This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Efficacy and Safety Study of ARC-4558 for Management of Pain Associated With Painful Diabetic Neuropathy (NCT00695565), a randomized phase 2 study. The primary outcome is Change From Baseline to Week 12 in the Average Daily Pain NPRS (Numeric Pain Rating Scale) Score; mLOCF Imputation.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00695565 |
| Phase | Phase 2 |
| Condition | Painful Diabetic Neuropathy |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 180 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Arcion Therapeutics Inc |
| Results posted | Yes |
2. Clinical Question
Population
People enrolled in a study of painful diabetic neuropathy, a condition associated with pain in the feet in this trial’s primary endpoint description. The registry record reports enrollment of 180, but does not give further eligibility details or a fuller description of the study population.
Intervention
Clonidine topical gel, also called ARC-4558, containing 0.1% clonidine hydrochloride.
Comparator
Placebo gel, described as vehicle without clonidine.
Primary question
How did the average daily pain score change from baseline to Week 12 in each randomized group? The registry record names this endpoint but does not report the group results or a between-group estimate.
The clinical question is framed around pain recorded by participants in their feet. Subjects rated their average pain over the past 24 hours at bedtime using a 0–10 Numeric Pain Rating Scale (NPRS). A score of 0 meant “no pain,” and a score of 10 meant “worst possible pain.” The primary comparison focuses on change from baseline to Week 12, with change defined as the Week 12 score minus the baseline score. On that scale of change, more negative values indicate more improvement.
The study also listed secondary questions about weekly average pain, worst daily pain, reductions in average pain, pain severity and interference, sleep, and depression scores. Those outcomes broaden the scope of the questions assessed, but the registry record does not report their results. The trial’s stated purpose was to determine whether ARC-4558 was effective in managing pain associated with painful diabetic neuropathy; the posted information does not establish an answer to that question.
3. Trial Design
This was a phase 2, randomized, double-blind, parallel-group study comparing clonidine topical gel with placebo gel. The registry record identifies Arcion Therapeutics Inc as the sponsor and lists enrollment of 180. The study is marked completed. Its start is listed as 2008-05, and primary completion is listed as 2009-12.
Randomization means that assignment to the study groups was determined by a chance-based process rather than solely by clinical choice. In general, random assignment can help balance measured and unmeasured participant characteristics across groups, although it does not guarantee that the groups will be identical. The record does not report the randomization method, any stratification factors, or details of how assignment was concealed.
Double masking means that the record identifies the study as masked at two levels, but does not specify which roles were masked or how masking was maintained. The parallel-group model means that the study compared groups assigned to different interventions rather than describing a crossover design. The record does not report treatment duration beyond the Week 12 endpoint timeframe, dosing instructions, or adherence information.
The placebo is described as vehicle without clonidine; the active gel is described as containing 0.1% clonidine hydrochloride. These descriptions clarify the intended contrast, but do not provide information about how closely the products matched in appearance or use. Details of eligibility criteria, participant characteristics, geographic locations, recruitment, and the protocol’s operational procedures are not reported in the registry record.
Although the record gives the enrollment figure, it does not report the planned sample-size justification or the assumptions used to choose that enrollment. The registry record also does not report the randomization ratio as a design detail, though the posted adverse-event groups each list 90 at risk. No inference about the original planning process should be drawn from those safety denominators.
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: Subjects were required to meet all eligibility criteria at both the Screening and Baseline visits. If a subject met the Screening criteria but not the Baseline criteria, the subject was not eligible for enrollment. Two subjects were randomized but were not treated because they were found ineligible. They are not counted in the 180 enrolled.
Overall Study
| Stage | Placebo Gel | Clonidine Topical Gel (ARC-4558) |
|---|---|---|
| STARTED | 90 | 90 |
| COMPLETED | 77 | 81 |
| NOT COMPLETED | 13 | 9 |
Reasons for not completing this period:
| Reason | Placebo Gel | Clonidine Topical Gel (ARC-4558) |
|---|---|---|
| Lost to Follow-up | 4 | 4 |
| Adverse Event | 3 | 1 |
| Protocol Violation | 3 | 1 |
| Withdrawal by Subject | 1 | 1 |
| Lack of Efficacy | 1 | 1 |
| Subject did not follow instructions | 1 | 1 |
Analysis population for the primary outcome, as defined in the registry: One treated subject had no recorded scores and could not be included. Imputation was mLOCF (modified Last Observation Carried Forward): LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication (in which case Baseline Observation Carried Forward (BOCF) was used).
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: ITT (Intent-to-Treat)
| Characteristic | Unit | Placebo Gel | Clonidine Topical Gel (ARC-4558) | Total |
|---|---|---|---|---|
| Participants analysed | 90 | 90 | 180 | |
| Age, Continuous | years | 57.6 (SD 9.5) | 59.4 (SD 9.9) | 58.5 (SD 9.7) |
| Sex: Female, Male: Female | Participants | 48 | 46 | 94 |
| Sex: Female, Male: Male | Participants | 42 | 44 | 86 |
| Region of Enrollment: United States | participants | 90 | 90 | 180 |
6. Primary Endpoint
The registry lists the primary outcome as Change From Baseline to Week 12 in the Average Daily Pain NPRS (Numeric Pain Rating Scale) Score; mLOCF Imputation, measured over Baseline (average of Days -7 to -1) and Week 12 (Average of Days 78 to 84).
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | units on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change from baseline to Week 12 in average daily pain on the Numeric Pain Rating Scale. Participants scored pain in their feet each day at bedtime, rating average pain over the past 24 hours. The recorded scale ran from 0, “no pain,” to 10, “worst possible pain.” Baseline is described as the average of Days -7 to -1, and the Week 12 measure as the average of Days 78 to 84.
The endpoint is expressed as Week 12 minus baseline. Therefore, a more negative change represents a greater reduction in the measured pain score. This direction is important: a negative change is not a worsening simply because it carries a minus sign. The endpoint is a continuous measure, and the record identifies its summary as a mean with standard deviation.
General statistical context: a continuous outcome retains information about the magnitude of scores and their changes, rather than reducing each participant’s response to a yes-or-no category. A group mean describes the average change, while the standard deviation describes the spread of individual changes around that average. Neither quantity alone shows how precisely the between-group contrast is estimated; that requires an uncertainty measure such as a confidence interval.
Using change in daily pain scores provides a defined way to compare pain ratings over the study period. The registry record does not include the baseline or Week 12 group means, the mean changes, a treatment contrast, or an uncertainty interval. Consequently, the size and precision of the primary endpoint result are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clinically interpretable primary outcome and gives its measurement schedule, scale, and direction. It does not, however, report the observed primary outcome values. No group mean change, between-group difference, confidence interval, or p-value is reported in the registry record. The available information therefore describes what was intended to be compared, but not the numerical result of that comparison.
The direction of the endpoint is specified: change equals the Week 12 score minus the baseline score, so more negative values indicate more improvement. That convention would help readers interpret a reported estimate, but it cannot establish which group had a more favorable observed change when the group results are absent. It also cannot establish whether any observed difference was large, small, or estimated precisely.
General statistical context: an estimated treatment contrast is more informative when accompanied by a confidence interval. The estimate describes the observed difference between groups under the chosen analysis, while the interval conveys uncertainty about that estimate. A p-value addresses compatibility with a specified null hypothesis under model assumptions; it does not measure the size or clinical importance of an effect. None of these primary comparison results is reported in the registry record.
The posted safety figures are separate from the primary efficacy endpoint. The record lists 3 serious adverse events among 90 at risk in each group. It lists other adverse events affecting 28 in the placebo group and 19 in the clonidine group, with 90 at risk in each. These are descriptive counts. Without further information about event definitions, timing, severity, and analysis, they do not establish why events occurred or whether the difference in counts reflects a treatment effect.
The record lists several serious-event terms, each with a stated frequency of 1.1%, but does not identify the treatment group for each term in the information available. Death counts are not reported in the registry record. No safety interpretation should extend beyond the categories and figures explicitly posted.
The trial is marked completed, but completion status does not substitute for outcome reporting. Likewise, enrollment and study design details cannot fill the gap in the missing efficacy estimates. The appropriate statistical conclusion is limited: the record describes a randomized comparison and its primary measurement, while the result of that comparison is not reported in the registry record.
9. Statistical Methods Explained
General statistical context: the methods used to analyze a clinical trial determine how observed measurements are summarized and compared. Interpretation depends not only on the outcome definition, but also on the analysis population, handling of missing observations, model assumptions, and the uncertainty reported around estimates. The registry record provides some endpoint and imputation details, but not a full statistical analysis plan or the primary comparison results.
What does a mean change represent?
The primary outcome is continuous and summarized using a mean and standard deviation. A mean change represents the average of participants’ changes between the defined baseline and Week 12 periods. The standard deviation describes how dispersed those individual changes are. A standard deviation is not the same as a confidence interval: it describes variation among observations, whereas a confidence interval describes uncertainty around an estimated quantity.
For a randomized comparison, a key result would ordinarily describe the contrast in mean change between the clonidine and placebo groups, with an uncertainty interval and an appropriate statistical test if reported. The registry record does not report that contrast, its confidence interval, or its p-value. It also does not report whether the primary analysis adjusted for baseline values or other covariates.
How should the scale direction be read?
The endpoint is calculated as Week 12 minus baseline. A score that falls over time therefore produces a negative change, and a more negative change represents more improvement on the stated scale. This is a matter of interpreting the defined outcome, not a claim that either group actually improved. Because no group estimates are reported, the direction convention alone cannot answer the treatment comparison.
What does mLOCF mean in this record?
The primary endpoint description names modified Last Observation Carried Forward (mLOCF) imputation. It describes LOCF for subjects who discontinued early, except when withdrawal was associated with an adverse event potentially related to study medication. The description is cut off after beginning to state what happens in that exception, so the handling of those observations is not fully reported in the registry record.
General statistical context: LOCF carries a participant’s last observed value forward to a later time point when the later value is missing. This can retain observations in an analysis, but it treats the carried-forward value as if it represented the later time point. That assumption may not reflect the participant’s actual unobserved outcome. A modified rule can apply a different approach in specified circumstances; readers need the complete rule to assess its implications. The registry record does not provide the full mLOCF procedure, sensitivity analyses, or a comparison with alternative missing-data methods.
What do the planning assumptions mean?
The registry record describes a sample-size illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the trial was designed using those assumptions. The registry record does not report the trial’s own sample-size justification or the numerical planning outputs in the information available.
General statistical context: a planning calculation estimates the sample size that would be needed under chosen assumptions about the target effect, variability, significance level, and desired power. Changing those assumptions changes the resulting planning estimate. Calculations based on an effect observed in the same study are especially distinct from a prespecified design justification: they describe hypothetical planning scenarios and do not change the precision of the completed trial’s actual estimate.
Why do uncertainty and model assumptions matter?
A confidence interval is a range of values compatible with the data under the analysis method and its assumptions. Wider intervals indicate less precision than narrower intervals, all else equal. A model may also rely on assumptions about the distribution of outcomes or the relationship between measurements. The registry record identifies a mean and standard deviation for the primary endpoint, but does not report the model used for the group comparison or diagnostics of its assumptions.
General statistical context: when data are more variable than a model assumes, uncertainty can be understated if that extra variability is ignored. This issue is often described as over-dispersion in settings where a model expects less variability than the observations display. The record does not identify an over-dispersion analysis or a particular model for the primary continuous endpoint, so this general issue should not be mistaken for a reported feature of this trial.
The record lists 14 outcome measures and 2 analyses, but does not report how the analyses relate to the outcomes or describe a complete testing plan. The particular statistical methods used, confidence intervals, p-values, covariate adjustments, and sensitivity analyses are not reported in the registry record. Those omissions limit assessment of both the results and the robustness of any conclusions.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 14 outcome measures, including the primary endpoint and secondary outcomes covering pain at other time points, pain reductions, pain severity and interference, sleep, and depression scores. It also lists 2 analyses. The relationship between those analyses and the full set of outcome measures is not reported in the registry record.
General statistical context: when investigators test multiple outcomes or multiple comparisons, the chance of at least one apparently unusual result can increase if every test is interpreted separately at the same threshold. A prespecified testing hierarchy, adjustment method, or clear distinction between primary and exploratory analyses can help readers interpret a collection of results. The registry record does not report a multiplicity strategy, testing hierarchy, or adjustment procedure. No claim about statistical significance across the outcomes can be made from the outcome list alone.
For missing data, the primary endpoint description states that mLOCF was used. It specifies LOCF for early discontinuation except when withdrawal was associated with an adverse event potentially related to study medication, but the description of that exception is incomplete. The full missing-data rule and any sensitivity analyses are not reported in the registry record. One treated subject had no recorded scores and could not be included; the record does not identify that subject’s group.
The analysis population is not fully characterized. The registry record does not report whether the primary analysis used an intention-to-treat population, a per-protocol population, or another defined set, nor does it give a complete account of exclusions. The incomplete population description and missing analysis details make it difficult to assess how the planned analysis was implemented.
These limits do not establish that the analysis was inappropriate. They mean that the registry record does not give enough detail to evaluate multiplicity control, the complete handling of missing observations, or the population used for the primary comparison.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Placebo Gel | 3 | 90 | 3.3% |
| Clonidine Topical Gel (ARC-4558) | 3 | 90 | 3.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Placebo Gel | 28 of 90 |
| Clonidine Topical Gel (ARC-4558) | 19 of 90 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo Gel | Clonidine Topical Gel (ARC-4558) |
|---|---|---|---|
| Acute Coronary Syndrome | Cardiac disorders | 0 of 90 | 1 of 90 |
| Atrial Fibrillation | Cardiac disorders | 0 of 90 | 1 of 90 |
| Abdominal Pain Upper | Gastrointestinal disorders | 1 of 90 | 0 of 90 |
| Pancreatitis Acute | Gastrointestinal disorders | 1 of 90 | 0 of 90 |
| Chest Pain | General disorders | 1 of 90 | 0 of 90 |
| Abscess Neck | Infections and infestations | 0 of 90 | 1 of 90 |
| Pneumonia | Infections and infestations | 0 of 90 | 1 of 90 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo Gel | Clonidine Topical Gel (ARC-4558) |
|---|---|---|---|
| Headache | Nervous system disorders | 10 of 90 | 6 of 90 |
| Pain in Extremity | Musculoskeletal and connective tissue disorders | 7 of 90 | 3 of 90 |
| Nasopharyngitis | Infections and infestations | 4 of 90 | 5 of 90 |
| Pain | General disorders | 6 of 90 | 0 of 90 |
| Toothache | Gastrointestinal disorders | 1 of 90 | 5 of 90 |
Serious events with the highest arm-level rate: acute coronary syndrome (1.1%), atrial fibrillation (1.1%), abdominal pain upper (1.1%), pancreatitis acute (1.1%), chest pain (1.1%).
The registry record lists serious adverse events for each group as 3 affected among 90 at risk. For other adverse events, it lists 28 affected in the placebo group and 19 in the clonidine group, with 90 at risk in each group. These are the posted counts and denominators; they should be read as safety summaries rather than as results for the primary pain endpoint.
The record also lists Acute Coronary Syndrome, Atrial Fibrillation, Abdominal Pain Upper, Pancreatitis Acute, Chest Pain, and Abscess Neck among the serious-event terms, each with a frequency of 1.1%. The treatment group corresponding to each listed term is not reported in the registry record. Death counts are not reported in the registry record.
General statistical context: adverse-event counts do not by themselves show whether an event was caused by a study treatment. Interpretation can depend on how events were defined, whether repeated events in one person were counted separately, when events occurred, and how severity and relatedness were assessed. Those details are not reported in the registry record. The figures also do not show the uncertainty around a comparison between groups. They should therefore be treated as descriptive, not as proof of a safety difference or of no difference.
12. What the Result Does, and Does Not, Mean
The study record establishes that a randomized, double-blind, parallel-group comparison of clonidine topical gel and placebo gel was conducted for painful diabetic neuropathy. It defines a primary endpoint based on daily foot-pain ratings and specifies how the change score is oriented. It also gives limited information about missing scores and posts adverse-event counts.
Those design details do not reveal the trial’s efficacy result. The registry record does not report the primary group means, the estimated difference between groups, a confidence interval, or a p-value. It is therefore not possible to state how the observed pain scores changed in either group, how the groups compared, or how precise any comparison was. The study’s stated purpose is not itself a finding.
General statistical context: a result can be statistically compatible with a range of effect sizes, and statistical significance alone would not determine whether a difference is important to participants. Assessment ordinarily considers the estimated magnitude, its precision, the outcome’s interpretation, and the analysis’s limitations. In this record, the necessary primary estimates are not reported, so those considerations cannot be applied to the treatment comparison.
The safety counts describe the posted adverse-event categories, but do not establish causation. They do not replace a detailed review of event definitions, timing, severity, and participant-level patterns, which are not reported in the registry record. No conclusions about the overall balance of benefits and harms can be drawn from the available information alone.
The record’s completed status and enrollment figure provide context about the study, but do not address the missing results. The most defensible reading is narrow: the registry record documents the question and some design and safety details, while the primary outcome findings and key statistical details are not reported in the registry record.
13. Why This Trial Matters Statistically
This trial is statistically notable as a randomized, double-blind, parallel-group comparison with a defined continuous primary endpoint. The endpoint uses repeated daily pain ratings to form baseline and Week 12 averages, then expresses change as Week 12 minus baseline. Stating that more negative values indicate more improvement makes the direction of the intended measure explicit and helps prevent sign errors when reading a reported estimate.
The record also illustrates why outcome definitions and results need to be read together. Knowing the scale, timing, and direction tells readers what a result would represent, but cannot substitute for the group estimates or their uncertainty. The primary result, its precision, and the analysis method are not reported in the registry record. Consequently, the statistical question that motivated the comparison remains unanswered by the posted information.
General statistical context: randomized assignment can support a fair comparison, but interpretation still depends on follow-up, missing-data handling, analysis choices, and transparent reporting. The named mLOCF approach is only partly described, and the record does not report a full analysis plan or multiplicity strategy. These details matter because they shape how observed measurements become estimates and how uncertainty is assessed.
The posted safety counts further demonstrate the distinction between descriptive figures and causal conclusions. Counts can summarize events recorded in each group, but they do not by themselves explain why those events occurred or quantify uncertainty in a treatment comparison. Overall, the record is useful for understanding the trial’s design and intended measurement, while its missing efficacy and methodological details place a clear limit on statistical interpretation.
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 important trial-specific limitation in the registry record is the absence of primary outcome results. Although the endpoint, scale, time points, summary type, and direction are described, no group changes or between-group estimate are reported. Confidence intervals and p-values are also not reported in the registry record, leaving both the size and precision of the primary comparison unknown.
The primary endpoint’s mLOCF description is incomplete. It describes LOCF for early discontinuation, with an exception for withdrawal associated with a potentially related adverse event, but the text does not finish specifying how that exception was handled. The record notes that one treated subject had no recorded scores and could not be included, without identifying the group or fully defining the analysis population.
Other trial details that would help assess applicability and analysis are not reported in the registry record, including eligibility criteria, baseline participant characteristics, the statistical model for the primary comparison, the randomization procedure, and a complete analysis plan. The relationship between the 2 analyses and the 14 outcome measures is not described. A multiplicity strategy and missing-data sensitivity analyses are not reported.
Safety information is also limited. The record posts serious and other adverse-event counts and lists serious-event terms, but does not assign the listed terms to a group in the information available. Death counts are not reported in the registry record. Further detail about event definitions, timing, severity, and relatedness is not reported.
These are limitations of what can be evaluated from the registry record. They do not establish that the trial failed to collect the information or that any particular analysis was invalid; the relevant details are simply not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Efficacy and Safety Study of ARC-4558 for Management of Pain Associated With Painful Diabetic Neuropathy — NCT00695565.
- Registry record last updated 2016-11-08; status last verified 2016-09.
- Results first posted 2016-11-08.
- 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.
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18. Record Summary
The record describes a completed phase 2 randomized, double-blind, parallel-group study sponsored by Arcion Therapeutics Inc. It compares placebo gel, described as vehicle without clonidine, with clonidine topical gel containing 0.1% clonidine hydrochloride. Enrollment is listed as 180; the start is 2008-05 and primary completion is 2009-12.
The primary endpoint is change from baseline to Week 12 in average daily foot-pain NPRS score, with more negative changes indicating more improvement. The endpoint description names mLOCF imputation but does not fully describe its exception rule. The primary outcome estimates and the statistical comparison are not reported in the registry record.
The record lists 14 outcome measures and 2 analyses. Safety summaries include 3 serious adverse events among 90 at risk in each group, and other adverse events affecting 28 in the placebo group and 19 in the clonidine group, with 90 at risk in each. Death counts are not reported in the registry record.