Safety and Efficacy Study of GDC-0853 Compared With Placebo and Adalimumab in Participants With Rheumatoid Arthritis (RA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of GDC-0853 Compared With Placebo and Adalimumab in Participants With Rheumatoid Arthritis (RA) (NCT02833350), a randomized phase 2 study. The primary outcome is Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Day 84, Comparison Between GDC-0853 and Placebo (Cohort 1).

2. Clinical Question

3. Trial Design

The registry record describes a randomized, double-blind, parallel-group Phase II trial with two cohorts. It is listed as completed, with enrollment of 578. The recorded start date is 2016-09-09 and the primary completion date is 2018-07-02. The study evaluated GDC-0853 in participants with active rheumatoid arthritis, using placebo controls and, in Cohort 1, an active adalimumab comparator.

Cohort 1 enrolled participants with an inadequate response to previous methotrexate therapy. Its groups received low-, mid-, or high-dose GDC-0853 with placebo matched to adalimumab; placebo matched to GDC-0853 with adalimumab; or placebos matched to both treatments. The primary endpoint was the percentage achieving ACR50 at Day 84, comparing each GDC-0853 dose with placebo. Adalimumab was included as an active comparator, but it was not the primary comparison.

Cohort 2 enrolled participants with an inadequate response or intolerance to previous TNF therapy. It compared high-dose GDC-0853 with placebo. The registry summary describes background methotrexate therapy in both cohorts. The treatment descriptions specify 12 weeks of study treatment, with GDC-0853 taken orally and adalimumab or its matched placebo given subcutaneously in Cohort 1.

The registry record identifies the study as dose-ranging and reports 30 outcome measures and 286 analyses. It does not report a sample-size justification, the planned allocation ratio, or a detailed statistical analysis plan. Those design details are not reported in the registry record.

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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) All randomized participants who received any part of an infusion of study medication were included in the ITT analysis. Number of participants for whom data were collected is indicated for each time point.

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 population (SAF) included all subjects that received treatment.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Day 84, Comparison Between GDC-0853 and Placebo (Cohort 1), measured over Day 84.

The primary endpoint is the percentage of participants achieving an ACR50 response at Day 84 in Cohort 1. A response requires at least 50% improvement from baseline in both the total 68-joint tender joint count and the 66-joint swollen joint count, as well as improvement in three of five additional ACR core-set measures. These measures cover pain, patient and physician assessments of disease activity, physical function measured with the Health Assessment Questionnaire, and an acute-phase reactant, either C-reactive protein or erythrocyte sedimentation rate.

This composite endpoint captures several dimensions of rheumatoid arthritis rather than relying on a single symptom or laboratory measure. Requiring improvement in both joint counts and several additional measures makes the response definition broad, though it also means that a participant must meet multiple criteria to count as a responder. The percentage summarizes how many participants in each group met that definition at the specified assessment time.

The registry record reports a 95% confidence interval for each group’s response estimate. A confidence interval describes the uncertainty around an estimated response percentage: narrower intervals indicate greater precision, while wider intervals indicate less precision. The endpoint is a response proportion, not a measure of the average amount of improvement among all participants.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: a participant either meets the ACR50 response definition at Day 84 or does not. The group-level result is reported as a percentage. Confidence intervals accompany these percentages to show the precision of the estimates. In general, a confidence interval is a range of values compatible with the observed data under the analysis method. It is not a guarantee that the true value lies within that particular interval.

What does the sponsor’s comparison estimate?

The reported comparisons use the Cochran-Mantel-Haenszel method and describe a weighted difference between groups. In general, this method can combine comparisons across strata while accounting for the stratification used in an analysis. The registry record does not specify the stratification variables or provide a detailed account of the model implementation. The reported weighted differences should therefore be read as the sponsor’s stated comparison estimates, not reconstructed from the displayed percentages.

A confidence interval for a group difference expresses uncertainty about the size and direction of the comparison. When an interval includes zero, it is compatible with no difference under that interval’s method; when it excludes zero, it is not. A p-value assesses compatibility between the observed data and a specified null hypothesis under the analysis assumptions. Neither a confidence interval nor a p-value describes the probability that a treatment is beneficial, and neither substitutes for judging the magnitude and precision of an estimate.

What are the recalculated comparisons?

For selected continuous secondary outcomes, the posted recalculations are simple, unadjusted comparisons derived from group summary statistics. They are not the sponsor’s own reported analyses. For the FACIT-F change outcome, the recalculated comparisons use the low-dose group as the reference and compare the mid- and high-dose groups with it. The reported mean differences are -0.79 and -0.05, respectively, and both confidence intervals include zero. The corresponding unadjusted p-values are 0.683 and 0.979.

For the two pharmacokinetic outcomes, the recalculations compare the mid- and high-dose groups with the low-dose group in Cohort 1. The estimated mean differences are positive for both outcomes and dose comparisons, with confidence intervals that do not include zero; the reported unadjusted p-values are <0.001. These measurements describe drug concentration, not clinical response. A statistical difference in a pharmacokinetic measure should not be treated as evidence of a difference in rheumatoid arthritis outcomes.

The recalculated confidence intervals and p-values are unadjusted. They do not account for the number of secondary outcomes or comparisons, and they do not replace any prespecified sponsor analysis. No discrepancy between the recalculations and a sponsor analysis is indicated for these outcomes; the registry record lists no sponsor-reported analyses for them.

How should planning illustrations be read?

The sample-size illustrations use observed effects and assumptions of a two-sided significance level of 0.05, equal allocation between two groups, and a normal approximation. Entries describe participants per arm for 80% power or participants per arm for 90% power at specified fractions of the observed effect. They are planning illustrations only. Because they are based on effects observed in this trial, they are not independent evidence that the trial had adequate power, and they must not be read as observed power.

Planning figures based on an observed effect can be unstable, particularly when the estimate is small or imprecise. The registry record does not report the trial’s own sample-size justification or the assumptions used to design the study. The posted illustrations cannot fill that gap or establish what the study was originally designed to detect.

Why do analysis choices matter?

For binary outcomes, the method used to compare proportions can affect the estimate and its uncertainty, particularly when results are stratified or group sizes differ. For continuous outcomes, unadjusted comparisons based on means and standard deviations do not incorporate covariates, stratification, or multiplicity adjustments unless these are explicitly included. A reported analysis should be interpreted according to its stated method and population, rather than assumed to be interchangeable with a recalculation from summary statistics.

10. Analyses Reported by the Sponsor

For the primary ACR50 endpoint, the registry record reports sponsor analyses for each GDC-0853 dose versus placebo using the Cochran-Mantel-Haenszel method. Those analyses are the appropriate source for the sponsor’s inferential conclusions about the primary comparisons. The low-dose interval includes zero, while the mid- and high-dose intervals do not. The corresponding reported p-values are 0.250, 0.016, and < 0.001 for low, mid, and high dose, respectively.

The recalculations presented for selected continuous secondary outcomes are different in scope. They use posted group means, standard deviations, and sample sizes to make simple unadjusted comparisons. The registry record does not list sponsor-reported analyses for those outcomes. These calculations therefore offer a separate descriptive statistical perspective, not a correction or replacement for an official sponsor analysis.

No discrepancy is identified between a sponsor result and a recalculation in the record. The primary comparison should not be described as recalculated: its sponsor-reported weighted estimates and inference take precedence. For the secondary calculations, the unadjusted results should be treated as exploratory, especially because the registry record includes many outcome measures and analyses but does not report whether or how multiplicity was addressed.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 30 outcome measures and 286 analyses. It does not report whether the primary endpoint was protected by a prespecified testing hierarchy, whether secondary comparisons were adjusted for multiplicity, or how the family of tests was defined. This matters because testing many hypotheses increases the chance that at least one result will appear statistically notable by chance. The sponsor-reported primary comparisons and the unadjusted recalculations for selected secondary outcomes should therefore be distinguished rather than treated as one confirmatory set.

The record identifies the primary endpoint population as the Intent-to-Treat population and describes it as all randomized participants who received any part of an infusion of study medication. It also states that the number of participants for whom data were collected is indicated at each time point. The record does not explain how missing Day 84 outcome data were handled, whether participants with missing response components were counted as responders or nonresponders, or whether any imputation or sensitivity analyses were used. Those details are not reported in the registry record.

The registry record also does not provide a detailed statistical analysis plan, specify interim analyses, or report the trial’s sample-size justification. It does not describe the planned handling of protocol deviations or provide enough detail to assess whether analysis decisions were made before results were examined. These omissions limit assessment of the prespecification and robustness of the reported analyses.

The simple recalculations for continuous secondary outcomes use the group summary statistics and make unadjusted comparisons. They do not address missing-data assumptions or multiplicity. Their estimates and intervals should be interpreted as descriptive recalculations, not as a full reconstruction of the study’s analysis plan. The record does not report whether any other missing-data or multiplicity procedures were used for those outcomes.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.9%), myocardial infarction (0.9%), cellulits (0.9%), pyelonephritis obstruction (0.9%), chronic obstructive pulmonary disease (0.9%).

The safety figures report serious adverse events, other adverse events, and deaths by study group. In Cohort 1, serious adverse events were reported for 0 of 40 participants in the low-dose group, 1 of 109 in the mid-dose group, 3 of 110 in the high-dose group, 1 of 110 in the double-placebo group, and 2 of 111 in the adalimumab group. In Cohort 2, serious adverse events were reported for 0 of 49 participants in each group.

One death was reported in the Cohort 1 high-dose group; no deaths were reported in the other listed groups. Other adverse events were reported in 9 of 40, 18 of 109, 11 of 110, 15 of 110, and 16 of 111 participants across the Cohort 1 groups, respectively, and in 3 of 49 and 7 of 49 participants in the Cohort 2 groups. The serious-event terms listed in the record each have a reported frequency of 0.9%.

These are descriptive counts over the study’s recorded observation period. They do not establish that a treatment caused or prevented an event, and the group counts should be interpreted with the study’s size and follow-up in mind. The registry record does not provide detailed event narratives or a comparative statistical analysis of safety outcomes.

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

The primary result describes the proportion of Cohort 1 participants meeting the ACR50 response definition at Day 84 in each randomized group. The sponsor’s reported analysis estimates weighted differences between each GDC-0853 dose and placebo, with confidence intervals that convey uncertainty. The reported intervals differ across dose comparisons: the low-dose interval includes zero, while the mid- and high-dose intervals exclude zero.

This result is limited to the population, outcome definition, and assessment time recorded for the trial. It does not establish the duration of any response beyond the reported timeframe, nor does it describe every outcome relevant to participants. ACR50 is a composite threshold: it records whether a participant met a particular set of response criteria, not the full pattern or magnitude of change in every measure.

The primary comparison is GDC-0853 versus placebo in Cohort 1. The study also included an adalimumab group, but the primary endpoint analysis is not a direct comparison of GDC-0853 with adalimumab. Cohort 2 enrolled a different treatment-history population and used a separate placebo comparison, so its findings cannot be assumed to be interchangeable with those of Cohort 1.

The secondary recalculations are unadjusted and should not be elevated to the status of prespecified confirmatory results. In particular, pharmacokinetic differences concern measured drug concentrations rather than clinical response. The registry record does not report enough information about multiplicity, missing-data handling, or the sample-size rationale to resolve all questions about statistical robustness. These limits affect how confidently the posted estimates can be generalized or interpreted, but they do not change what the reported group estimates and analyses state.

14. Why This Trial Matters Statistically

This trial illustrates why a statistical reading should separate the endpoint estimate from the method used to compare groups. The displayed response percentages are group-level estimates, while the sponsor’s inferential comparisons are Cochran-Mantel-Haenszel weighted differences. Those quantities are related, but the weighted comparison is not simply the same as subtracting the displayed percentages. Keeping the distinction clear helps avoid treating a descriptive summary as though it were the full analysis.

The design also has two cohorts with different treatment histories and comparison structures. Cohort 1 supplies the primary placebo-controlled question and includes an active comparator; Cohort 2 is a separate placebo-controlled cohort. Combining them without regard to those differences would obscure the population and comparison each estimate represents.

The record’s many outcomes and analyses make multiplicity an important interpretive issue. Primary and secondary findings do not carry equal evidential weight, and unadjusted secondary p-values should be treated cautiously. The posted sample-size illustrations are another useful statistical teaching point: planning calculations based on observed effects can describe hypothetical sample requirements under stated assumptions, but they are not observed power and do not reveal the trial’s original design justification.

Finally, safety counts and clinical response estimates answer different questions. Counts can describe the events recorded in each group, but small group counts and the absence of detailed comparative safety analyses limit what can be inferred. Reading the estimates alongside their uncertainty and the registry’s reporting gaps is essential to a proportionate 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 primary outcome is reported at Day 84, and the registry record does not provide a longer-term primary comparison. The endpoint is a composite response threshold, so the percentage meeting ACR50 does not reveal the distribution of individual component changes or the experience of participants who did not meet the threshold.

The primary analysis population is described as randomized participants who received any part of an infusion of study medication. The record does not clarify how this population definition was applied across the oral and subcutaneous study treatments, or how missing outcome data were handled. It also does not report sensitivity analyses for missing data. These omissions make it difficult to assess the impact of incomplete follow-up on the response estimates.

The sponsor-reported primary analysis is described by method and weighted difference, but the registry record does not specify the stratification variables or provide a detailed statistical analysis plan. It does not report a sample-size justification, interim analyses, or the multiplicity strategy. The listing of 286 analyses makes the absence of a reported multiplicity plan particularly relevant to interpretation of secondary findings.

The recalculated continuous comparisons are unadjusted and use summary statistics. They cannot reproduce analyses that might include covariate adjustment or other modeling details not reported in the record. The pharmacokinetic outcomes also measure drug exposure rather than clinical response. Finally, the safety information is presented as counts without a detailed comparative statistical analysis or event narratives. These limitations constrain interpretation of precision, robustness, and generalizability.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of GDC-0853 Compared With Placebo and Adalimumab in Participants With Rheumatoid Arthritis (RA) — NCT02833350.
• Registry record last updated 2020-06-12; status last verified 2020-06.
• Results first posted 2019-09-10.
• 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

This completed randomized, double-blind, parallel-group Phase II trial studied GDC-0853 in two rheumatoid arthritis cohorts. Cohort 1 compared several GDC-0853 doses with placebo and included an adalimumab group; Cohort 2 compared high-dose GDC-0853 with placebo. The primary endpoint was ACR50 response at Day 84 in Cohort 1.

The sponsor reported Cochran-Mantel-Haenszel weighted comparisons of each GDC-0853 dose with placebo. The record also contains secondary outcome and safety results, plus unadjusted recalculations for selected continuous outcomes. The registry record does not report the sample-size justification, detailed missing-data handling, interim analyses, or multiplicity strategy.