Improving Buprenorphine Detoxification Outcomes With Isradipine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Improving Buprenorphine Detoxification Outcomes With Isradipine (NCT01895270), a randomized phase 1, phase 2 study. The primary outcome is Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6).

2. Clinical Question

The clinical question was whether adding isradipine to buprenorphine detoxification was associated with a different change over time in illicit opioid use, assessed using urine toxicology screens during the taper. The registry describes the study as a pilot examining tolerability and preliminary efficacy; the primary registered outcome concerns opioid-positive urine results.

The intended clinical focus was broader than the primary endpoint: the registry summary also describes withdrawal symptoms, craving, illicit opioid use, tolerability, and safety. The posted primary result specifically concerns urine toxicology during the taper, so it should not be read as a direct result for every outcome named in the study summary.

3. Trial Design

The registry describes a randomized, quadruple-masked, parallel-group phase 1 and phase 2 trial, sponsored by the University of Arkansas. The listed condition is opioid dependence. The study status is completed. The registry lists an enrollment of 28, a start date of 2013-10, and primary completion in 2016-04.

Participants were assigned to isradipine or placebo. The isradipine arm description specifies a controlled-release formulation and a 10 mg/day maintenance dose. It states that dosing was supervised 6 days per week, with a take-home dose for Sunday given on Saturday. The placebo description identifies microcrystalline cellulose and states that two capsules per day were administered starting week 1 day 3 through the end of the isradipine taper. The registry record does not report further details of the dose procedures in the available arm description.

The study summary calls the trial a pilot and describes the intended investigation as involving up to 60 opioid-dependent individuals. The registered enrollment is 28; these are different descriptions in the record and should not be conflated. The registry record does not report the randomization sequence method, allocation concealment procedures, or which roles were included in quadruple masking.

The primary endpoint was change over time in illicit opioid use measured using urine toxicology screens during the taper, described as weeks 5–6. Testing was scheduled thrice weekly for approximately 2 weeks. The registry reports endpoint estimates for the isradipine and placebo groups and a mixed-model analysis. The analyzed endpoint counts are smaller than the registered enrollment, and the analysis population is defined by dose receipt and return for a visit with a urine screen. Reasons that participants were not included in the endpoint analysis 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.

Before assignment: 96 consented to screen under a separate screening protocol. Of these, 28 signed consent for this clinical trial. Of 28 signing informed consent, 3 signed informed consent but did not start the trial: one was assigned to ISR and one to PLA. One was lost to follow up before they could be cleared for study entry

Study Medications Induction (W1-4)

Reasons for not completing this period:

Buprenorphine Taper (W5 to W6D3)

Reasons for not completing this period:

Isradipine Taper (W7-8)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Urine data of subjects that received at least one dose of isradipine and returned for at least one visit in which a urine drug screen was obtained were included in the analysis

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: These numbers refer to those that actually started the clinical trial proper.

6. Primary Endpoint

The registry lists the primary outcome as Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6), measured over thrice weekly for approx 2 weeks (taper).

The primary endpoint was change over time in illicit opioid use, assessed through urine toxicology screens for heroin and several opioids during the buprenorphine taper. The registry describes urine collection thrice weekly for approximately 2 weeks, during weeks 5–6. The reported unit is opioid-positive urine, and the endpoint is summarized using least-squares means with standard errors.

Urine toxicology is an objective measurement of detected opioid use at the times specimens are collected. Repeated measurements during a taper allow the analysis to consider how results change over time, rather than relying only on a single test. Such a measure can describe the pattern recorded during the specified observation period, but it does not by itself capture every aspect of withdrawal, craving, or treatment experience. Nor does the primary endpoint represent all outcomes mentioned in the study summary.

The endpoint analysis population was restricted to participants who received at least one dose of isradipine and returned for at least one visit at which a urine drug screen was obtained. This eligibility definition matters when interpreting the results: the reported estimates characterize the analyzed urine data, not necessarily every enrolled participant. The registry record does not report how unobserved urine tests were handled, or whether the analysis accounted for missed visits in a particular way.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What do the least-squares means represent?

The registry reports least-squares means for the primary continuous endpoint. In general, a least-squares mean is a model-based estimate of a group mean. Unlike a simple raw average, it may reflect the structure of the fitted model. The registry record does not report enough detail to identify all covariates or other model specifications used to obtain these estimates, so the values should be described as the posted model-based summaries rather than treated as unadjusted averages.

The reported estimates are -1.25 opioid-positive urine for isradipine and -0.36 for placebo. The accompanying standard errors are 0.74 and 0.58, respectively. A standard error describes the estimated sampling variability of an estimate under the model and data assumptions. It is not the spread of individual urine results, and it does not describe the range of outcomes among participants. A confidence interval would provide a range of values compatible with the estimate under a specified confidence procedure; no confidence interval is posted for these group estimates.

Why analyze a slope over time?

The primary outcome is explicitly framed as change over time, and the sponsor reports a mixed models analysis of slope. In general, a slope expresses how an outcome changes as time advances. Comparing slopes can address whether the patterns of change differ between groups, rather than asking only whether their average outcome levels differ at one point. The registry reports a slope value of .34 and p = .42, but does not provide a confidence interval or enough model detail to reconstruct the interpretation of the slope’s direction and scale independently.

A mixed model is a general approach for analyzing repeated or grouped observations while accounting for dependence among measurements. Repeated urine tests from the same participant are generally not independent observations: results from one person may be more alike than results from different people. A suitable repeated-measures model can represent that dependence, instead of treating every urine test as if it came from an unrelated participant. The registry identifies the method as a mixed models analysis but does not report its covariance structure, estimation method, assumptions, or full model formula. Those details are therefore not reported in the registry record.

How should the p-value be read?

In general, a p-value summarizes how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions were true. It is not the probability that a treatment effect exists, and it does not measure the size or importance of an effect. The reported p = .42 is the result of the sponsor’s mixed-model slope analysis. It does not establish equality between groups. Interpreting the magnitude and precision of the slope would be better supported by a confidence interval, which is not reported in the registry record.

Statistical significance is not the same as clinical importance. A small p-value can occur for an effect that is not important to participants, while a larger p-value can occur when data are too limited or uncertain to distinguish among a range of effects. Here, the registry supplies a p-value but no confidence interval for the comparison. The endpoint estimates and their standard errors give some information about uncertainty in the group summaries, but they do not directly give the uncertainty for the slope comparison.

What does the analysis population mean?

The registry states that urine data were included for subjects who received at least one dose of isradipine and returned for at least one visit with a urine drug screen. In general, defining an analysis population by post-assignment events such as receiving a dose and returning for measurement can mean that the analyzed participants do not represent everyone randomized. The record does not report the number randomized to each group, the number excluded from this endpoint analysis, or the reasons for any exclusions. It also does not report whether the primary analysis followed an intention-to-treat principle.

Because urine tests were scheduled repeatedly, missing observations could affect the estimated pattern over time. In general, mixed models can use available repeated observations under assumptions about the missing-data process, but the method alone does not establish that those assumptions are appropriate. The registry record does not report the amount or pattern of missing urine data, any imputation method, or sensitivity analyses for missingness. Readers therefore cannot assess from the posted description how robust the slope result is to incomplete urine testing.

What cannot be inferred from the posted statistics?

The registry does not report a confidence interval for the sponsor’s slope estimate, the full model specification, or a recalculated two-arm comparison from the group summaries. Simple recalculation from group summaries would not necessarily reproduce a repeated-measures mixed-model result, which can depend on within-participant information and modeling choices that are not captured by the posted means and standard errors. The sponsor’s analysis is therefore the directly reported inferential result. More generally, neither a p-value nor a point estimate alone resolves questions about precision, missing-data assumptions, or the broader outcomes named in the study summary.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Isradipine", "Placebo")
n   <- c(5, 7)
m   <- c(-1.25, -0.36)
sp  <- c(0.74, 0.58)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Isradipine  5  -1.250  1.655  -3.305  0.805
CARM  Placebo  7  -0.360  1.535  -1.779  1.059

11. Analyses Reported by the Sponsor

The sponsor’s reported inferential result is a mixed models analysis of slope, with a value of .34 and p = .42 for the isradipine and placebo groups. A confidence interval for this slope is not reported in the registry record. The posted least-squares mean changes and standard errors are separate group summaries; they should not be mistaken for the sponsor’s slope comparison.

No recalculated two-arm comparison is reported for this continuous endpoint. The registry record indicates that values needed for such a comparison are missing or not estimable. A simple unadjusted comparison based only on group summaries would also not necessarily reproduce the repeated-measures mixed-model analysis, which can incorporate information about the pattern and dependence of measurements over time. The record does not include the full model specification needed to reconstruct that analysis.

No discrepancy between the posted group summaries and sponsor analysis is flagged in the registry record. The sponsor’s mixed-model result is therefore the principal reported inferential result, while the group means provide descriptive context. The p-value should be read as a test result under the sponsor’s model, not as a measure of effect magnitude or a direct statement about clinical importance.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and one reported analysis, and no secondary outcome measures are posted. The study summary nevertheless describes several areas of interest, including withdrawal symptoms, craving, illicit opioid use, tolerability, and safety. The primary posted endpoint is urine toxicology during the taper; results for the other outcomes are not reported in the registry record.

When many outcomes, time points, or analyses are examined, the chance of finding an apparently notable result by chance can increase. In general, multiplicity procedures can address that issue by adjusting inference or by specifying a primary analysis in advance. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a broader statistical analysis plan. It is therefore not possible to determine from the record whether the posted analysis was the only analysis planned or how any additional analyses were handled.

The endpoint analysis population required receipt of at least one isradipine dose and return for at least one urine-screen visit. This defines which urine data were included, but the registry record does not report how many randomized participants did not meet the criterion or why. It does not report whether all randomized participants were analyzed in their assigned groups.

Urine screening was scheduled thrice weekly for approximately 2 weeks during the taper. The record does not report how many scheduled specimens were missing, whether missingness differed by group, how incomplete repeated measurements were handled, or whether sensitivity analyses were conducted. These omissions limit assessment of the assumptions behind the mixed-model result. A mixed model can be useful for repeated measurements, but it does not automatically remove the potential effects of missing data; interpretation depends on the model and missing-data assumptions. Those details 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 1% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports no serious adverse events affecting participants in either arm: 0 among 11 at risk in the isradipine group and 0 among 14 at risk in the placebo group. Deaths are reported as 0 in each group. The listed counts at risk are safety figures and should not be confused with the smaller counts contributing to the primary endpoint summaries.

Other adverse events were reported as affecting 10 among 11 at risk in the isradipine group and 8 among 14 at risk in the placebo group. These are counts of participants affected, not counts of separate event episodes. The registry record does not provide the event terms or severity breakdown for these other adverse events in the registry record for this analysis. The list of top serious adverse-event terms is empty.

Zero reported serious adverse events in these groups does not establish that serious harms are impossible or that the groups have equivalent safety. The observed counts describe what was recorded among those at risk in this trial. The registry record does not report further detail needed to assess the range or timing of events, and the safety counts should be interpreted separately from the efficacy endpoint analysis.

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

The posted findings describe a small analyzed endpoint population with repeated urine screens during the buprenorphine taper. The isradipine and placebo arms have reported least-squares mean changes of -1.25 and -0.36 opioid-positive urine, respectively, with standard errors of 0.74 and 0.58. The sponsor’s mixed-model slope analysis reports a value of .34 and p = .42. Taken together, these statistics do not provide strong evidence against the null hypothesis in that analysis, but they do not prove that the groups had the same pattern or that an effect is absent.

The result is specific to the registered primary outcome: change over time in opioid-positive urine screens during the taper. It does not directly answer whether withdrawal symptoms or craving changed, and no secondary outcome measures are posted. The study summary describes those broader aims, but results for them are not reported in the registry record.

The endpoint estimates are based on urine data from participants meeting the stated dose-and-return criterion. The registry enrollment is 28, while endpoint summaries list 5.0 participants for isradipine and 7.0 for placebo. These figures refer to different parts of the record and should not be treated as interchangeable. The reasons for the difference and the handling of incomplete observations are not reported in the registry record.

The trial is described as a pilot, and its results should be understood as estimates from the posted study rather than as a definitive answer to every question about adjunct isradipine. The registry does not provide a confidence interval for the slope analysis or the full model details, which limits assessment of precision and reproducibility. The statistics describe the recorded observations and analysis; they do not by themselves establish clinical benefit, lack of benefit, or a treatment recommendation.

15. Why This Trial Matters Statistically

This trial illustrates why the endpoint definition and analysis population matter when interpreting a clinical result. The study summary names a broad set of interests, but the primary posted endpoint is a specific repeated measure: opioid-positive urine screens during the taper. Keeping the conclusion tied to that outcome avoids treating a result for urine toxicology as if it answered questions about withdrawal symptoms, craving, or every aspect of tolerability.

It also shows the distinction between group summaries and a longitudinal comparison. Least-squares mean changes describe each group’s estimated outcome, whereas the sponsor’s mixed-model analysis tests a slope over time. These statistics answer related but different questions. The slope result, p-value, and group standard errors should not be treated as interchangeable evidence.

The endpoint analysis population is much narrower than the registered enrollment, and the eligibility rule depends on dose receipt and return for a urine-screen visit. That makes transparency about exclusions and missing measurements important. The registry record does not provide the full accounting needed to understand why the analyzed groups are smaller or how incomplete repeated urine data were handled.

Finally, the absence of a reported confidence interval for the slope limits direct assessment of its precision. A p-value alone cannot show the range of effects compatible with the data. These issues are especially consequential in a pilot record: the posted estimates can inform understanding of the observed data, but their interpretation depends on the analysis details and outcome coverage that are reported.

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.

Several trial-specific limitations affect interpretation of the primary result. The endpoint summaries are based on 5.0 participants in the isradipine arm and 7.0 in the placebo arm, whereas registered enrollment is 28. The registry defines the endpoint analysis population by receiving at least one isradipine dose and returning for at least one urine-screen visit. It does not report a complete participant flow or reasons for the difference between enrollment and the endpoint analysis counts.

The primary outcome is based on repeated urine screens during a limited period of the taper, described as weeks 5–6. The registry does not report the number of scheduled urine tests completed per participant, the extent or pattern of missing urine data, or the method used to handle missing observations. These gaps make it difficult to assess how incomplete measurement may have influenced the estimated change over time.

The registry reports a mixed models analysis but does not provide the full model specification, including the covariance structure or other details needed to reproduce the analysis. A confidence interval for the slope estimate is also not reported. The stated p-value therefore cannot be paired with a posted interval showing the precision of the comparison.

The available primary result does not address all aims named in the study summary. No secondary outcome measures are posted, and results for withdrawal symptoms and craving are not reported in the registry record. The registry also does not report a multiplicity plan or detailed analysis plan. As a pilot study, its posted estimates are best interpreted as limited evidence about the specified urine-screen endpoint, with important uncertainty about analysis precision, missing data, and broader outcomes.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Improving Buprenorphine Detoxification Outcomes With Isradipine — NCT01895270.
• Registry record last updated 2017-06-05; status last verified 2017-05.
• Results first posted 2017-06-05.
• 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

NCT01895270 is a completed randomized, quadruple-masked, parallel-group phase 1 and phase 2 trial sponsored by the University of Arkansas. The registry lists opioid dependence as the condition, enrollment of 28, a start date of 2013-10, and primary completion in 2016-04. The comparison was adjunct isradipine versus placebo during buprenorphine detoxification.

The primary outcome was change over time in illicit opioid use measured using urine toxicology during the taper. The registry reports least-squares mean changes of -1.25 for isradipine and -0.36 for placebo, with standard errors of 0.74 and 0.58. The sponsor’s mixed-model slope analysis reports .34 with p = .42 and no confidence interval. The endpoint analysis population was defined by dose receipt and return for at least one urine-screen visit. No secondary outcome measures are posted.