SUBLOCADE Rapid Initiation Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for SUBLOCADE Rapid Initiation Study (NCT03993392), a na phase 4 study. The primary outcome is Participants Who Experienced Any Precipitated Withdrawal Within One Hour After SUBLOCADE Administration.

2. Clinical Question

3. Trial Design

This is a Phase 4, open-label, single-group study of rapid initiation of extended-release buprenorphine subcutaneous injection. The registry lists 26 participants as the enrollment and identifies Indivior Inc. as the sponsor. The study status is completed. The listed start date is 2019-08-29, and the primary completion date is 2019-12-26.

The intervention sequence named in the record is TM buprenorphine followed by SUBLOCADE 300 mg. The brief summary states that the study evaluated the safety and tolerability of initiating SUBLOCADE after a shorter period of TM buprenorphine treatment. The record also describes participants stopping their current opioid before clinic assessment for withdrawal symptoms; those confirmed to be in withdrawal received 4 mg TM buprenorphine. The remaining arm description is cut off, so other procedural details are not reported in the registry record.

There was no random allocation, masking, or parallel control group. A single-group design can describe what occurred among participants receiving the study sequence, but it cannot by itself separate effects of that sequence from other influences or establish how outcomes compare with a different approach. The record does not report a planned comparative estimand or a control-arm analysis.

The registry lists a primary outcome concerning precipitated withdrawal, alongside secondary outcomes addressing treatment-emergent adverse events, COWS scores and opioid craving scores. Although the record lists the outcome measures, numerical results for the primary and secondary outcomes are not reported in the registry record. The recorded enrollment should therefore not be mistaken for the number assessed for every outcome; the outcome-specific analysis population and missing assessments can differ.

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: Reasons not enrolled: * 10 patients did not meet inclusion/exclusion criteria; * 3 did not meet Day 1 check-in criteria; * 3 withdrew consent; * 3 were not entered because the study was closed to enrolment; * 4 patients were for other reasons

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS): Participants who receive a SUBLOCADE injection and have data for \>=1 COWS assessment at the Pre-SUBLOCADE timepoint just before the SUBLOCADE injection and a COWS assessment within one hour after the SUBLOCADE injection. One participant did not have a COWS score at one hour so is not 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.

Population: Safety and Full Analysis sets (same participants in each population)

6. Primary Endpoint

The registry lists the primary outcome as Participants Who Experienced Any Precipitated Withdrawal Within One Hour After SUBLOCADE Administration, measured over Day 1: Pre-SUBLOCADE evaluation taken after TM buprenorphine treatment and prior to injection: SUBLOCADE evaluation taken within one hour of SUBLOCADE injection.

The primary endpoint is the count of participants who experienced any precipitated withdrawal within one hour after SUBLOCADE administration. The registry defines precipitated withdrawal as an increase in the Clinical Opiate Withdrawal Scale (COWS) score of at least 6 compared with the pre-SUBLOCADE score, occurring within that hour.

COWS is described as an 11-item instrument that assesses signs and symptoms of opioid withdrawal. Its total score ranges from 0 to 48. The registry describes scores below 5 as not indicative of withdrawal, scores from 5 to 12 as mild, 13 to 24 as moderate, 25 to 36 as moderately severe, and 37-48 as severe. These categories describe score levels; the primary endpoint uses a change from the pre-injection score rather than a particular post-injection category.

A change-based definition is useful when the question concerns a worsening after an intervention: it compares each participant's post-injection score with that participant's own pre-injection assessment. A threshold can make the event definition more specific than simply recording any score increase. It does not, however, convey every aspect of withdrawal severity or duration.

The registry specifies assessment before injection and within one hour afterward. The number of participants meeting the endpoint, and any uncertainty interval for that count or proportion, are not reported in the registry record. Thus the endpoint definition is available, but its observed frequency cannot be evaluated from the registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a count: the number of participants meeting a defined event criterion. The underlying participant-level classification is binary—each participant either meets the precipitated-withdrawal definition or does not. In a single-group study, the count can be described alongside the number assessed, and a proportion can describe the observed frequency. Neither the primary event count nor its analysis denominator is reported in the registry record, so no such estimate can be interpreted.

Why use a change threshold?

The endpoint compares a post-injection COWS score with the pre-SUBLOCADE score. This within-participant comparison accounts for the fact that withdrawal scores can already be present before injection. A threshold of at least 6 points defines which increases qualify as the endpoint; smaller changes do not meet that stated criterion. This operational definition makes the outcome reproducible in principle, provided the assessments are available and timed as specified. It does not mean that changes below the threshold are clinically irrelevant, nor does the endpoint summarize the full course of symptoms.

General statistical interpretation of an event count depends on both the count and the number of participants assessed. A count without its denominator cannot establish an event frequency. Even a proportion, if reported, would be an estimate from the study population rather than a guarantee of the frequency in other settings. A confidence interval would describe the statistical uncertainty around an estimate under its method's assumptions; no confidence interval for this primary outcome is reported in the registry record.

What does the analysis population mean?

The registry defines the full analysis set as participants who received a SUBLOCADE injection and had data for at least one COWS assessment at the pre-injection timepoint and a COWS assessment within one hour afterward. This definition is specific to the primary outcome. It does not necessarily match enrollment or the population used for the safety summaries. The record notes one participant without a COWS score at one hour, but does not state the total number included in the primary analysis or how any missing assessment was handled.

In general, missing outcome data matter because the outcome status of a participant without an adequate assessment may be unknown. Excluding such a participant, treating the missing result as no event, or using a statistical imputation procedure can lead to different estimates. The registry does not report a missing-data method for this endpoint, so it is not possible to determine what approach was used beyond the stated analysis-set definition.

How should the single-group structure be read?

The study is recorded as single-group, open-label, and not randomized. A descriptive analysis can report outcomes observed after the study sequence. It cannot provide a randomized treatment contrast, and it is vulnerable to alternative explanations such as changes over time, participant selection, and assessment expectations. These are general considerations, not findings that those influences occurred in this study. Masking is listed as none; for an outcome involving clinical assessment, knowledge of treatment can be a potential source of measurement influence in general.

The registry lists no statistical analyses. It therefore does not report an inferential model, a prespecified hypothesis test, an adjustment strategy, or a method for estimating uncertainty for the primary endpoint. Those details are not reported in the registry record. A count-based endpoint does not by itself specify whether results should be presented descriptively, with an interval, or as part of a formal test.

What do planning illustrations mean?

General sample-size illustrations based on an observed effect answer a different question from trial results: they show the number of participants per arm that a hypothetical future comparison might require under stated assumptions. The registry's stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect set as a stated fraction of the observed effect. They are planning illustrations, not observed power and not evidence that this study was designed as a two-arm trial.

Such illustrations depend on the effect chosen and on their statistical assumptions. The registry record does not report the trial's own sample-size justification. Because the observed primary endpoint result is not reported in the registry record, the underlying observed effect cannot be assessed from the information available. The hypothetical planning assumptions should not be read as a protocol analysis plan or as a comparison conducted in this study.

The record lists secondary measures spanning adverse-event counts, COWS scores and opioid craving scores. Different outcome types can require different summaries and models. For example, repeated measurements raise questions about within-participant correlation, while event counts can require attention to the amount of observation and event distribution. These are general methodological considerations; the specific analysis choices for the listed outcomes are not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("TM Buprenorphine Followed by SUBLOCADE 300 mg")
n      <- c(23)
events <- c(1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  TM Buprenorphine Followed by SUBLOCADE 300 mg  23  1  4.3  0.1  21.9  0.8  21.0  1.0  21.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and multiple secondary outcomes, but does not report a statistical analysis plan or a multiplicity strategy. When several outcomes or timepoints are tested, the chance of at least one apparently noteworthy result can increase if each is treated as an independent confirmatory test. General approaches include identifying a primary hypothesis in advance, adjusting testing thresholds, or treating secondary analyses as exploratory. The registry record does not say whether any such approach was planned or used.

The primary analysis population requires an injection, a pre-SUBLOCADE COWS assessment, and at least one COWS assessment within one hour. The record states that one participant did not have a COWS score at one hour. It does not report the primary analysis denominator, the endpoint status of that participant, or the method used to handle missing assessments. Since the stated population permits a score within the hour, the missing score at one hour alone does not establish whether that participant was excluded.

Secondary outcome results and their analysis populations are not reported in the registry record. The registry also lists no statistical analyses. Details such as handling of missing repeated measurements, adjustment for multiple testing, and the basis for selecting analysis populations are therefore not reported in the registry record. These omissions limit assessment of how robustly the results were analyzed, independently of the outcome definitions.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts for two groups. In the Induction Phase group, 0 participants with serious adverse events are recorded among 26 at risk. In the Safety Population (Post -SUBLOCADE) group, 0 are recorded among 24 at risk. No serious adverse event terms are listed. The registry also reports 0 deaths in each group.

For other adverse events, the record lists 4 affected participants among 26 at risk in the Induction Phase group and 20 among 24 at risk in the post-SUBLOCADE safety group. These are participant counts, not counts of all event episodes. The registry does not provide the event terms or enough detail in these figures to determine severity, duration, timing, or whether events were considered related to treatment.

Zero recorded serious events does not prove that serious events are impossible or that risk is absent; it describes what the registry reports for these groups. The group counts should not be treated as a randomized comparison. Differences between group summaries cannot establish that the treatment sequence caused a difference, particularly because the groups represent study phases rather than randomized alternatives.

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

The registry record establishes the study's focus: safety and tolerability of initiating SUBLOCADE after a shorter period of TM buprenorphine treatment, with a primary endpoint based on a COWS increase within one hour of injection. It also gives the endpoint definition and selected adverse-event counts. Those details help clarify what investigators intended to measure and how the primary event was classified.

The record does not report the primary endpoint result. It therefore does not establish how many participants experienced precipitated withdrawal under the specified definition, nor how precise any estimate would be. Secondary outcome results are also not reported in the registry record. The listed outcomes alone cannot be used to infer changes in withdrawal scores, craving, or treatment-emergent adverse events beyond the reported safety counts.

The study's single-group design means it does not directly compare the rapid initiation sequence with another schedule. Even if an outcome count were available, it would be a description of participants in this study and would not by itself show what would have happened under an alternative approach. The open-label design and missing details about analysis methods further limit what can be concluded from the registry information.

The safety figures record no serious adverse events and no deaths in either listed group, while also recording participants affected by other adverse events. These observations should be read as registry counts, not as proof of absence of risk or as a causal treatment effect. In general, conclusions about safety depend on event definitions, observation, follow-up, and completeness of reporting, details that are not all available in the registry record.

Accordingly, the record is useful for identifying the research question, design, endpoint definition, and reported safety summaries. It does not provide enough outcome or analysis information to determine the primary endpoint frequency, quantify uncertainty, or make a comparative conclusion.

14. Why This Trial Matters Statistically

This study illustrates the importance of separating an endpoint's definition from its result. The registry gives a specific rule for precipitated withdrawal: an increase of at least 6 points on COWS from the pre-injection score within one hour. That makes the intended outcome interpretable, but without the observed count and its denominator, readers cannot estimate its frequency or precision.

It also highlights why analysis populations need to be explicit. Enrollment is not automatically the denominator for every outcome. The primary analysis set depends on injection and availability of pre-injection and post-injection COWS assessments, while safety summaries are reported for named groups. The note that one participant lacked a one-hour score raises a relevant missing-data question, but the registry does not give the denominator or handling method needed to resolve it.

The single-group, unmasked design is another important statistical feature. It can describe observations during a treatment sequence, but it cannot offer a randomized comparison with an alternative initiation strategy. This distinction matters when interpreting safety counts or any future reported event frequency: descriptive evidence is not the same as a causal contrast.

Finally, the record lists a range of secondary outcomes, yet does not report statistical analyses or a multiplicity approach. When multiple outcomes and assessment times are considered, analysis choices affect how evidence should be weighed. Reporting the endpoint results, denominators, missing-data handling, and analysis methods would be necessary for a fuller statistical appraisal. The case demonstrates that transparent definitions are valuable, but definitions alone cannot substitute for reported results.

15. 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 main limitation for interpreting the primary question is that its numerical result is not reported in the registry record. Although the endpoint definition and analysis population are described, the event count, analysis denominator, estimate of frequency, and uncertainty interval are not available. The secondary outcomes are listed but their numerical results are also not reported.

The study has no randomized comparator and is open-label. As a result, it cannot provide a direct randomized contrast between this initiation sequence and another strategy. The registry does not report masking, and lists none. The record also does not report the trial's sample-size justification, a statistical analysis plan, or statistical analyses.

Outcome completeness is not fully characterized. The record notes one participant without a COWS score at one hour, while the analysis-set definition allows an assessment within the hour. It does not explain how this participant contributed to the primary analysis, or give the resulting denominator. Missing-data handling for the primary and secondary outcomes is not reported in the registry record.

The arm description is incomplete, limiting detail about study procedures beyond the stated TM buprenorphine and SUBLOCADE sequence and the described initial assessment and dose. The adverse-event summaries provide affected-participant counts and at-risk group sizes but do not list serious event terms or describe the other adverse events in detail. These limits make it difficult to assess event type, timing, severity, attribution, and completeness beyond the reported counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: SUBLOCADE Rapid Initiation Study — NCT03993392.
• Registry record last updated 2025-03-25; status last verified 2025-03.
• Results first posted 2020-12-09.
• 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.

19. Record Summary

NCT03993392 is a completed Phase 4, open-label, single-group study sponsored by Indivior Inc. It evaluated initiating SUBLOCADE after a shorter period of TM buprenorphine treatment in participants with opioid-use disorder. The registry lists enrollment of 26, a start date of 2019-08-29, and a primary completion date of 2019-12-26.

The primary outcome is participants experiencing precipitated withdrawal within one hour after injection, defined as a COWS increase of at least 6 from the pre-SUBLOCADE value. The numerical primary result is not reported in the registry record. The record lists secondary outcomes involving adverse events, COWS, and opioid craving scores, but their results and statistical analyses are not reported.

Serious adverse events and deaths are recorded as 0 in both listed safety groups. Other adverse events are recorded for 4 participants in the Induction Phase group and 20 in the post-SUBLOCADE safety group. The design does not include a randomized comparator, so these summaries are descriptive rather than comparative treatment effects.