S-Adenosyl Methionine (SAMe) to Treat Patients With Chronic Hepatitis C: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for S-Adenosyl Methionine (SAMe) to Treat Patients With Chronic Hepatitis C (NCT00475176), a na phase 2 study. The primary outcome is Improvement in Viral Kinetics During the First 2 Weeks of Therapy.

2. Clinical Question

3. Trial Design

This completed phase 2 study enrolled 24 participants and used a single-group model. Allocation is recorded as not applicable, and masking as none. These features mean the study was not designed as a blinded, randomized comparison of separate treatment groups. Its primary endpoint instead describes a comparison of viral-kinetic slopes between a first and second course. The registry does not fully specify the operational relationship between those courses and the treatment sequence, so that comparison should not be treated as a standard parallel-group contrast.

The planned sequence began with peginterferon and ribavirin for 2 weeks, followed by a 4-week washout period without medication, then SAMe for 2 weeks. Participants subsequently received peginterferon, ribavirin, and SAMe together for 12-48 weeks, depending on response to treatment. The registry describes clinic visits and blood tests to monitor symptoms, drug side effects, HCV levels, liver enzyme levels, and immune responses. It does not give a complete account of how these measurements were scheduled for the primary kinetic analysis.

The record identifies chronic hepatitis C as the condition and describes potential eligibility for adults who had not responded successfully to prior interferon and ribavirin or peginterferon and ribavirin treatment. Enrollment was 24. The start and primary completion dates are recorded as 2007-05 and 2011-05, respectively. The sponsor is the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

The registry does not report a sample-size justification or a detailed statistical analysis plan. It lists zero analyses and does not give a primary endpoint estimate, uncertainty interval, or test result. Thus, the design and endpoint can be described, but the registry record does not support an assessment of the magnitude or precision of the primary finding.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Of 24 patients enrolled, 3 patients completed first course only due to adverse effects or personal reason. A fourth patient completed both courses but missed blood draws in both courses, precluding calculation of accurate first- and second-phase kinetic parameters. These 4 patient were excluded from 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.

6. Primary Endpoint

The registry lists the primary outcome as Improvement in Viral Kinetics During the First 2 Weeks of Therapy, measured over Days 7 to 14 of therapy.

The primary endpoint is titled “Improvement in Viral Kinetics During the First 2 Weeks of Therapy.” Its description focuses on whether the slope of HCV RNA decline in a second course improved compared with the slope in a first course, during days 7 to 14 of therapy. A slope describes the direction and rate of change over time; comparing slopes can therefore address whether the pattern of viral-level change differs between treatment periods, rather than simply comparing one measurement at a single time.

Serial viral measurements are relevant to this question because a change over time is needed to estimate a slope. The registry’s description of clinic visits and blood tests establishes that blood testing was part of participant monitoring, but the exact measurement schedule used to derive the primary endpoint is not reported. Nor does the record specify the threshold or rule used to classify an endpoint as an “improvement.”

There is an important distinction between the endpoint’s narrative description and its result metadata: the record describes a comparison of slopes but classifies the measure as a number of participants. Without a definition of how slope changes were converted into participant counts, the endpoint’s precise statistical form is unclear. The record also does not report the resulting count or estimate, so the direction and size of any observed difference cannot be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint concerns change in viral kinetics over time. In general, a kinetic slope summarizes how a measured quantity changes across a period of observation. Comparing two slopes asks whether the pattern of change differs between periods. Such an analysis depends on repeated measurements, a defined time origin, and a specified method for estimating each slope. The registry record names days 7 to 14 of therapy and describes a first-versus-second-course comparison, but it does not report the detailed calculation method or how the two courses were mapped to the treatment sequence.

What would an effect estimate describe?

In general, an effect estimate would summarize the size and direction of the endpoint contrast under the chosen definition. For a slope comparison, the estimate would need to state which course is subtracted from which, the units used, and whether it represents an average across participants or a participant-level classification. The registry describes “improvement” and labels the measure as a number of participants, but does not report a threshold for classifying improvement or an estimate. These details are needed to interpret the endpoint consistently.

A confidence interval, in general, describes a range of values compatible with the data and the statistical model under a specified confidence procedure. Its width reflects precision: narrower intervals indicate more precise estimates, while wider intervals indicate less precision. No confidence interval is reported for the primary endpoint in the registry record. Without an estimate and interval, readers cannot assess the plausible range of the primary contrast from this record.

What can a significance test establish?

In general, a significance test evaluates how compatible data are with a specified null hypothesis, conditional on the model and assumptions used. A p-value is not the probability that the null hypothesis is true, and it does not measure clinical importance. The registry record reports no primary p-value or analysis. No significance conclusion can therefore be made from the endpoint description or from enrollment alone.

The record lists zero analyses. It does not describe the statistical model, covariate adjustment, handling of repeated measures, or any assumptions used to estimate viral-kinetic slopes. These omissions matter because repeated measurements from one participant are related, and the way that relationship is represented can affect standard errors and uncertainty intervals. This is a general statistical issue; the record does not establish which approach was used in this study.

How should the planning illustration be understood?

A planning illustration based on an observed effect is different from the trial’s original design justification and from an analysis of observed outcomes. The illustration’s stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. Those assumptions do not describe the registered single-group design, which has no two-arm allocation. Any figures calculated under those assumptions are hypothetical planning values, not observed power and not evidence that the study had a particular probability of detecting an effect. The trial’s own sample-size justification is not reported in the registry record.

More generally, power is a design-stage probability calculated under assumptions about an effect, variability, sample size, and analysis. It is not a property that can be recovered from an observed p-value after a study. When planning values are based on an observed effect, they depend on that estimate and can be especially uncertain when the estimate itself is imprecise. They should be read as illustrations rather than as a measure of the strength of evidence in the completed study.

Why do endpoint definitions and data structure matter?

The endpoint narrative describes a comparison of slopes, while the result metadata classify the endpoint as a participant count. A participant-count outcome would ordinarily require a rule assigning each person to a category, whereas a slope is a quantitative summary of change. This general distinction matters because different outcome forms call for different summaries and models. The record does not state whether slope changes were converted into a binary participant outcome, nor does it define such a rule. The statistical interpretation therefore cannot be settled from the registry description alone.

Over-dispersion is a general concern for count data when observed variation exceeds what a simple count model assumes. It can lead to understated uncertainty if ignored. The primary outcome is described in inconsistent terms, and the record gives no model details, so there is no basis to say whether over-dispersion was relevant or how it was handled. Likewise, repeated-measure correlation and missing blood draws could influence an analysis of slopes, but the registry does not describe any adjustments or sensitivity analyses.

These statistical concepts explain what information would be needed to interpret a kinetic endpoint; they do not establish the method used by the investigators. The registry record does not report a full analysis plan, numerical outcome results, or uncertainty estimates. Accordingly, the design assumptions, endpoint definition, and result should not be reconstructed by inference.

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("Hepatitis C Treated With Peginterferon and Ribavir")
n      <- c(20)
events <- c(14)
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  Hepatitis C Treated With Peginterferon and Ribavir  20  14  70.0  45.7  88.1  48.1  85.5  47.8  85.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and a secondary outcome covering early virological response and sustained virological response. It does not report how many statistical tests were planned, whether any hierarchy among outcomes was specified, or whether an adjustment for multiple comparisons was planned. Multiplicity is a general issue when several outcomes or analyses are tested: interpreting each test separately can increase the chance of at least one apparently unusual result. No conclusion about the study’s multiplicity control can be drawn from the record.

Missing measurements are directly relevant to the primary endpoint description. Of 24 enrolled participants, 3 completed the first course only because of adverse effects or personal reason. A fourth completed both courses but missed blood draws in both, precluding calculation of accurate first- and second-phase kinetic parameters. The registry text says these 4 participants were excluded, but the statement is incomplete and does not identify precisely which analysis or population they were excluded from. The handling of other missing data is not reported.

The record does not describe imputation, a missing-data model, sensitivity analyses, or an analysis population definition. In general, missingness can affect an estimate when the availability of measurements is related to participant characteristics or outcomes. The stated reasons for the three first-course-only completions and the missed blood draws for the fourth participant make the missingness relevant to interpretation, but the record does not provide enough information to determine its effect.

No analysis population such as an intention-to-treat or per-protocol population is defined in the registry record. The number enrolled should therefore not be assumed to equal the number included in the primary analysis.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

Most frequent non-serious adverse event terms

The registry records one adverse-event group titled “Hepatitis C Treated With Peginterferon and Ribavirin.” It lists 24 participants at risk for serious events and zero affected by a serious event. For other adverse events, it lists 24 at risk and one affected. It gives no serious adverse-event terms. These are counts for the recorded group, not a comparison between treatment groups, and the single-group design offers no concurrent randomized safety comparator.

The death field is null. That should be read as no numerical death count reported in that field, not as a reported count of zero deaths. The registry does not provide further details about the one other event, its seriousness, timing, or relationship to treatment. It also does not clarify how the adverse-event grouping relates to every stage of the treatment sequence.

Counts alone do not describe event severity, duration, or context. They also do not establish that an event was caused by a particular intervention. The posted figures are limited safety information and should not be interpreted as a comparative measure of risk or as a complete account of all events during the study.

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

The record establishes that a phase 2, single-group study of SAMe with peginterferon and ribavirin was completed, with 24 participants enrolled. It describes an intended primary comparison of HCV RNA decline slopes between a second and first course during days 7 to 14 of therapy. It also lists secondary outcomes related to viral response. These registry entries show what question the study set out to examine, but they do not reveal the primary result.

The registry does not report a numerical estimate, confidence interval, p-value, or analysis for the primary outcome. It does not report numerical findings for the listed secondary outcomes either. Therefore, the registry record cannot establish whether the slope comparison favored one course, how large any difference was, or how precisely it was estimated. Absence of a posted result is not the same as evidence of no effect.

The design also does not support a randomized between-group treatment comparison: it is recorded as single-group with no allocation and no masking. A within-participant course comparison may address a different question from a comparison with a separate control group. Without a clear description of the course definitions and analysis, the primary contrast cannot be interpreted as a direct estimate of a treatment effect relative to an untreated or alternative-treatment group.

Likewise, the safety counts describe the registry’s recorded group but do not establish comparative safety. The serious-event count is zero, the other-event count is one, and the death count is not numerically reported. The record does not provide event details or a control group for comparison.

The most defensible reading is therefore limited: the registry describes the intervention sequence, enrollment, outcome questions, and some adverse-event counts, but leaves the efficacy analyses and key statistical details unreported. It does not warrant a claim that SAMe does or does not change viral kinetics or that the treatment combination is effective or ineffective.

14. Why This Trial Matters Statistically

This trial is statistically notable for posing a kinetic question within a single-group treatment sequence. Rather than defining its primary question as a simple comparison of final viral measurements, the registry describes a comparison of HCV RNA decline slopes across treatment courses. That framing draws attention to the timing and pattern of response, and to the need for repeated measurements and a clear definition of each course.

The record also illustrates why an endpoint must be operationally defined before its result can be interpreted. Its prose describes slopes, while its result metadata describe a number of participants. Without a stated threshold or calculation rule, the exact outcome form is ambiguous. This is not merely a wording issue: a quantitative slope and a participant count have different statistical interpretations and generally require different summaries.

Incomplete measurement is another important feature. Three participants completed only the first course for reasons recorded as adverse effects or personal reason, and a fourth missed blood draws in both courses. Since the endpoint relies on kinetic parameters, these circumstances matter to the analysis population and to the interpretation of missing data. The record does not explain the final handling of those participants.

Finally, a completed study record can describe a question without reporting the analysis needed to answer it. Here, the absence of a primary estimate, uncertainty interval, and test result means the statistical evidence cannot be evaluated from the registry entry. This distinction between study design and posted results is central to responsible interpretation.

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 registry record does not report a primary result or a statistical analysis, despite describing the primary endpoint and listing the study as completed. No estimate, uncertainty interval, or test result is available for the viral-kinetics comparison. The secondary outcome descriptions also lack numerical results. This prevents assessment of the direction, size, and precision of the findings.

The endpoint definition is incomplete. The narrative describes improvement in slopes of HCV RNA decline, but the result metadata classify the measure as a number of participants. No threshold for improvement, slope calculation method, or detailed course mapping is reported. The primary endpoint population description ends after stating that four participants were excluded, without specifying the analysis from which they were excluded.

The single-group model and absence of masking limit the kinds of comparisons described by the design. There is no randomized parallel control group in the record. The primary within-course comparison is not fully defined, and the registry does not report how period effects or other potential influences on changes between courses were addressed.

Additional details are not reported in the registry record, including a sample-size justification, a full statistical analysis plan, analysis populations, missing-data methods, multiplicity procedures, and sensitivity analyses. The adverse-event information is also sparse: the record lists counts but no serious-event terms, details for the other event, or numerical death count. These limitations restrict interpretation of both efficacy and safety, without establishing that analyses or information were absent outside the registry entry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: S-Adenosyl Methionine (SAMe) to Treat Patients With Chronic Hepatitis C — NCT00475176.
• Registry record last updated 2013-07-05; status last verified 2013-05.
• Results first posted 2013-07-05.
• 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.

19. Record Summary

The record describes NCT00475176, a completed phase 2, single-group study of SAMe with peginterferon and ribavirin for chronic hepatitis C. It records 24 enrolled participants and describes a primary comparison of viral-kinetic slopes in a second course versus a first course during days 7 to 14 of therapy. The listed secondary outcomes concern a 2-log decline in HCV RNA by Week 12 and sustained eradication of HCV RNA.

The treatment sequence included peginterferon and ribavirin, a washout period, SAMe, and then all three interventions together. The primary endpoint result and statistical analysis are not reported in the registry record. Safety entries list zero serious events and one other event among 24 at risk; the death field has no numerical count. The record also notes incomplete treatment or blood-draw data for four participants, but does not fully specify their analysis disposition.