Restoring Cognitive Control (ReCon) in Acute Nicotine Withdrawal: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Restoring Cognitive Control (ReCon) in Acute Nicotine Withdrawal (NCT03887429), a randomized phase 2 study. The primary outcome is Safety and Tolerability of SXC-2023..

2. Clinical Question

This was a phase 2 exploratory study. Its primary endpoint was safety and tolerability, assessed through the frequency of serious adverse events, adverse events leading to discontinuation, and adverse events judged related to study medication. The record also describes the study’s purpose as exploring activity, but it does not identify a single activity outcome for a treatment-effect comparison in the information available for this analysis.

The crossover design is relevant to the question because treatment periods, rather than only parallel groups, are described. The registry lists sequences in which SXC-2023 came before placebo and sequences in which placebo came before SXC-2023, at both doses. The posted adverse-event summaries distinguish treatment exposure periods. They are descriptive counts, not a reported adjusted comparison of treatment effects.

3. Trial Design

The registry record describes a randomized, quadruple-masked, phase 2 crossover study with an enrollment of 34. Its title is “Restoring Cognitive Control (ReCon) in Acute Nicotine Withdrawal,” and the official title describes an exploratory, placebo-controlled crossover study of SXC-2023 in non-treatment-seeking adults undergoing acute nicotine withdrawal. The study status is completed.

The study evaluated SXC-2023 at 200 mg and 800 mg, with placebo as the comparator. Each listed treatment period lasted 5 days, with once-daily dosing. The arm descriptions include sequences in which SXC-2023 was followed by placebo and sequences in which placebo was followed by SXC-2023. Each sequence description includes a 9 day washout between periods. The record does not explain the rationale for that washout or provide additional details about period-specific procedures.

Randomized allocation and quadruple masking are recorded, but the record does not state the randomization method, identify which roles were masked, or describe how allocation was concealed. It also does not give the number assigned to each sequence or dose. The enrollment figure does not by itself establish how many participants completed each period or contributed to each adverse-event summary.

The study started on 2019-03-04, and primary completion was recorded as 2019-07-02. The sponsor was Promentis Pharmaceuticals, Inc. The brief summary says participants voluntarily abstained from cigarettes and that the study explored safety, tolerability, and activity when SXC-2023 or placebo was dosed for 5 days.

A crossover framework can allow treatment-period observations from the same participant to contribute to comparisons, but the registry record does not specify the analysis used to account for within-participant correlation, treatment sequence, period, or carryover. Those details matter when interpreting a crossover study and cannot be inferred from the design label alone.

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Safety and Tolerability of SXC-2023., measured over Up to 5 days.

The primary endpoint is titled “Safety and Tolerability of SXC-2023.” It is recorded as a number of events, with a timeframe of up to 5 days. The endpoint description says it was assessed using the frequency of serious adverse events, adverse events leading to discontinuation, and adverse events judged to be related to study medication.

Safety and tolerability endpoints are used to describe undesirable events observed during treatment and to identify events that may warrant closer examination. The categories have distinct meanings: seriousness, discontinuation, and judged relationship to study medication are not interchangeable classifications. The endpoint description names all three, but the registry’s posted group summaries in this record report serious adverse events, other adverse events, and deaths. It does not provide separate counts for discontinuations or events judged related to study medication.

The timeframe is short: up to 5 days. Accordingly, the reported counts describe events recorded during the specified treatment exposure periods, rather than longer-term safety. The record does not provide event-level descriptions for the serious adverse event category; no serious adverse event terms are listed in the registry summary. Absence of listed terms should not be read as detail about events that were not reported.

As a general statistical point, event counts are descriptive. They indicate how many events or affected participants were recorded, but interpretation also depends on exposure, ascertainment, follow-up, and how the analysis handled repeated treatment periods. Those methodological details are not fully reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods determine how observations are turned into estimates and how uncertainty is represented. The registry record identifies a randomized, quadruple-masked crossover design, but it does not report a detailed statistical analysis plan. The discussion below explains general concepts relevant to that design and distinguishes them from methods explicitly documented in the record.

What does a crossover design imply?

In a crossover study, treatment sequence and treatment period can matter because the same participant may receive more than one treatment. A within-participant comparison can account for stable differences between participants, but it also requires appropriate handling of the repeated measurements. As a general matter, analyses may need to consider treatment, period, sequence, and possible carryover. The registry lists sequences and a 9 day washout, but it does not state whether or how any of those factors were included in the analysis.

The posted adverse-event summaries are organized by treatment exposure: 200 mg SXC-2023, 800 mg SXC-2023, and placebo. They report numbers at risk and numbers affected, rather than a participant-level crossover estimate. A simple comparison of those counts would not necessarily preserve the paired structure of the design. The record does not provide the individual-level data or a reported method for accounting for repeated exposure, so a paired treatment effect cannot be reconstructed from the group summaries.

What do counts convey?

Counts are a direct way to describe recorded events or affected participants. The registry’s adverse-event information distinguishes serious events, other events, and deaths. These categories should be read as recorded: “serious” is not synonymous with “related,” and “other” does not state whether an event was judged to be caused by treatment. The endpoint description includes discontinuation and relationship to study medication, but separate summaries for those categories are not reported in the registry record.

As a general statistical point, counts alone offer limited information about precision. A count can be affected by the amount of exposure and by whether participants contribute observations during more than one treatment period. Rates or model-based estimates can sometimes address exposure or repeated observations, but the registry record does not report such estimates for these outcomes. No new rates or comparisons are calculated from the posted counts.

Why might event data require special methods?

General methods for event counts may assume that the variance is similar to the mean. When counts vary more than such a model expects, over-dispersion can make standard errors too small if it is ignored. Alternative approaches can allow additional variability. Whether over-dispersion is relevant depends on the outcome and data structure; the registry record does not report a count model or an assessment of over-dispersion for these safety summaries.

For binary outcomes such as whether an individual experienced an event, an analysis might estimate a risk or a treatment contrast. For event totals, an analysis might model counts with an exposure term. These are general possibilities, not methods documented for this trial. The record’s endpoint is described as a number of events, while the adverse-event summaries give affected counts and denominators. It does not explain the exact unit used in each summary or state a model connecting them.

How should uncertainty be interpreted?

As a general statistical concept, a confidence interval expresses uncertainty around an estimate under the chosen model and assumptions. It is not a guarantee that the true value lies within the interval. For a treatment contrast, the interval would help show which differences remain compatible with the observations and how precise the estimate is. The registry record does not report confidence intervals for the safety counts, so their precision as comparative treatment effects is not established in this record.

A p-value, when reported, quantifies how unusual data at least as extreme as those observed would be under a specified null model. It does not measure the probability that the null hypothesis is true, nor does it describe clinical importance. No p-value for a single safety comparison is reported in the registry record. The fact that 3 analyses are listed does not reveal which tests were conducted, their hypotheses, or their results.

What does the planning illustration mean?

Sample-size illustrations are planning calculations under stated assumptions. The stated assumptions for any illustration are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. For non-time-to-event outcomes, such illustrations are described as participants per arm; time-to-event illustrations refer to total events. They are not observed power, do not describe the trial’s actual allocation, and do not establish the study’s original design rationale. The registry record does not report a trial sample-size justification.

As a general point, an illustration based on an observed effect is conditional on that observed effect and on the calculation assumptions. It should not be interpreted as evidence that a study had adequate power, particularly when the trial’s own design assumptions and analysis plan are not reported. The record does not give a single primary treatment contrast or the full inputs needed to evaluate a specific planning calculation for this safety endpoint.

What is not documented?

The registry record does not report the statistical model, the approach to multiplicity, the handling of missing observations, the analysis populations, or a detailed method for accounting for crossover periods. It also does not report whether interim analyses were planned or conducted. These omissions limit what can be said about how the posted counts were analyzed. General statistical principles can explain why these choices matter, but they cannot fill in unreported trial methods.

10. Multiplicity, Missing Data and Analysis Populations

The endpoint description includes several safety categories, and the study record lists 8 outcome measures and 3 analyses. The primary outcome has several categories or time points and is not reduced to one comparison in the available summary. The registry record does not state which outcomes were designated for formal testing, how many hypotheses were tested, or whether any adjustment for multiple comparisons was planned or used.

As a general statistical point, examining multiple outcomes or treatment contrasts can increase the chance of a false-positive finding if each is tested without accounting for the broader set of tests. Methods to address multiplicity depend on the aims and analysis plan. Because the plan and test results are not reported, no conclusion about multiplicity control is possible.

Missing-data methods and analysis populations are also not reported in the registry record. The enrollment was 34, while treatment-period summaries list 16 at risk for each SXC-2023 dose and 31 for placebo. The record does not explain participant flow, missing observations, exclusions, or whether the same participants contributed to more than one treatment group. It therefore cannot establish whether the denominators represent all randomized participants, all treated participants, or another analysis population.

For crossover data, missingness in one period can affect the availability of within-participant comparisons. As a general matter, the consequences depend on why observations are missing and on the analysis method. The record does not describe missingness patterns or the method used to address them. These gaps make the adverse-event counts suitable for descriptive reading, but they do not support reconstructing a complete comparative analysis.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

During 200 mg SXC-2023 treatment, the registry reports 0 serious adverse events among 16 at risk; during 800 mg SXC-2023 treatment, it reports 0 among 16 at risk. During placebo treatment, it reports 0 among 31 at risk. The reported number of deaths is 0 for each treatment group. No serious adverse event terms are listed.

These figures describe what was recorded in the registry for the reported exposure groups. A zero count means no event in that category was reported for that group; it does not show that the true risk is zero. The denominators differ, and the crossover design means the treatment-period groups should not automatically be interpreted as independent sets of people.

The record also reports other adverse events: 5 affected during 200 mg SXC-2023 treatment, 3 during 800 mg SXC-2023 treatment, and 13 during placebo treatment. These counts do not establish whether events were related to study medication or led to discontinuation. Although those categories are part of the primary endpoint description, separate counts for them are not reported in the registry record. No inferential comparison or uncertainty interval is reported for these safety summaries.

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

The posted results describe adverse events recorded during short treatment periods in a randomized, quadruple-masked crossover study. They report no serious adverse events and no deaths in the 200 mg SXC-2023, 800 mg SXC-2023, or placebo treatment summaries. They also report other adverse events in each treatment group, with the counts and numbers at risk. These observations are a limited account of the safety data recorded during the specified periods.

They do not establish that one treatment has fewer adverse events than another. The registry does not report a single comparative estimate, its confidence interval, or a p-value for the safety outcome. The treatment-period denominators differ, and the summaries do not explain how the crossover structure was handled in analysis. A visual or arithmetic contrast between counts would not resolve those design and analysis issues.

The results also do not answer every component of the primary endpoint. The endpoint description includes adverse events leading to discontinuation and events judged related to study medication, but separate counts for those categories are not reported. The registry does not list serious-event terms, provide details about event timing or duration, or describe longer-term follow-up in the information.

As a general statistical point, absence of a recorded event in a study group is not proof that the event cannot occur. The extent of uncertainty depends on the number of observations, the amount of exposure, outcome ascertainment, and the analysis. Without reported uncertainty estimates and fuller analysis details, the precision of comparative safety effects cannot be determined from these counts alone.

The study is described as exploratory and its brief summary includes activity as an aim, but the safety summaries do not establish an effect on cognitive control, nicotine withdrawal, or smoking behavior. They should not be treated as evidence of efficacy or as a basis for medical decisions. The registry record supports a narrow descriptive interpretation of the reported adverse-event counts and leaves important comparative and longer-term questions unresolved.

13. Why This Trial Matters Statistically

This study is statistically notable because it combines a crossover design with safety outcomes recorded across multiple treatment periods. A crossover framework can be useful when participants receive more than one study treatment, but it raises analysis questions about within-participant dependence, period, sequence, and possible carryover. The registry reports randomized allocation, quadruple masking, and a 9 day washout, yet does not report how the statistical analysis addressed those features.

The record also illustrates the difference between an endpoint’s stated scope and the detail available in posted results. The primary endpoint description includes serious adverse events, events leading to discontinuation, and events judged related to medication. The available summaries report serious adverse events, other adverse events, and deaths, without separate discontinuation or related-event counts. That distinction matters because descriptive event categories do not all answer the same safety question.

Unequal numbers at risk across the treatment summaries and the crossover structure make raw counts difficult to interpret as direct treatment comparisons. The registry does not report a comparative estimate or uncertainty interval that accounts for these features. The reported zero serious adverse events in each group is a factual observation, but it is not a precise comparative estimate or evidence that underlying risks are identical.

Finally, the record lists multiple outcomes and analyses without a detailed statistical plan. For readers assessing clinical-trial evidence, transparent reporting of analysis populations, missing data, multiplicity, and model choices helps distinguish descriptive findings from confirmatory inference. Those details are not reported in the registry record, so the strongest statistical reading remains bounded to the posted counts and study design.

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 the number of participants assigned to each treatment sequence, the number completing each treatment period, or the participant flow underlying the adverse-event denominators. Although enrollment was 34, the summaries list 16 at risk during each SXC-2023 dose and 31 during placebo. The record does not explain whether participants contributed to multiple summaries or how the denominators were defined.

The primary endpoint description names serious adverse events, adverse events leading to discontinuation, and events judged related to study medication. Separate counts for discontinuations and related events are not reported. Serious-event terms are also not listed. The summaries therefore provide only part of the detail needed to characterize the endpoint as described.

The registry record does not report a treatment-effect estimate, confidence interval, p-value, detailed statistical plan, analysis populations, or approach to missing data and multiplicity. It does not explain whether the analyses accounted for repeated treatment periods, sequence, period effects, or carryover. These gaps prevent reconstruction of a comparative crossover analysis from the posted counts.

The exposure timeframe is up to 5 days, so these summaries do not describe longer-term event patterns. The record does not provide additional detail about event timing, duration, or severity for the other adverse events. It also does not supply detailed eligibility criteria or enough information to assess how broadly the results apply beyond the participants described as non-treatment-seeking adults with tobacco use disorder who voluntarily abstained from cigarettes.

Finally, the record describes the study as exploratory, and it does not reduce the primary outcome to one comparison. The safety counts should therefore be read as descriptive registry results rather than as a complete or definitive comparative safety analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Restoring Cognitive Control (ReCon) in Acute Nicotine Withdrawal — NCT03887429.
• Registry record last updated 2020-07-17; status last verified 2020-07.
• Results first posted 2020-07-17.
• 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

NCT03887429 is a completed phase 2 randomized, quadruple-masked crossover study titled “Restoring Cognitive Control (ReCon) in Acute Nicotine Withdrawal.” It enrolled 34 and was sponsored by Promentis Pharmaceuticals, Inc. The study started on 2019-03-04, with primary completion recorded as 2019-07-02.

The study compared once-daily SXC-2023 at 200 mg or 800 mg with placebo over 5 day treatment periods. The listed sequences included a 9 day washout between periods. The population is described as adults with tobacco use disorder who voluntarily abstained from cigarettes, and the official title describes non-treatment-seeking adults undergoing acute nicotine withdrawal.

The primary endpoint addressed safety and tolerability over up to 5 days, including serious adverse events, events leading to discontinuation, and events judged related to study medication. The registry reports no serious adverse events or deaths in the treatment-period groups. It also reports other adverse events, but does not provide separate discontinuation or related-event counts. The record does not report a single comparative safety estimate or a detailed statistical analysis plan.