Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH (NCT01672879), a randomized phase 2 study. The primary outcome is Change From Baseline in Hepatic Venous Pressure Gradient (HVPG).

2. Clinical Question

3. Trial Design

This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial of SIM in people with compensated cirrhosis secondary to NASH. The registry lists an enrollment of 259 and identifies Gilead Sciences as the sponsor. The study status is terminated. The start date is 2012-10-29 and the primary completion date is 2016-09-26; the reason for termination is not reported in the registry record.

The randomized phase included SIM 200 mg, SIM 700 mg, and matching placebo. The assigned infusions were scheduled every 2 weeks for up to 240 weeks. The registry also describes an optional open-label phase in which participants could receive SIM 700 mg every 2 weeks for up to an additional 240 weeks. The record does not explain who could enter the optional phase or how participation in it was determined.

The primary outcome was change from baseline in HVPG from baseline to Week 96. The analysis population is described as participants in the Full Analysis Set with available data. The record does not state how many participants contributed data to this endpoint, whether all randomized participants were included in the Full Analysis Set, or how missing endpoint values were handled.

Randomization and masking describe features of the trial design, not the results of the treatment comparisons. The record identifies quadruple masking but does not specify which roles were masked. It also does not report the randomization method, allocation concealment details, or the statistical methods used for the sponsor-reported LSMeans. Those details should not 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.

Before assignment: 453 participants were screened.

Blinded Phase (Up to 240 Weeks)

Reasons for not completing this period:

Open-Label Phase (Up to 240 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the Full Analysis Set with available data were analyzed.

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 Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Hepatic Venous Pressure Gradient (HVPG), measured over Baseline to Week 96.

HVPG is a pressure-gradient measure, and the primary endpoint records its change from baseline to Week 96 in mmHg. Because the endpoint is a continuous measurement, the registry reports group means and standard deviations. A mean change describes the average direction and magnitude of change within a group; the between-group comparison asks how the average change differs between a SIM group and placebo.

In general, a continuous endpoint can retain more information about the range of observed measurements than an outcome reduced to categories. Its interpretation still depends on how it was measured, which participants had available data, and the analysis model. Those details matter because a mean can be influenced by the distribution of values and by missing observations. The registry identifies the endpoint and the Full Analysis Set with available data, but it does not report measurement procedures, missing-data methods, or the analysis model.

The registry names change in HVPG as the primary outcome, but it does not provide a clinical threshold for a meaningful change. The numerical results therefore describe the measured endpoint and its statistical uncertainty. They do not, on their own, establish what size of change would be clinically important.

7. Results Posted in the Registry

• SIM 200 mg: mean -0.10 versus -0.10 on control; difference 0.00 (95% CI -1.33 to 1.33), standardized effect d = 0.00; z-test p = 1.000.
• SIM 700 mg: mean 0.00 versus -0.10 on control; difference 0.10 (95% CI -1.30 to 1.50), standardized effect d = 0.02; z-test p = 0.888.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a group mean describe?

For a continuous outcome, the mean is the arithmetic average of the observed measurements in a group. Here, the outcome is change in HVPG from baseline to Week 96, in mmHg. A negative group mean indicates an average decrease in the measured value; a positive mean indicates an average increase. The means reported for SIM 200 mg and placebo are both -0.1, while the mean for SIM 700 mg is 0.0. These are group summaries, not individual participant trajectories.

The standard deviations reported for the groups describe variability among measurements around each group mean. The registry lists standard deviations of 3.76 for SIM 200 mg, 4.23 for SIM 700 mg, and 4.01 for placebo. A standard deviation is not the uncertainty of the group mean: it describes participant-level spread, whereas uncertainty in a mean also depends on the amount of data and the analysis. The reported analysis counts for the primary endpoint are 63, 66, and 68 for the SIM 200 mg, SIM 700 mg, and placebo groups, respectively.

What is a mean difference?

A between-group mean difference compares the average outcome in one group with the average outcome in another. The recalculated comparisons use SIM minus placebo, so a positive estimate means the SIM group mean is numerically higher than the placebo group mean, and a negative estimate would mean it is lower. The recalculated estimate is 0.0 for SIM 200 mg versus placebo and 0.1 for SIM 700 mg versus placebo.

These are unadjusted recalculations from the posted summary statistics. They are not adjusted for other variables and should not be mistaken for a reproduction of the sponsor’s model. In general, adjustment can change an estimate when the analysis accounts for covariates or uses a different model. The registry reports sponsor comparisons as differences in LSMeans, but does not report the method used to estimate them. Therefore, the two types of estimates should be described separately rather than treated as identical.

How should standard errors and intervals be understood?

In general, a standard error describes the sampling variability of an estimated quantity. It is not the same as the standard deviation of individual observations. The recalculation uses the group standard deviations and analysis counts to estimate uncertainty in the mean differences. The posted recalculation reports pooled standard deviations of 3.892 for the SIM 200 mg comparison and 4.12 for the SIM 700 mg comparison.

A confidence interval gives a range of values compatible with the data under the statistical method and its assumptions. It reflects both the estimated difference and its uncertainty. The recalculated interval for SIM 200 mg extends from -1.331 to 1.331, while the interval for SIM 700 mg extends from -1.296 to 1.496. Each includes zero. The sponsor’s reported 95% confidence intervals are -1.2 to 1.5 for SIM 200 mg and -1.2 to 1.4 for SIM 700 mg. Because the sponsor uses LSMeans and the recalculation uses unadjusted means, differences in interval endpoints need not indicate an error or contradiction.

What does the p-value add?

In general, a p-value is calculated under a null hypothesis and a statistical model. It describes how unusual the observed result, or a more extreme result, would be if that null model were correct. The recalculated unadjusted p-values are 1.0 for SIM 200 mg and 0.888 for SIM 700 mg. They are not probabilities that the null hypothesis is true, and they do not measure the probability that a result will reproduce in another study.

The recalculated p-values are unadjusted. If multiple outcomes or comparisons are tested, the chance of at least one apparently notable result can change; statistical procedures can account for that issue. In general, such procedures are called multiplicity adjustments. The registry lists 2 outcome measures and 4 analyses, but does not report the sponsor’s multiplicity strategy or whether the posted p-values were adjusted. The sponsor-reported analyses do not include p-values.

What does over-dispersion mean in general?

Over-dispersion is a concern when outcome variability is greater than a statistical model expects. It is especially relevant to some count or binary outcomes, where overly restrictive variance assumptions can make standard errors too small and intervals too narrow. The primary endpoint in this trial is continuous, and the registry reports group standard deviations. It does not report an over-dispersion diagnosis or a model for the primary endpoint. A reader should not infer that over-dispersion was assessed or that a particular correction was used.

How should the planning illustrations be read?

The planning illustration is based on the observed SIM 700 mg effect and describes participants per arm for 80% and 90% power under its stated assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also considers planning for 100%, 75%, and 50% of the observed effect. These are hypothetical sample-size calculations, not observed power and not evidence about the trial’s original design. The record does not report that these assumptions were used when the trial was planned, or provide the trial’s own sample-size justification.

10. Confidence Intervals and Precision

The recalculated estimate for SIM 200 mg versus placebo is 0.0 mmHg, with an interval from -1.331 to 1.331. The recalculated estimate for SIM 700 mg versus placebo is 0.1 mmHg, with an interval from -1.296 to 1.496. Both intervals include zero, so the posted summaries are compatible with no mean difference as well as with differences in either direction under the recalculation’s assumptions.

In general, a confidence interval is a way to express uncertainty in an estimate. A wider interval indicates less precision than a narrower interval, all else equal. Precision depends on factors including the variability of measurements, the amount of information available, and the analysis method. The group standard deviations are several mmHg, while the estimated differences are close to zero; this context helps explain why the intervals span values on both sides of zero.

The sponsor-reported LSMeans comparisons have 95% confidence intervals from -1.2 to 1.5 for SIM 200 mg and from -1.2 to 1.4 for SIM 700 mg. These are not exactly the same estimates as the unadjusted recalculations, and the registry does not report enough methodological detail to reproduce the sponsor analysis. The intervals should therefore be interpreted in relation to their respective analyses.

Neither interval establishes that the true difference is zero, nor does it identify which differences would matter clinically. The registry does not report a clinically meaningful threshold for HVPG change. Precision about the statistical estimate and importance to patients are separate questions, and the posted record does not resolve the latter.

11. Analyses Reported by the Sponsor

The registry’s sponsor-reported results are differences in LSMeans. For SIM 200 mg versus placebo, the reported difference is 0.1 with a 95% confidence interval from -1.2 to 1.5. For SIM 700 mg versus placebo, the reported difference is 0.1 with a 95% confidence interval from -1.2 to 1.4. Sponsor-reported p-values are not reported.

The recalculated comparisons use the posted group means, standard deviations, and analysis counts. They produce a mean difference of 0.0 for SIM 200 mg and 0.1 for SIM 700 mg, with unadjusted p-values of 1.0 and 0.888, respectively. These recalculations are simple, unadjusted comparisons; the sponsor’s LSMeans may reflect a different analysis, but the method is not reported in the registry record. The intervals and estimates should not be treated as exact duplicates of one another.

The record does not flag a discrepancy between its sponsor results and the recalculations. The sponsor’s analysis remains the primary reported analysis, while the recalculations are useful as a transparent comparison based on summary statistics. Neither set of estimates should be interpreted as proving a particular clinical effect.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 2 outcome measures and 4 analyses, while the number of posted secondary outcomes is 0. The primary outcome reported in detail is change from baseline in HVPG. The record does not explain how the sponsor treated multiple comparisons or multiple outcomes, whether any hierarchy of tests was specified, or whether p-values were adjusted for multiplicity. The sponsor-reported analyses do not include p-values, and the recalculated p-values are explicitly unadjusted.

In general, multiplicity matters when several statistical tests are conducted: without an appropriate strategy, the chance of at least one false-positive finding can increase. Possible strategies include prespecifying a primary comparison, adjusting significance thresholds, or interpreting secondary findings as exploratory. These are general concepts, not descriptions of what this trial did. The registry record does not report a multiplicity plan, so it cannot be reconstructed from the posted results.

The primary endpoint population is described as participants in the Full Analysis Set with available data. The record does not state the operational definition of that set, how many participants had available endpoint data, or how missing values were handled. It also does not report whether missingness was related to treatment group or outcome values. In general, missing-data assumptions can affect an estimate if participants with missing measurements differ systematically from those with observed measurements.

The trial is randomized, but the posted endpoint results are based on available data in the stated analysis population. Without information about missing data and the full analysis specification, the degree to which the posted comparison preserves the intended randomized contrast cannot be assessed from this record alone. Interim analyses, stopping rules, and the statistical analysis plan are not reported in the registry record. The reason the trial was terminated is also not reported.

13. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hepatic encephalopathy (12.5%), acute kidney injury (7.5%), abdominal pain (5.0%), ascites (5.0%), hypokalaemia (5.0%).

The registry reports serious adverse event counts during the blinded phase for SIM 200 mg, SIM 700 mg, and placebo, and for SIM 700 mg during the open-label phase. The serious adverse event figures are 37 among 87 at risk for blinded-phase SIM 200 mg, 36 among 86 at risk for blinded-phase SIM 700 mg, 25 among 85 at risk for blinded-phase placebo, and 17 among 40 at risk for open-label SIM 700 mg. The record also reports other adverse event counts: 85 among 87, 81 among 86, 83 among 85, and 32 among 40, respectively.

These are counts among the reported at-risk groups, not estimates of comparative risk adjusted for follow-up or other factors. The open-label group is not a randomized placebo comparison, so its figures should not be read as directly comparable to the blinded groups. The registry lists serious adverse event terms including hepatic encephalopathy at 12.5%, acute kidney injury at 7.5%, abdominal pain at 5.0%, ascites at 5.0%, hypokalaemia at 5.0%, and hyponatraemia at 5.0%.

Deaths are not reported in the registry record. The adverse-event summary does not establish causation, and it does not by itself support a comparative safety conclusion.

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

The posted primary-outcome results describe mean change in HVPG from baseline to Week 96 in the Full Analysis Set participants with available data. The group means were -0.1 mmHg for SIM 200 mg, 0.0 mmHg for SIM 700 mg, and -0.1 mmHg for placebo. The recalculated unadjusted differences are close to zero, and both recalculated intervals include zero. The sponsor’s LSMeans comparisons are also reported with intervals spanning zero.

These findings describe the estimates and uncertainty in the registry record. They do not prove that the treatments have identical effects, because the intervals allow a range of possible differences. They also do not establish that any possible difference would be clinically important: a threshold for meaningful HVPG change is not reported. The record does not provide other clinical outcomes that would allow the primary endpoint to be interpreted alongside a broader assessment of patient outcomes.

The results do not establish effects beyond the reported endpoint, time point, analysis population, and trial groups. The registry describes an optional open-label phase, but the primary comparisons reported are from the randomized phase. The open-label safety counts do not replace a randomized comparison and cannot be interpreted as such.

The statistical interpretation is also limited by missing analysis details. The Full Analysis Set is described as including participants with available data, but the amount and handling of missing data are not reported. The sponsor’s LSMeans method, multiplicity strategy, and statistical analysis plan are not reported. The registry lists the study as terminated but does not report why. These absences constrain interpretation; they should not be filled with assumptions.

15. Why This Trial Matters Statistically

This trial illustrates why an estimated treatment difference should be read together with its uncertainty. The recalculated mean differences are close to zero, but the intervals extend on both sides of zero. A point estimate alone would omit that uncertainty; a p-value alone would not show the range of values compatible with the data. Neither is a substitute for a clinical threshold, which is not reported for this endpoint.

It also illustrates that similar-looking estimates can come from different analyses. The sponsor reports LSMeans, while the recalculation uses unadjusted group means. The estimates are close, but the methods are not documented in enough detail to treat them as identical. Keeping the sponsor analysis and the simple recalculation distinct avoids suggesting that summary statistics reproduce a full analysis model.

The trial record also shows the importance of reporting analysis populations and missing-data handling. The endpoint analysis is described as using the Full Analysis Set with available data, but the record does not state how many participants had endpoint measurements or what happened to missing values. Without those details, readers cannot fully assess how the analysis population relates to the randomized groups.

Finally, the sample-size illustration is not the trial’s design justification and is not observed power. It is a planning exercise under stated assumptions, based on the observed effect. Separating such an illustration from the trial’s actual design history helps prevent a retrospective calculation from being mistaken for a prespecified decision.

16. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the reason for termination, despite listing the study status as terminated. It also does not report the sponsor’s statistical analysis plan, the method used to estimate LSMeans, the multiplicity strategy, interim analyses, or stopping rules. These omissions prevent a full reconstruction of how the primary analysis was specified and conducted.

The primary endpoint analysis is described as including Full Analysis Set participants with available data, but the definition of that population, the number with available Week 96 measurements, and missing-data methods are not reported. The record does not describe whether measurement availability differed across randomized groups. Thus, the posted summary statistics alone cannot show how missing measurements may have affected the estimates.

The registry provides standard deviations and group means but not individual-level data or additional distributional summaries. The reported endpoint is a mean change, so the results do not describe the range of participant-level outcomes or the proportion of participants with particular changes. No clinical-importance threshold is reported for HVPG change.

The sponsor analyses are reported as LSMeans differences, but the analysis method is not specified. The unadjusted recalculations therefore serve as a separate summary-statistic comparison and cannot verify every aspect of the sponsor analysis. The registry also does not report sponsor p-values for the LSMeans comparisons.

Safety data include counts for blinded and open-label phases, but deaths are not reported. The record does not provide enough detail to infer causation from adverse events or to make an adjusted comparison across phases. The open-label group is not a randomized comparator. These limitations are specific to the information reported in the registry and should not be replaced by assumptions about the conduct of the trial.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH — NCT01672879.
• Registry record last updated 2019-03-27; status last verified 2019-03.
• Results first posted 2019-03-27.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

20. Record Summary

NCT01672879 is a randomized, double-blind, placebo-controlled phase 2b trial of SIM in compensated cirrhosis secondary to NASH. The registry lists an enrollment of 259, a parallel-group design, and a terminated status. SIM 200 mg and SIM 700 mg were compared with placebo in the blinded phase; an optional open-label phase is also described.

The primary endpoint was change from baseline in HVPG from baseline to Week 96. The sponsor reported LSMeans differences of 0.1 for both SIM comparisons, with 95% confidence intervals spanning zero. Unadjusted recalculations from posted summary statistics also produce estimates close to zero, with intervals that include zero. The record does not report the reason for termination, the sponsor’s analysis method, multiplicity handling, or missing-data procedures.