessment day and order. Changes over time, including any changes not caused by doravirine, cannot be separated by randomization in this design. The registry record does not report further design features or analyses that would address this issue. This does not invalidate the measurements, but it limits what can be attributed specifically to the added drug based on the posted description.
The safety summaries list no serious adverse events and no deaths in the reported periods. Other adverse events are shown by period, with differing counts across the combination, methadone-only, and follow-up periods. Those figures are descriptive and do not establish a causal relationship. The study is small and its primary endpoint is pharmacokinetic; the registry record does not report numerical exposure results or enough detail to extend interpretation beyond the reported measures. The appropriate reading is therefore that the registry documents the study question, regimen, and measurement plan, while leaving the primary comparison’s magnitude and precision unreported.
9. Statistical Methods Explained
The registry describes a single-group pharmacokinetic study. In general, pharmacokinetic studies characterize how drug concentrations change over time and summarize exposure using measures such as AUC. Here, the key measurement is R-methadone AUC0-24 under two conditions: methadone alone on Day 1 and methadone with doravirine on Day 6. The listed endpoint summary is a geometric mean with a 95% confidence interval. The registry record does not report the resulting numerical estimates or a specific model for comparing the two measurement days.
What does a within-participant comparison show?
Each participant contributes measurements under both treatment conditions. In general, a within-participant analysis focuses on the change or contrast between measurements from the same person. This can account for stable participant characteristics that might otherwise contribute to differences between separate groups. It does not remove all sources of uncertainty: measurement variability, changes over time, and other factors that differ between assessment days may still matter.
The sequence is fixed: methadone alone is measured on Day 1, and methadone plus doravirine is measured on Day 6. There is no randomized order described in the registry record. Thus, treatment condition and day are linked. Randomized order in a crossover design can help separate treatment effects from period or order effects; that feature is not described. The registry record also does not report a washout period. These points are relevant when interpreting any observed contrast, but the numerical contrast itself is not reported.
Why use AUC and a geometric mean?
In general, AUC combines concentration information over a defined interval, so it reflects overall exposure rather than one concentration measurement. The registry specifies sampling from predose through 24 hours postdose. A geometric mean is a way to summarize positive measurements on a multiplicative scale. It is often used for pharmacokinetic measures when values are more naturally compared as ratios than as absolute differences. This is a general explanation; the registry record does not provide the detailed analysis specification or explain the choice of summary.
A 95% confidence interval describes the statistical uncertainty around an estimated quantity under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, but interpretation depends on the estimate, the interval, the comparison scale, and the question being asked. In a similarity assessment, the interval would need to be considered against an appropriate prespecified similarity range. That range and the numerical interval for this study are not reported in the registry record, so no conclusion about precision relative to a decision boundary can be drawn.
What can be inferred from the sampling and assay description?
The registry record lists plasma sampling at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on both assessment days. It says samples were analyzed for R- and S-methadone, using liquid-liquid extraction followed by liquid chromatographic-tandem mass spectrometric detection. The lower limit of quantification was 0.025 ng/mL for each enantiomer, and the analytical range was 0.025 - 15.0 ng/mL. These details describe how concentrations were measured. They do not, on their own, establish that all samples were quantifiable or that the primary comparison was precise.
The registry record does not report how values below the quantification limit were handled, how the AUC was calculated, whether any measurements were missing, or whether sensitivity analyses were conducted. These methodological details can affect the interpretation of pharmacokinetic estimates, but they should not be inferred from the assay description alone.
How should the planning illustrations be read?
In general, sample-size calculations describe how many participants might be needed under specified assumptions to detect a chosen effect with a chosen error rate and power. The planning section on this page uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its effect is framed as a fraction of the observed effect. Such calculations are illustrations, not observed power and not a description of the study’s own sample-size justification. The registry record does not report that justification.
The study itself is single-group and the primary comparison is between two days in the same participants, while the planning assumptions describe equal allocation between two arms. The illustration should therefore not be treated as a direct description of this trial’s design. The observed primary effect needed as an input is not reported in the registry record, and the numerical planning outputs are not. A planning calculation cannot substitute for the actual estimate and confidence interval.
The record reports 12 outcome measures and 9 analyses, but does not give enough detail to reconstruct the analysis methods for each. The primary endpoint is described, but details such as a formal contrast model, adjustment factors, handling of missing measurements, or multiplicity strategy are not reported. The methods information supports a clear description of what was measured and when, while leaving important analysis and result details unavailable.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 12 outcome measures and 9 analyses. It does not describe which analyses were prespecified, how outcomes were prioritized beyond identifying the primary endpoint, or whether any multiplicity adjustment was planned or used. In general, when several hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis accounts for the number and structure of tests. This is a general consideration, not a claim that a particular error occurred in this study.
The primary outcome population is stated as all treated participants. The record does not give further detail about the analysis population for the primary comparison, participant flow after enrollment, exclusions, or whether every participant had usable measurements on both assessment days. It also does not report how missing concentration values or missing AUC measurements were handled. These omissions prevent assessment of whether missingness or exclusions could have affected the posted estimates.
The registry record does not report a detailed statistical analysis plan, an interim-analysis plan, or a sample-size justification. It identifies a geometric-mean endpoint and 95% confidence interval but does not report the comparison model or a similarity boundary. These are relevant details for interpreting a similarity hypothesis. The posted record also does not give numerical primary estimates, so the effect of any analysis choices cannot be evaluated from the available information.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Maintenance Methadone (Day 1) | 0 | 14 | 0.0% |
| Maintenance Methadone + Doravirine (Days 2 to 6) | 0 | 14 | 0.0% |
| Maintenance Methadone (Day 7) | 0 | 14 | 0.0% |
| Safety Follow-Up (Days 8 to 21) | 0 | 14 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Maintenance Methadone (Day 1) | 0 of 14 |
| Maintenance Methadone + Doravirine (Days 2 to 6) | 0 of 14 |
| Maintenance Methadone (Day 7) | 0 of 14 |
| Safety Follow-Up (Days 8 to 21) | 0 of 14 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Maintenance Methadone (Day 1) | 0 of 14 |
| Maintenance Methadone + Doravirine (Days 2 to 6) | 7 of 14 |
| Maintenance Methadone (Day 7) | 2 of 14 |
| Safety Follow-Up (Days 8 to 21) | 1 of 14 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Maintenance Methadone (Day 1) | Maintenance Methadone + Doravirine (Days 2 to 6) | Maintenance Methadone (Day 7) | Safety Follow-Up (Days 8 to 21) |
|---|---|---|---|---|---|
| Drug withdrawal syndrome | General disorders | 0 of 14 | 2 of 14 | 1 of 14 | 0 of 14 |
| Headache | Nervous system disorders | 0 of 14 | 2 of 14 | 0 of 14 | 0 of 14 |
| Abdominal discomfort | Gastrointestinal disorders | 0 of 14 | 1 of 14 | 0 of 14 | 0 of 14 |
| Blood urine present | Investigations | 0 of 14 | 0 of 14 | 0 of 14 | 1 of 14 |
| Dizziness | Nervous system disorders | 0 of 14 | 1 of 14 | 0 of 14 | 0 of 14 |
| Euphoric mood | Psychiatric disorders | 0 of 14 | 1 of 14 | 0 of 14 | 0 of 14 |
| Sinus congestion | Respiratory, thoracic and mediastinal disorders | 0 of 14 | 0 of 14 | 1 of 14 | 0 of 14 |
The safety summaries report 14 participants at risk in each listed period. No serious adverse events and no deaths are reported in the methadone-only Day 1 period, the methadone-plus-doravirine Days 2 to 6 period, the methadone-only Day 7 period, or the safety follow-up Days 8 to 21. The registry record lists no serious adverse-event terms.
Other adverse events are reported for 7 participants during Days 2 to 6 with methadone plus doravirine, 2 during methadone on Day 7, and 1 during safety follow-up. None are reported for Day 1. These are period-specific summaries. They should not be added together to infer a number of distinct participants, because the registry record does not say whether the same participant could contribute events in more than one period or how repeated events were counted.
In general, an absence of reported serious events in a small study does not establish that serious events cannot occur. These figures are descriptive, and the registry record does not establish that an event was caused by a particular treatment. The summaries describe what was reported during the listed periods, not a comparative safety analysis between randomized groups.
12. What the Result Does, and Does Not, Mean
The record documents a Phase 1 study designed to measure R-methadone exposure with methadone alone and with doravirine added. It gives the dosing sequence, the measurement days, the AUC0-24 endpoint, the assay description, and the stated hypothesis of similarity. It also reports safety counts by treatment period. These details allow readers to understand the study’s question and the kind of evidence it was intended to generate.
What the posted record does not show is the primary endpoint result. The geometric means, confidence intervals, and a numerical comparison between Day 1 and Day 6 are not reported in the registry record. Consequently, the direction, size, and precision of any observed difference cannot be described from this information. The study’s stated hypothesis does not establish that the exposures were similar, and the reported design alone cannot answer whether they were.
Even if numerical results were available, interpretation of a similarity question would require attention to the comparison scale and a prespecified criterion for similarity. The registry record does not report a numerical boundary for that criterion. The fixed order of assessment also means that the treatment conditions coincide with different study days. In general, this can make treatment-related and time-related changes difficult to distinguish without additional design or analysis information.
The safety summaries show no reported serious adverse events or deaths in the listed periods, and they report other adverse events by period. Those observations are descriptive and should not be taken as proof of absence of risk or as causal evidence. Overall, the record is informative about the trial’s structure and endpoints, but its posted content does not support a conclusion about the primary exposure comparison or a broader treatment effect.
13. Why This Trial Matters Statistically
This trial illustrates how pharmacokinetic questions can be framed around exposure under different dosing conditions. AUC0-24 gives a summary across a dosing interval, and measuring the same participants under both conditions creates a within-participant comparison. Those features are useful to recognize when reading a pharmacokinetic study, because the design and endpoint determine what the resulting estimates could address.
It also shows why a stated hypothesis and a result are not interchangeable. The registry record says the primary hypothesis concerns similarity in R-methadone exposure, but does not report the numerical estimates or confidence intervals needed to assess that question. For similarity questions, a reader generally needs both the estimated comparison and an explicit criterion for how much difference is acceptable. Neither can be recovered from the hypothesis wording alone.
The fixed sequence is another statistical feature worth noticing. Participants were assessed first on methadone alone and later on methadone with doravirine. In general, a within-participant design can account for stable differences between people, but a fixed order can leave treatment condition entangled with time or order. This makes design details important when moving from a measured association to an interpretation about the added treatment.
Finally, the record distinguishes pharmacokinetic outcomes from safety summaries. Period-based event counts describe what was reported during those periods, but they are not a randomized safety comparison. Together, these features make the study a useful example of why transparent estimates, uncertainty intervals, analysis details, and design limitations are all needed to interpret clinical trial results.
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 registry record does not report numerical results for the primary AUC0-24 endpoint. Without the geometric means and confidence intervals, the magnitude, direction, and precision of the primary comparison cannot be assessed. It also does not report a numerical similarity margin, which would be needed to evaluate the stated similarity question against a defined criterion.
The comparison uses a fixed sequence: methadone alone on Day 1 followed by methadone with doravirine on Day 6. There is no randomized order described. Treatment condition is therefore linked to assessment day, and the registry record does not report how any time or order effects were addressed. A washout period is not described in the registry record.
The study enrolled 14 participants, and the endpoint population is described as all treated participants. The record does not report detailed participant flow, missing-data handling, the number with complete paired measurements, or the analysis population for every outcome. It also does not report a sample-size justification, detailed analysis plan, multiplicity approach, or interim-analysis details.
The safety information is presented as period-specific counts, with no serious adverse events or deaths reported. The record does not provide enough detail to determine whether participants with other adverse events appeared in more than one period or how events were counted. These limitations mean the available record supports description of the planned comparison and reported safety summaries, but not a full evaluation of the primary result or broader conclusions.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045) — NCT02715700.
- Registry record last updated 2019-06-25; status last verified 2019-06.
- Results first posted 2019-06-03.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
This completed Phase 1 study enrolled 14 participants maintained on stable methadone. Participants continued methadone from Day 1 through Day 7 and received doravirine 100 mg once daily from Day 2 through Day 6. The primary endpoint was R-methadone AUC0-24, measured on Day 1 with methadone alone and Day 6 with methadone plus doravirine.
The registry record specifies a geometric-mean summary with a 95% confidence interval, but does not report the primary endpoint estimates or a numerical similarity criterion. It reports no serious adverse events or deaths in the listed periods and gives period-specific counts for other adverse events. The fixed treatment sequence, missing analysis details, and absence of numerical primary results limit interpretation of the posted record.