A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN) (NCT00517530), a non-randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants Who Experienced a Dose-limiting Toxicity in Phase I of the Study.

2. Clinical Question

3. Trial Design

GAUGUIN was an open-label, multicentre Phase I/II study of obinutuzumab monotherapy in participants with CD20+ malignant disease. The registry lists an enrollment of 134 and classifies the overall allocation as nonrandomized. The study started in 2007-09, had primary completion in 2013-11, and is recorded as completed. Its design included dose escalation in Phase I and a randomized dose-assignment component in parts of Phase II; the overall nonrandomized classification should not be read as meaning that every Phase II dose assignment was nonrandomized.

In Phase I, participants in the NHL arm received multiple ascending intravenous doses between 50 and 2000 mg. The CLL arm received multiple ascending doses between 400 and 2000 mg. The Phase I primary objective was safety and tolerability. Its primary endpoint assessed the percentage of participants with a dose-limiting toxicity during the defined observation periods.

In Phase II, the study evaluated participants with relapsed or refractory CLL, iNHL, or aNHL. The iNHL and aNHL groups were randomized between the 400/400 mg and 1600/800 mg schedules. Each schedule was delivered over a maximum of 8 cycles, with each cycle lasting 21 days. The CLL group received the 1000/1000 mg schedule and was not randomized because only one dose level was used. The trial was open-label, so treatment assignment was not masked.

Participants who had responded and whom the investigator considered might gain additional benefit could be enrolled in a retreatment period. The registry describes retreatment as intravenous obinutuzumab given at the investigator's request. It does not report the number of participants who entered retreatment or the reasons for individual retreatment decisions. The study's listed secondary outcomes include response, progression-free survival, duration of response, event-free survival, peripheral B-cell recovery, and pharmacokinetics. Outcome results for these measures 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

Analysis population for the primary outcome, as defined in the registry: Safety population: All enrolled participants in Phase I, who had received at least 1 dose of obinutuzumab by 6 months.

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: All enrolled participants who had received at least 1 dose of obinutuzumab.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Experienced a Dose-limiting Toxicity in Phase I of the Study, measured over Baseline to 28 days after the last infusion of obinutuzumab (up to 6 months).

The primary endpoint is the percentage of participants who experienced a dose-limiting toxicity in Phase I. A dose-limiting toxicity was defined as an adverse event related to obinutuzumab that occurred within the first 28 days of each administration. B-cell depletion and lymphopenia were excluded from this definition because the registry describes them as expected outcomes of treatment. The stated timeframe is from baseline to 28 days after the last infusion, up to 6 months.

This endpoint is used in dose-escalation research to describe treatment-related toxicity within a specified observation window. The percentage expresses how often the defined event occurred in the relevant population; it is not a measure of all adverse events, nor does it summarize the severity or duration of every event. The definition also makes the attribution and timing rules important: an event must be considered obinutuzumab-related and fall within the specified period to meet the endpoint definition.

The registry identifies the safety population as all enrolled Phase I participants who received at least one dose by 6 months. It does not report the observed percentage, the number of Phase I participants included in the endpoint analysis, or an uncertainty interval for the endpoint. Therefore, the endpoint definition and intended population can be described, but the posted record does not support a numerical conclusion about the primary outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help explain what the registered endpoint and study design can, and cannot, establish. The registry record does not report a detailed statistical analysis plan. Descriptions of general concepts below are general explanations, not claims about unreported procedures in GAUGUIN.

What does a percentage endpoint describe?

A percentage of participants with an event is a binary-outcome summary: each participant either meets the endpoint definition or does not. The percentage describes the observed frequency in the analysis population. It depends on a clear event definition, an appropriate denominator, and complete enough follow-up to identify events within the observation window. For GAUGUIN's primary endpoint, the definition includes attribution to obinutuzumab, the timing of an adverse event relative to each administration, and specified exclusions. The registry does not report the endpoint numerator or denominator, so its observed frequency cannot be interpreted from the posted record.

A percentage alone does not show how precisely the underlying event frequency has been estimated. A confidence interval is a statistical range used to express uncertainty around an estimate under the assumptions of the method. The registry record does not report a confidence interval for the primary endpoint. Without an estimate and its uncertainty, readers cannot judge the precision of that endpoint result.

Why does the observation window matter?

Safety endpoints depend on when events are counted. An event outside the specified period may not qualify for a time-limited endpoint even if it is clinically important. Here, the DLT definition uses the first 28 days of each administration, while the listed endpoint timeframe refers to baseline through 28 days after the last infusion, up to 6 months. The record also excludes B-cell depletion and lymphopenia from the DLT definition. These rules determine which events count for the endpoint; they do not mean that other adverse events were absent. How events were attributed, collected, or adjudicated beyond the definition is not reported in the registry record.

How should dose escalation be understood?

In a dose-escalation study, participants receive increasing dose levels according to the study design, and safety observations are used to characterize tolerability across those levels. This is a different purpose from estimating a treatment effect against a separate control group. Phase I in GAUGUIN is described as dose escalating and nonrandomized. The record gives the dose ranges by disease arm, but does not report cohort sizes, escalation decision rules, stopping rules, or the statistical methods used to select doses. Those design details should not be inferred from the fact that doses were escalated.

The use of more than one dose level does not by itself make dose groups directly comparable. Participants may be enrolled at different times or in different disease groups, and the record does not provide enough detail to assess whether the Phase I groups were comparable. In Phase II, randomization applied to dose assignment for iNHL and aNHL, whereas CLL received a single dose level. Randomization can support a fairer comparison between assigned groups by reducing systematic differences on average, but it does not remove the need to report the group results, denominators, uncertainty, and analysis methods. Those Phase II results are not reported in the registry record.

What do the planning illustrations mean?

The sample-size illustrations are planning calculations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For non-time-to-event outcomes, they are expressed as participants per arm for a specified power; time-to-event planning is expressed as a total number of events. These are planning illustrations, not observed power and not evidence about how the trial was designed. The record does not report the trial's own sample-size justification or analysis plan. Because GAUGUIN was not a single randomized comparison across all participants, a generic two-arm illustration should not be mistaken for a description of its full design.

For a binary endpoint, planning calculations depend on assumptions about the event frequency and the size of the difference one wishes to detect. Illustrations that use a fraction of an observed effect show how planning requirements can change when the target effect is smaller than the observed estimate. Such calculations are not substitutes for the trial's prespecified design assumptions, and they do not show that a study had a particular probability of detecting an effect after the fact. The record's own planning rationale is not reported.

Why are comparisons and uncertainty important?

A treatment-group percentage describes what was observed in that group; it does not, by itself, show what would have happened under another treatment or no treatment. A comparative estimate needs a defined comparison and the results in the relevant groups. The Phase II randomization described for iNHL and aNHL concerned two obinutuzumab schedules, not obinutuzumab versus a separate control. No comparative effect estimate is reported. For Phase I, the dose-escalation design does not establish a randomized control comparison.

Statistical uncertainty also matters when reading safety counts. The number of participants with an event is not the same as the number of event episodes, and a participant may have more than one event. The record reports participant counts for the broad safety categories, but does not describe recurrence or event-level details in the information. A percentage for an adverse-event term also does not convey severity, duration, or whether the event met the primary DLT definition. Those are separate questions requiring their own results and definitions.

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("50/100 mg - Phase I, NHL", "100/200 mg - Phase I, NHL", "200/400 mg - Phase I, NHL", "400/800 mg - Phase I, NHL", "800/1200 mg - Phase I, NHL", "1200/2000 mg - Phase I, NHL")
n      <- c(3, 3, 3, 3, 3, 3)
events <- c(0, 0, 0, 0, 0, 0)
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  50/100 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  100/200 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  200/400 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  400/800 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  800/1200 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  1200/2000 mg - Phase I, NHL  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures, including response outcomes, progression-free survival, duration of response, event-free survival, peripheral B-cell recovery, retreatment response, and maximum plasma concentration. It does not report analysis entries. The statistical plan for handling multiple outcomes or multiple comparisons is not reported in the registry record. Multiplicity refers generally to the interpretive issue that arises when many outcomes or comparisons are examined: the chance of obtaining at least one apparently notable result can increase, depending on the analyses and decision rules. No specific correction, hierarchy, or testing strategy can be attributed to this study from the recorded information.

Missing-data methods are not reported in the registry record. The material does not say how missing endpoint assessments, incomplete follow-up, withdrawals, or participants without evaluable response data were handled. The primary safety population is defined as enrolled Phase I participants who received at least one dose by 6 months, but the number in that population is not given. The record does not state whether every participant in that population had complete observation for the endpoint.

The analysis population for the primary endpoint is described as a Phase I safety population. The populations used for the listed Phase II outcomes are not reported in the registry record. The record also does not report an intention-to-treat definition, per-protocol population, censoring rules for time-to-event outcomes, or methods for handling participants who entered retreatment. These omissions limit the ability to assess whether the analyses matched the outcome definitions or how robust the results would be to missing information. They do not establish that any particular method was or was not used outside the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: infusion related reaction (6.0%), febrile neutropenia (3.7%), pyrexia (3.0%), tumour lysis sydrome (3.0%), anaemia (1.5%).

The safety summary lists 134 participants at risk for serious adverse events and 46 participants with such events. It separately lists 134 at risk in the other adverse-event category and 123 participants with events in that category. These counts describe the registry's broad safety categories. They should not be treated as counts for the primary dose-limiting-toxicity endpoint, which has its own relatedness, timing, and exclusion criteria.

The listed serious adverse-event terms and percentages are infusion related reaction at 6.0%, febrile neutropenia at 3.7%, pyrexia at 3.0%, tumour lysis sydrome at 3.0%, anaemia at 1.5%, and thrombocytopenia at 1.5%. They provide a registry summary of reported terms, but the record does not give event-level narratives, duration, recurrence, or treatment-arm denominators for these terms in the material. A participant count and an event-term percentage are not interchangeable: one participant may experience more than one event, and a term-specific percentage does not describe the entire safety profile.

These figures are descriptive. They do not establish that an event was caused by treatment, nor do they permit comparisons with an untreated group or another treatment. The record does not report deaths in the adverse-event summary. Absence of a reported death count in that summary should not be interpreted as a finding about deaths during the study.

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

The posted information establishes that GAUGUIN was an open-label Phase I/II study of obinutuzumab in CD20+ malignant disease, with dose escalation in Phase I and randomized dose assignment for the iNHL and aNHL Phase II groups. It also specifies the Phase I primary endpoint and its event definition. These details allow readers to understand what the study was designed to examine and how the primary safety outcome was defined.

The registry record does not report the primary endpoint result. It therefore does not show the observed percentage of Phase I participants with a dose-limiting toxicity or the precision of that estimate. The record also does not report the Phase II response or survival results, or a statistical comparison of the two dose schedules. Design descriptions alone cannot answer whether one dose schedule had a different outcome from another.

The safety summaries do show participant counts in broad adverse-event categories and percentages for selected serious adverse-event terms. These are descriptive safety data. They are not a substitute for the defined primary endpoint, and they do not establish treatment causation or comparative risk. The study did not include a separate control treatment in the design described, and the registry information does not provide comparative results for the randomized dose groups.

More generally, the absence of a result in the registry record is not evidence of no effect or no event. It means that the result cannot be assessed from the record. Readers should distinguish the study's objectives, the outcomes it defines, the safety counts that are posted, and the estimates that are not reported. No medical conclusion about treatment benefit or lack of benefit follows from the available statistical information alone.

14. Why This Trial Matters Statistically

GAUGUIN illustrates why a trial's overall label does not always capture every design feature. The registry classifies allocation as nonrandomized, while also describing randomized assignment between two obinutuzumab doses in the iNHL and aNHL parts of Phase II. CLL had one dose level and was not randomized. Separating these design features matters: conclusions from randomized dose assignment, if results were available, would address a different question from observations across Phase I dose escalation or from the single-dose CLL group.

The trial also highlights the importance of endpoint definitions in safety research. A dose-limiting toxicity is not simply any adverse event. It is defined through treatment relatedness and a specified observation period, with stated exclusions. The broad serious adverse-event counts and selected event-term percentages answer related but distinct descriptive questions. Keeping these categories separate avoids treating a general safety summary as if it were the primary endpoint.

The record makes the distinction between objectives and results especially important. A study may list a substantial set of secondary outcomes, but a list of intended measures is not evidence that their results are available. Here, the primary endpoint result and Phase II outcome estimates are not reported in the registry record. Recognizing that gap prevents design details and safety summaries from being mistaken for efficacy findings or precise estimates.

Finally, planning calculations should be read as illustrations rather than as trial characteristics. The sample-size assumptions described in the record do not supply the study's own design justification, and planning quantities are not observed power. This distinction is important when interpreting a trial that combines disease groups, dose-escalation cohorts, and randomized dose assignment in only some Phase II populations.

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 most important limitation for statistical interpretation is that the registry record does not report the primary endpoint result. It gives the DLT definition and safety-population description but not the corresponding event count, percentage, denominator, or uncertainty interval. As a result, the primary safety question cannot be answered quantitatively from the posted information.

The study combines multiple disease groups and phases with different designs. Phase I used nonrandomized dose escalation, while Phase II randomized iNHL and aNHL participants between two dose schedules and used a single dose level in CLL. The overall enrollment of 134 does not reveal the number of participants in each phase, disease group, dose level, or analysis population. These design differences mean that a single overall summary cannot be assumed to represent each subgroup or answer the same question for every group.

The open-label design means treatment assignment was not masked. The registry does not report further detail about outcome assessment procedures. No Phase II response, survival, or dose-comparison estimates are reported in the information. Details needed to judge those analyses, including missing-data handling, analysis populations, and methods for time-to-event outcomes, are also not reported in the registry record.

The serious adverse-event summary is informative as a descriptive account but does not supply event-level detail, a separate control group, or comparative risk estimates. It also should not be conflated with the narrower DLT definition. Finally, the registry record does not report the trial's own sample-size rationale, dose-escalation decision rules, multiplicity strategy, or full statistical analysis plan. These limitations restrict what can be concluded from the record; they do not establish that the study team did not use procedures that are unreported there.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN) — NCT00517530.
• Registry record last updated 2016-10-11; status last verified 2016-08.
• Results first posted 2015-09-22.
• 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

GAUGUIN (NCT00517530) was a completed, open-label Phase I/II study sponsored by Hoffmann-La Roche. It enrolled 134 participants with CD20+ malignant disease and evaluated intravenous obinutuzumab monotherapy. Phase I used dose escalation in NHL and CLL; Phase II assigned iNHL and aNHL participants to different obinutuzumab doses, while the CLL group received one dose level without randomization.

The primary Phase I endpoint was the percentage of participants who experienced a dose-limiting toxicity, defined by treatment relationship and a specified observation period, with stated exclusions. The primary endpoint result is not reported in the registry record. The record lists 46 participants with serious adverse events and 123 in the other adverse-event category, with 134 at risk in each; it also lists percentages for selected serious adverse-event terms. Phase II outcome results and detailed statistical analysis methods are not reported in the registry record.