This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Comparison of Gadovist 75% Standard Dose to Dotarem at Full Standard Dose (NCT03602339), a non-randomized phase 4 study. The primary outcome is Degree of Lesion Contrast Enhancement.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03602339 |
| Phase | Phase 4 |
| Condition | Magnetic Resonance Imaging |
| Allocation | Non-Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 157 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Bayer |
| Results posted | Yes |
2. Clinical Question
Population
Participants had suspected or confirmed central nervous system lesions. The first study arm included patients with suspected or confirmed lesions; the second arm was a subgroup with lesions confirmed after gadoterate. The primary analysis population was the Full Analysis Set, defined by the availability of electronic case report form entries and images for the unenhanced and both contrast-enhanced MRI sequences.
Intervention
Gadobutrol, identified in the record with the brands Gadavist and Gadovist, was administered at 0.075 mmol/kg body weight. The study’s stated purpose was to assess image quality with a reduced dose of this contrast agent.
Comparator
Gadoterate, identified with the brands Dotarem and Clariscan, was administered at 0.1 mmol/kg body weight. In the first arm, participants received gadoterate after unenhanced MRI. Participants in the confirmed-lesion subgroup had a second unenhanced MRI and then contrast-enhanced MRI after gadobutrol.
Primary question
For lesions evaluated by blinded readers, how did the average rating of lesion contrast enhancement after gadobutrol compare with the rating after gadoterate? Readers used a four-point scale, from no enhancement to excellent enhancement. The registry record gives the endpoint definition but does not report numerical primary-endpoint results, so the size and precision of the observed comparison cannot be described.
3. Trial Design
LEADER 75 was a Phase 4, completed study of contrast-enhanced MRI in people with suspected or confirmed central nervous system lesions. The registry lists an enrollment of 157 and identifies the design as nonrandomized and crossover. The sponsor was Bayer. The recorded study dates run from 2018-11-14 to primary completion on 2020-03-13.
The study sequence was not a simple comparison of separate, randomly assigned groups. In the first arm, participants with suspected or confirmed lesions underwent unenhanced MRI and then contrast-enhanced MRI after gadoterate. Participants with gadoterate-confirmed lesions, described as a subgroup of the first arm, underwent a second unenhanced MRI and contrast-enhanced MRI after gadobutrol. Thus, the second contrast-agent assessment was limited to the confirmed-lesion subgroup rather than being a second examination for every participant in the first arm.
The registry lists masking as none, while the primary endpoint description says that three readers were blinded when scoring images. These statements concern different aspects of the study: the record does not describe the trial as masked overall, but it does describe blinded readers for this endpoint. The nature of reader blinding beyond that description is not reported in the registry record.
Because treatment allocation was nonrandomized and the study arms do not form a like-for-like control comparison, differences between the observed ratings would need to be interpreted with caution. The crossover label does not remove the importance of the sequence and subgroup structure. The registry record does not report the allocation process, a statistical analysis plan, or additional details about how the order of imaging or the selection of participants for the second examination was handled.
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: From 166 participants screened, 9 participants were screening failure and a total of 157 participants were enrolled, 157 received study drug for period 1 however 142 received study drug for period 2.
Overall Study
| Stage | Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW |
|---|---|
| STARTED | 157 |
| Completed Period 1 (Gadoterate) | 155 |
| Started Period 2 (Gadobutrol) | 142 |
| COMPLETED | 142 |
| NOT COMPLETED | 15 |
Reasons for not completing this period:
| Reason | Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW |
|---|---|
| Withdrawal by Subject | 9 |
| Physician Decision | 2 |
| Other reason | 4 |
Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) was used for analysis, which is defined as All participants for whom electronic case report form (eCRF) entries and images are available for unenhanced MRI, combined unenhanced and gadobutrol enhanced MRI, and combined unenhanced and gadoterate enhanced MRI.
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.
| Characteristic | Unit | Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW |
|---|---|---|
| Participants analysed | 157 | |
| Age, Continuous | years | 58.9 (SD 13.3) |
| Age, Customized: In utero | Participants | 0 |
| Age, Customized: Preterm newborn infants (gestational age < 37 wks) | Participants | 0 |
| Age, Customized: Newborns (0-27 days) | Participants | 0 |
| Age, Customized: Infants and toddlers (28 days-23 months) | Participants | 0 |
| Age, Customized: Children (2-11 years) | Participants | 0 |
| Age, Customized: Adolescents (12-17 years) | Participants | 0 |
| Age, Customized: Adults (18-64 years) | Participants | 94 |
| Age, Customized: From 65-84 years | Participants | 62 |
| Age, Customized: 85 years and over | Participants | 1 |
| Sex: Female, Male: Female | Participants | 71 |
| Sex: Female, Male: Male | Participants | 86 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 27 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 2 |
| Race (NIH/OMB): White | Participants | 109 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 19 |
6. Primary Endpoint
The registry lists the primary outcome as Degree of Lesion Contrast Enhancement, measured over Up to 20 days.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | Scores on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was the degree of lesion contrast enhancement, measured as scores on a scale up to 20 days. Three blinded readers assessed the images, and the reported endpoint was defined as the average reader score. Readers scored up to five lesions using image sequences and a four-point scale: 1 indicated no enhancement, 2 moderate or weak enhancement, 3 good or clear enhancement, and 4 excellent or clear and bright enhancement.
This endpoint is intended to describe how strongly lesions appear to enhance after administration of a contrast agent. A reader-based scale turns visual judgments into ordered scores that can be summarized across readers and lesions. The use of multiple readers can capture variation in image interpretation, while the average reader score provides a summary of those ratings. The registry identifies the endpoint as a mean with standard deviation.
In general, a mean describes the central level of scores, while a standard deviation describes how spread out scores are around that mean. The scale is ordered, but the registry’s chosen summary treats it as a continuous measure. The record does not report the numerical means, standard deviations, comparison estimate, or uncertainty interval for this primary endpoint. Consequently, it is not possible from the registry record to describe the observed difference in enhancement ratings or its precision.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record sets out a question about image-based lesion enhancement after two contrast-agent regimens: gadobutrol at 0.075 mmol/kg body weight and gadoterate at 0.1 mmol/kg body weight. It describes a reader-scored primary endpoint and identifies the analysis population. It does not report numerical results for that endpoint. There is therefore no posted primary estimate to interpret, and no basis in the registry record for describing the direction, size, or precision of a difference in mean scores.
The study’s stated aim was to examine whether images obtained with reduced-dose gadobutrol had similar quality to images obtained with full-dose gadoterate. A claim of similarity requires more than the study aim or endpoint definition. In general, interpretation would depend on the observed comparison, its uncertainty, and the prespecified criteria used to judge similarity. A similarity or noninferiority margin is not reported in the registry record. Without the primary result and that context, the study aim should not be mistaken for a demonstrated finding.
The structure also matters. Allocation was nonrandomized, and the gadobutrol assessment was performed in a subgroup with gadoterate-confirmed lesions. That means the two image assessments were not described as a balanced comparison of independently randomized groups. The registry identifies a crossover model, but the arm descriptions show that the second examination was restricted to the confirmed-lesion subgroup. Any comparison would need to be understood in light of this sequence and subgroup selection.
The registry reports several secondary outcome topics, including lesion counts, detection of malignant disease, diagnostic confidence, image quality, exploratory contrast enhancement, and treatment-emergent adverse events. It lists 12 outcome measures and 15 analyses. Numerical results for the primary endpoint are absent from the record, and the statistical approach for combining or comparing ratings is not reported. The presence of outcome topics alone does not establish what their results were or how they were analyzed.
Accordingly, the most defensible statistical reading is descriptive: the record documents a study designed to compare reader ratings under the two regimens, but it does not provide the primary numerical comparison needed to assess what the data showed. The safety counts are reported separately and should not be treated as evidence about imaging performance. Nor can the results be generalized beyond the studied setting without information about participant characteristics and additional results, which are not reported in the registry record.
9. Statistical Methods Explained
The primary endpoint is a reader-derived score summarized as a mean, with standard deviation identified as the measure of dispersion. The registry describes ratings by three blinded readers, scoring up to five lesions on a four-point scale, and an average reader score as the reported measure. These details define what the score represents, but they do not specify the full statistical procedure used to compare the regimens.
What does a mean score communicate?
In general, a mean is a measure of the central level of a set of observations. Here, the endpoint description concerns reader scores for lesion enhancement. A mean can offer a concise summary across the scored observations, but it can hide variation among readers, lesions, or participants. The registry record does not give the numerical mean for either regimen, so no central score or contrast between regimens can be stated.
The score categories are ordered from no enhancement through excellent enhancement. In general, treating an ordered rating scale as a continuous measure means using numerical distances between categories in a summary such as a mean. That approach can be useful for reporting, but the meaning of an average depends on assumptions about how the ordered categories are represented. The registry identifies the primary measure as a mean; further details about assumptions, model choice, or sensitivity analyses are not reported in the registry record.
What does the standard deviation describe?
In general, a standard deviation describes the spread of observations around a mean. It is different from a confidence interval: a standard deviation summarizes variability in the observed scores, whereas a confidence interval describes uncertainty around an estimate. The endpoint description identifies standard deviation, but numerical values are not reported for the primary outcome. A confidence interval for the primary comparison is also not reported in the registry record.
Why does the study structure affect interpretation?
The record labels the study nonrandomized and crossover. In general, random allocation helps make treatment groups comparable with respect to both measured and unmeasured characteristics, while a crossover design can allow within-participant comparisons when the same participants receive each condition. Here, the arm descriptions qualify that interpretation: the gadobutrol examination was performed for participants in a subgroup whose lesions were confirmed after gadoterate. The record does not describe the second examination as being completed by all participants, and it does not report a random allocation procedure.
In general, repeated observations from the same participant may be statistically related rather than independent. A suitable analysis may need to account for that relationship. The record does not report whether the primary analysis used a paired comparison, a model for correlated observations, or another method. It also does not report adjustment for factors such as reader, lesion, or participant, so none should be assumed.
What can a confidence interval add?
In general, a confidence interval gives a range of values compatible with the data under a specified statistical method and assumptions. It helps readers assess the precision of an estimate, rather than only its direction or central value. It is especially relevant when assessing whether results support a similarity claim, because that judgment depends on both the estimate and its uncertainty in relation to a prespecified margin. The registry record does not report a primary comparison estimate, confidence interval, or similarity margin.
How should planning illustrations be understood?
In general, a sample-size calculation is a planning exercise based on assumptions about an effect, significance level, allocation, and statistical method. The registry’s sample-size assumptions describe a planning illustration computed from the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. For non-time-to-event outcomes, those illustrations are defined in participants per arm. They are not a report of the study’s design justification, and they are not observed power. The registry record does not report the trial’s own sample-size justification or statistical plan. The planning description should therefore be kept separate from the design and from the unreported primary-endpoint results.
Over-dispersion is a general concern when observed variation is greater than a statistical model expects. If a model assumes less variability than is present, its uncertainty estimates can be too narrow. The registry record does not state that over-dispersion was assessed or that a particular model was used; this is a general consideration, not a reported analysis feature of this study.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 12 outcome measures and 15 analyses, with secondary topics including lesion identification, detection of malignant disease, diagnostic confidence, image quality, an exploratory contrast-enhancement algorithm, and treatment-emergent adverse events. When multiple outcomes or analyses are considered, the chance of at least one apparently notable result can increase. In general, a prespecified approach to multiplicity can help readers understand how evidence across several analyses was interpreted. The multiplicity strategy, if any, is not reported in the registry record.
The primary analysis population is described as the Full Analysis Set. It comprises participants for whom electronic case report form entries and images are available for unenhanced MRI, combined unenhanced and gadobutrol-enhanced MRI, and combined unenhanced and gadoterate-enhanced MRI. The record does not report the number included in this analysis population or how participants with incomplete images or records were handled. The enrolled population should not be assumed to be identical to the analysis population.
Missing-data methods are not reported in the registry record. There is no description of imputation, exclusion rules beyond the stated Full Analysis Set definition, or sensitivity analyses for missing observations. In general, missingness can affect interpretation if the availability of measurements is related to participant characteristics or outcomes. Without details on missingness and its handling, the potential impact cannot be assessed from the record.
The record also does not report a statistical analysis plan, any interim analyses, or adjustment procedures for the reader-, lesion-, or participant-level structure. These omissions limit the ability to evaluate how the reported outcomes were selected, analyzed, and interpreted.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Gadobutrol 0.075 mmol/kg BW | 0 | 143 | 0.0% |
| Gadoterate 0.1 mmol/kg BW | 0 | 156 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Gadobutrol 0.075 mmol/kg BW | 0 of 143 |
| Gadoterate 0.1 mmol/kg BW | 0 of 156 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Gadobutrol 0.075 mmol/kg BW | 1 of 143 |
| Gadoterate 0.1 mmol/kg BW | 4 of 156 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Gadobutrol 0.075 mmol/kg BW | Gadoterate 0.1 mmol/kg BW |
|---|---|---|---|
| Nausea | Gastrointestinal disorders | 0 of 143 | 1 of 156 |
| Paraesthesia | Nervous system disorders | 1 of 143 | 0 of 156 |
| Pruritus | Skin and subcutaneous tissue disorders | 0 of 143 | 1 of 156 |
| Urticaria | Skin and subcutaneous tissue disorders | 0 of 143 | 1 of 156 |
| Visual impairment | Eye disorders | 0 of 143 | 1 of 156 |
The registry reports serious adverse events separately for the two contrast-agent groups. For gadobutrol 0.075 mmol/kg body weight, 143 participants were at risk for serious adverse events and 0 were affected. For gadoterate 0.1 mmol/kg body weight, 156 participants were at risk and 0 were affected. No deaths were reported in either group.
The record also reports other adverse events: 1 affected participant among 143 at risk in the gadobutrol group, and 4 affected participants among 156 at risk in the gadoterate group. These are counts, not estimates of a causal treatment effect. The record does not identify serious adverse event terms; the list of top serious terms is empty.
In general, adverse-event counts describe what was recorded in a study and do not by themselves establish whether a treatment caused an event. Here, allocation was nonrandomized, and the study arms are not described as a like-for-like control comparison. The differing at-risk counts and the subgroup sequence also warrant caution when comparing the groups. The registry record does not provide further detail on event timing, severity beyond the serious-versus-other distinction, or a formal comparative safety analysis.
12. What the Result Does, and Does Not, Mean
The record establishes that LEADER 75 investigated reader-rated lesion contrast enhancement after reduced-dose gadobutrol and standard-dose gadoterate. It supplies the endpoint scale, reader description, analysis-population definition, and study sequence. However, it does not report numerical results for the primary endpoint. The statistical evidence needed to describe the observed average ratings, the contrast between regimens, or the precision of that contrast is therefore not available in the registry record.
The study purpose refers to whether the reduced-dose regimen produces images of similar quality to those obtained with the full-dose comparator. That purpose is a research question, not a result. In general, similarity cannot be established simply because two regimens were compared or because both were assessed using the same scale. It requires an interpretable estimate and uncertainty, along with a criterion for what degree of difference would count as acceptably similar. The registry record does not report a similarity margin or primary numerical comparison.
The nonrandomized structure further limits causal interpretation. Gadobutrol was assessed in a subgroup whose lesions had been confirmed after gadoterate, and the record does not describe random allocation. Consequently, the study structure should not be read as though it guaranteed balanced exposure groups or removed all potential sources of bias. The crossover designation does not by itself resolve those issues.
The reported adverse-event counts describe events recorded in the groups, but they do not establish comparative safety. Likewise, secondary outcome topics listed in the record do not establish their results. The strongest conclusion supported by the registry record is that the study was designed to evaluate imaging ratings and other outcomes in this setting, while the numerical primary findings and details needed for a full statistical assessment are not reported.
13. Why This Trial Matters Statistically
This trial raises a useful statistical question about how to compare image-based ratings when the study structure is nonrandomized and the second contrast-agent assessment occurs in a confirmed-lesion subgroup. Those design details matter because the interpretation of a comparison depends not only on the measurement scale but also on which participants contributed observations and how assessments relate to one another.
The endpoint also highlights a common issue in clinical research: visual judgments are converted into an ordered numerical scale and summarized with a mean. That can make results easier to communicate, but readers still need the estimate, its variability, and an account of how dependence among readers, lesions, and participants was handled. The registry describes three blinded readers and an average reader score, but does not report the numerical endpoint result or full analysis method.
The stated question concerns similarity between regimens. Statistically, such a question needs a defined criterion for interpreting how much difference is acceptable, as well as results precise enough to evaluate that criterion. The registry record does not report a similarity margin, primary estimate, or uncertainty interval. This distinction is important: a study’s objective and measurement plan do not, on their own, establish that the intended comparison met a particular standard.
The record therefore illustrates why design, analysis population, endpoint construction, and result reporting must be read together. It provides enough information to identify the scientific comparison and several interpretive constraints, but not enough to determine the observed primary contrast or its precision.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The main limitation for statistical interpretation is that numerical primary-endpoint results are not reported in the registry record. Without the means, standard deviations, comparison estimate, or uncertainty interval, the observed enhancement ratings and their precision cannot be assessed. The record also does not report a similarity margin, which is important for interpreting the stated aim of comparing image quality.
The nonrandomized allocation and subgroup sequence limit the interpretation of any contrast between regimens. The gadobutrol examination was performed for participants with gadoterate-confirmed lesions, rather than being described as a second assessment for all participants. The registry does not report details of the allocation process, the reasons participants did or did not receive the second examination, or whether order-related effects were evaluated.
The record gives a Full Analysis Set definition based on availability of electronic case report form entries and images for the relevant MRI sequences, but does not report the number in that population or the handling of missing data. It does not describe the statistical model, the treatment of repeated measurements, adjustments for readers or lesions, or sensitivity analyses. The multiplicity approach for the listed outcome measures and analyses is also not reported.
Finally, the registry provides limited detail for interpreting safety counts and no numerical primary outcome findings. These omissions do not establish that the study did not conduct such analyses; they mean the relevant methods and results are not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Comparison of Gadovist 75% Standard Dose to Dotarem at Full Standard Dose — NCT03602339.
- Registry record last updated 2021-06-14; status last verified 2021-05.
- Results first posted 2021-04-28.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT03602339 is the Phase 4 LEADER 75 study, titled “Comparison of Gadovist 75% Standard Dose to Dotarem at Full Standard Dose.” It was a completed, nonrandomized crossover study sponsored by Bayer, with enrollment listed as 157. The study dates run from 2018-11-14 to primary completion on 2020-03-13.
The primary endpoint was mean reader score for lesion contrast enhancement, assessed by three blinded readers using a four-point scale. The record describes a gadoterate examination followed by a gadobutrol examination in the subgroup with gadoterate-confirmed lesions. It also reports adverse-event counts and lists secondary outcome topics.
Numerical primary-endpoint results, the comparison’s precision, a similarity margin, and details of the statistical analysis plan are not reported in the registry record. The reported design and endpoint description therefore identify the question studied, but do not establish the observed imaging comparison.