Investigation of Faldaprevir Effect on Pharmacokinetics of Raltegravir: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Investigation of Faldaprevir Effect on Pharmacokinetics of Raltegravir (NCT01785160), a non-randomized phase 1 study. The primary outcome is AUC( Tau,ss).

2. Clinical Question

This is a pharmacokinetic question: it concerns drug concentrations over time, rather than a clinical outcome such as symptom change or disease control. AUC( Tau,ss) represents the area under the raltegravir plasma concentration-time curve during the dosing interval at steady state. The record also identifies safety and tolerability as an additional objective, but the primary endpoint is the pharmacokinetic measure.

The crossover structure makes the comparison within participants across treatment periods. In general, within-participant comparisons can account for stable differences between people, because each participant contributes measurements under more than one treatment condition. That statistical advantage does not by itself ensure that treatment conditions are comparable: a fixed sequence and the absence of randomization leave possible period or sequence effects to consider.

3. Trial Design

The registry describes NCT01785160 as a phase 1 study titled Investigation of Faldaprevir Effect on Pharmacokinetics of Raltegravir. Its official title describes an open-label trial with two periods in a fixed sequence, and the design fields identify it as non-randomized and crossover. The status is completed. The listed enrollment is 25.

The study involved healthy male and female volunteers, rather than a patient population described by a disease condition. One treatment condition was raltegravir alone; the other was raltegravir with faldaprevir. Both were administered orally with 240 ml water, with the combination condition using a soft gelatine capsule alongside coated tablets. The record does not provide enough detail to reconstruct all dosing instructions or the full schedule of study procedures.

The primary objective was to investigate faldaprevir’s effect on steady-state raltegravir pharmacokinetics. Safety and tolerability were an additional objective. The primary endpoint was AUC( Tau,ss), and the registry describes comparing the intrasubject geometric-mean ratio for the test and reference treatments. It also describes an analysis of variance on log-transformed parameters, with subject and treatment effects.

Because allocation was non-randomized and the treatment periods followed a fixed sequence, this should not be read as a randomized, parallel-arm trial. The design description and endpoint establish what the investigators intended to compare, but they do not establish that the periods were free of time-related influences. Details of washout, period effects, carryover assessment, and other sequence-related procedures are not reported in the registry record. The numerical primary result is also not reported in the registry record, so the magnitude and precision of the pharmacokinetic comparison cannot be evaluated from the registry entry.

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.

Treatment Period 1: Raltegravir

Reasons for not completing this period:

Washout Period of at Least 7 Days

Reasons for not completing this period:

Treatment Period 2: Raltegravir + Faldap

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic(PK) set:Subjects who received atleast 1 dose of study medication and who provided at least 1 observation for at least 1 PK endpoint without any important protocol violations relevant to the evaluation of relative bioavailability and did not experience emesis at or before 2 times median tmax on the pk study days of both trial periods

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 total number of participants N analysed for baseline characteristics is not same as the number of participants enrolled as one subject was not treated after being enrolled

6. Primary Endpoint

The registry lists the primary outcome as AUC( Tau,ss), measured over 0.5 hours (h) before drug administration and 48 hours (h),60,72,72.5,73,73.5,74,75,76,77,78,80,82 and 84(hours) after administration of RAL alone; 96 h,108,120,120.5,121,121.5,122,123,124, 125,126,128,130 and 132 hours after RAL and FDV administration.

AUC( Tau,ss) is the area under the plasma concentration-time curve for raltegravir over the dosing interval, measured at steady state. It captures drug exposure across the interval rather than relying on a single concentration measurement. The unit listed is ng*h/mL. The registry describes sampling before and after administration in both treatment conditions, with different stated collection times for raltegravir alone and raltegravir with faldaprevir.

Pharmacokinetic exposure measures are used to characterize how much drug is present in the body over time. General explanation: AUC can be informative when the question concerns whether one treatment condition changes overall exposure, since it incorporates concentration measurements across a period rather than reflecting only a peak or trough. Steady-state measurement is intended to describe exposure during a repeated-dosing condition once concentrations are considered at steady state; the registry record does not provide further operational detail about how steady state was established.

The endpoint was analyzed on a logarithmic scale, with the reported target being an intrasubject ratio of geometric means for the test and reference treatments. A ratio expresses the relative exposure between those conditions. The registry record describes calculating a point estimate and a two-sided 90% confidence interval, but does not report their numerical values. Consequently, the endpoint definition is available, while the result’s estimated direction, magnitude, and precision are not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes an analysis of variance on log-transformed pharmacokinetic parameters, including effects for subject and treatment. It also says that the comparison was expressed as an intrasubject ratio of geometric means with a two-sided 90% confidence interval. Those details describe the intended statistical approach; the numerical estimate and interval for the primary endpoint are not reported in the registry record.

Why use a logarithmic scale?

General explanation: Pharmacokinetic measurements are often positive and can vary multiplicatively. Taking logarithms changes a multiplicative comparison into an additive one for the model. After analysis, a contrast on the log scale can be transformed back to a ratio, which is why the registry describes geometric means and an intrasubject ratio. This does not mean the ratio is known: its numerical value is not reported in the registry record.

A geometric mean is based on averaging logarithms and transforming the result back to the original scale. It is useful when relative changes are of interest and measurements are not symmetrically distributed on their original scale. The record does not give the underlying participant-level concentrations, the geometric means for either condition, or the computed ratio.

What does the subject effect represent?

General explanation: In a crossover analysis, subject terms can account for persistent differences between participants. If some participants tend to have higher concentrations than others under both conditions, a within-participant treatment contrast can distinguish that stable variation from the contrast of interest. The record states that subject and treatment were included in the analysis of variance, but does not provide the full model specification, degrees of freedom, diagnostics, or model output.

The fixed-sequence design is an important qualification. In a randomized crossover, treatment order is allocated randomly; this record instead identifies allocation as non-randomized and the sequence as fixed. General explanation: when all participants follow a fixed order, changes over time can be entangled with treatment differences unless the design and analysis adequately address period and carryover effects. Details of any period term, washout, carryover evaluation, or sensitivity analysis are not reported in the registry record. It is therefore not possible to assess from the record how such issues were handled.

How should the confidence interval be read?

General explanation: A confidence interval describes the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision, while a wider interval indicates less precision. For a ratio, the interval helps show which relative exposure values are compatible with the data and model. The registry record specifies a two-sided 90% confidence interval, but does not report either endpoint. The interval’s width and its relation to a no-difference ratio therefore cannot be assessed.

The confidence level alone is not evidence that a difference was or was not observed. Nor does a confidence interval, by itself, resolve concerns about non-randomized treatment order, missing measurements, or model assumptions. Those issues concern how the estimate was obtained and how applicable it is to the study question.

What role does over-dispersion play?

General explanation: Over-dispersion means that observed variability is greater than a statistical model assumes. If present and not accounted for, uncertainty estimates can be too optimistic. The registry identifies an analysis of variance for log-transformed parameters, but does not report dispersion diagnostics, residual checks, or adjustments for over-dispersion. There is no basis in the registry record to say whether over-dispersion was present or affected the analysis.

What can be inferred from the posted analysis description?

The analysis description establishes that the intended comparison was based on log-transformed pharmacokinetic parameters and that the target summary was an intrasubject geometric-mean ratio with a two-sided 90% confidence interval. It does not give the estimated ratio, interval limits, p-value, or participant-level data. No calculation from the design description can recover those missing results. The registry record also does not report enough detail to independently reproduce the statistical analysis.

The sample-size assumptions described for planning illustrations are not the trial’s own design justification and are not observed power. General explanation: a sample-size illustration asks what enrollment might be needed under stated assumptions, while observed power is not a substitute for examining an estimated effect and its uncertainty. The registry record does not report a sample-size justification, and no planning output should be interpreted as evidence that the trial did or did not detect a pharmacokinetic difference.

10. Multiplicity, Missing Data and Analysis Populations

The registry record identifies the primary pharmacokinetic endpoint and an additional safety and tolerability objective. It lists two outcome measures and two analyses, but does not give sufficient detail to establish a complete hierarchy of outcomes or hypotheses. Any multiplicity adjustment, including whether one was used, is not reported in the registry record. It is therefore not possible to determine whether the stated confidence interval or any other analysis was adjusted for multiple comparisons.

Missing-data procedures are not reported in the registry record. The primary analysis population description says participants had to receive at least one dose and provide at least one observation for at least one pharmacokinetic endpoint, with additional protocol-violation and emesis criteria. The last part of the registry description is incomplete, so the full eligibility definition cannot be reconstructed. The record does not specify how missing concentration measurements, incomplete profiles, or participants without evaluable endpoint data were handled.

The record does not describe imputation, sensitivity analyses, or a comparison of included and excluded participants. It also does not state how deviations from the scheduled sampling times were treated. These omissions matter because a pharmacokinetic endpoint is built from measurements taken at specified times, and incomplete sampling can affect how an exposure estimate is derived. This is a general methodological consideration, not evidence that missingness occurred or changed the result in this trial.

Neither the population flow nor the reasons for the group-specific adverse-event denominators are explained. The stated enrollment and treatment-condition denominators should be read as separate registry figures, not combined to infer unique participants. Details about analysis populations and missing data are not reported in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists no serious adverse events among the 24 participants at risk in the raltegravir group, and none among the 23 participants at risk in the raltegravir plus faldaprevir group. The serious-event terms list is empty. Death counts are not reported in the registry record.

For other adverse events, the record reports 6 affected among 24 at risk for raltegravir and 13 affected among 23 at risk for raltegravir plus faldaprevir. These are group-specific counts. Because the study is a crossover, the groups should not be interpreted as separate, independent sets of participants, and their denominators should not be added to estimate a total number of unique participants.

These counts describe what the registry reports, but they do not by themselves establish whether an event was caused by a treatment. The record does not provide event timing, severity details for the other events, participant-level crossover histories, or a statistical comparison of adverse-event rates. The absence of reported serious events in these group summaries is not proof that serious events are impossible or that the treatments are free of risk. It is a description of the recorded counts, with the limitations of the registry summary.

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

The trial was designed to examine whether raltegravir exposure at steady state differed when raltegravir was taken with faldaprevir rather than alone. Its primary endpoint, AUC( Tau,ss), is a pharmacokinetic measure, and the record describes an analysis based on a within-participant ratio of geometric means. The numerical result needed to answer the primary question is not reported in the registry record: neither the ratio nor its two-sided 90% confidence interval is available.

That missing numerical information prevents interpretation of the estimated direction, magnitude, and precision of the comparison. The design and statistical description cannot substitute for the result itself. It would be inappropriate to infer that the combination increased, decreased, or left exposure unchanged based only on the endpoint name or analysis plan.

The trial’s setting also defines what its question can address. It enrolled healthy male and female volunteers and focused on pharmacokinetics. The record does not describe a clinical outcome or establish a conclusion about treatment benefit. Safety and tolerability were additional objectives, but the available adverse-event counts do not establish causality or provide a comprehensive risk assessment.

Its non-randomized, fixed-sequence crossover design should remain part of any interpretation. A crossover permits within-participant comparisons, but a fixed treatment order can make treatment and period effects difficult to separate unless the design and analysis address them. The registry record does not report enough detail to evaluate how period or carryover concerns were handled.

In short, the record documents a pharmacokinetic question and a stated analysis method, along with limited adverse-event counts. It does not provide the primary numerical estimate, its uncertainty, or sufficient design and analysis details to reach a numerical conclusion about the treatment comparison. The record should not be read as evidence that a clinical benefit or harm was demonstrated.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it illustrates the distinction between a well-defined pharmacokinetic question and a reported result. The registry names AUC( Tau,ss), specifies an intrasubject geometric-mean ratio, and describes a model on log-transformed parameters. Those choices make the intended estimand and broad analysis approach understandable. Yet the numerical ratio and confidence interval are not reported in the registry record, so the central comparison cannot be interpreted quantitatively.

The crossover design also highlights the role of treatment order. Within-participant comparisons can reduce the influence of stable between-person variability. In general, that can be useful when pharmacokinetic measurements differ substantially from one person to another. But this trial was non-randomized and used a fixed sequence. Statistical interpretation therefore depends on whether period and carryover effects were considered, and that information is not reported in the registry record.

The record also illustrates why the analysis population and missing-data rules matter. Pharmacokinetic endpoints depend on concentration observations over time. The registry gives a partial eligibility description for the pharmacokinetic set, but its final criterion is incomplete, and the handling of missing or incomplete observations is not reported. Without those details, the reader cannot fully assess which observations informed the endpoint or how incomplete profiles were treated.

Finally, the safety counts need to be understood in the context of crossover reporting. The group-specific denominators refer to treatment conditions and do not represent independent parallel arms. The figures can describe recorded events by condition, but the registry does not provide the detail needed for causal attribution or a formal comparison. This is a useful reminder that counts, design structure, and analysis detail all shape what a registry result can support.

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 most consequential limitation of the registry entry is that it does not report the numerical primary endpoint result. Although it describes a point estimate and two-sided 90% confidence interval, their values are absent. The magnitude, direction, and precision of the pharmacokinetic comparison therefore cannot be assessed from the registry record.

The design was non-randomized, open-label, and fixed-sequence. Those features do not invalidate a pharmacokinetic comparison by themselves, but they make period and sequence considerations relevant. The registry record does not describe washout procedures, a period effect in the model, carryover evaluation, or sensitivity analyses. The extent to which these issues were addressed is not reported in the registry record.

The population was healthy male and female volunteers, so the record does not describe pharmacokinetic findings in a patient population. The enrollment is listed as 25, while the adverse-event counts use separate treatment-condition denominators. The registry record does not explain the movement between or reasons for those denominators. Because this was a crossover, the group counts should not be treated as independent participant groups.

The pharmacokinetic analysis-set definition is incomplete in the registry record. It mentions dosing, at least one endpoint observation, protocol violations, and emesis, but the final criterion is cut off. The record also does not report missing-data handling, the full statistical model, model diagnostics, or numerical outcome data. These omissions limit reproducibility and the assessment of possible bias or uncertainty.

Safety reporting is also limited. The registry gives counts for serious and other adverse events, but not event timing, detailed severity, causal attribution, or a formal comparison. Death counts are not reported in the registry record. These limitations mean the summaries should be read descriptively, not as a complete safety evaluation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Investigation of Faldaprevir Effect on Pharmacokinetics of Raltegravir — NCT01785160.
• Registry record last updated 2015-08-03; status last verified 2015-07.
• Results first posted 2015-08-03.
• 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.

18. Record Summary

NCT01785160 is a completed phase 1, open-label, non-randomized crossover trial with a fixed sequence and two periods. It enrolled 25 healthy male and female volunteers. The primary objective was to examine the effect of faldaprevir on steady-state raltegravir pharmacokinetics; safety and tolerability were additional objectives.

The primary endpoint was AUC( Tau,ss), analyzed using log-transformed parameters in an analysis of variance that included subject and treatment effects. The planned summary was an intrasubject geometric-mean ratio with a two-sided 90% confidence interval. The numerical estimate and interval are not reported in the registry record.

The registry reports no serious adverse events in either treatment-condition group and reports other adverse events in both groups. These counts are descriptive and do not establish causality. Details of missing-data handling, multiplicity, and assessment of period or carryover effects are not reported in the registry record.