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 An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease (NCT02485899), a na phase 1, phase 2 study. The primary outcome is Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02485899 |
| Phase | Phase 1, Phase 2 |
| Condition | Jansky-Bielschowsky Disease, Batten Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 23 |
| Arms in the primary outcome | n/a |
| Lead sponsor | BioMarin Pharmaceutical |
| Results posted | Yes |
2. Clinical Question
Population
Patients with CLN2 disease who completed the 190-201 study were eligible to continue in the 190-202 extension. The record describes 24 subjects enrolled in 190-201 and says one terminated after a single infusion and was not included in the 190-202 Intent-to-Treat population. The registry enrollment field reports 23.
Intervention
BMN 190, described as recombinant human tripeptidyl peptidase-1, was administered at 300 mg by continuous intracerebroventricular infusion. The stated regimen was approximately 4 hours at a rate of 2.5 mL/hour, every 14 days. An intracerebroventricular access device was also listed.
Comparator
The study is described as a single-group, open-label extension, not as a randomized comparison. Its primary endpoint description refers to natural-history data as the context for assessing the outcome. Details of the natural-history comparison population and its observed results are not reported in the registry record.
Primary question
The endpoint asks about the probability of an unreversed 2-point decline in the Motor-language score or a score of 0, during follow-up up to Week 289. The record says the assessment uses Kaplan-Meier and Cox methods with covariate adjustment, but does not report the estimated probability, effect estimate, or confidence interval.
3. Trial Design
This is a Phase 1/2, open-label extension study of BMN 190 in patients with CLN2 disease. The registry describes a single-group model and lists allocation as not applicable. The study is not presented as a randomized trial with a concurrent control arm. It was intended to allow patients completing study 190-201 to continue treatment and to assess long-term safety and efficacy.
The intervention description specifies BMN 190 at 300 mg, administered by continuous intracerebroventricular infusion at 2.5 mL/hour for approximately 4 hours every 14 days. An intracerebroventricular access device is listed as an intervention. The record says the dose and regimen were based on the results of study 190-201; further details of how that regimen was selected are not reported in the registry record.
The registry lists enrollment as 23. The primary-outcome population description separately says 24 subjects were enrolled in 190-201, with one subject terminating after a single infusion and excluded from the 190-202 Intent-to-Treat population. The adverse-event record uses 24 as the number at risk. These entries refer to different record fields or populations, and a reconciliation is not reported in the registry record.
The study status is completed. The recorded start is 2015-02 and primary completion is 2020-12-10. Follow-up for the primary endpoint is described as extending up to Week 289. The registry does not report a concurrent control group, masking, or a randomized allocation procedure for this extension.
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: 190-202 is the extension of treatment \& follow-up for subjects enrolled in Study 190-201. The ITT analysis population was comprised of the 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (completed 48 weeks in 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). The safety analysis population in Study 190-202 was comprised of the 24 subjects in Study 190-201 who had an ICV access device implanted.
Overall Study
| Stage | 190-202 (300 mg) | Natural History Comparator |
|---|---|---|
| STARTED | 24 | 42 |
| COMPLETED | 17 | 42 |
| NOT COMPLETED | 7 | 0 |
Reasons for not completing this period:
| Reason | 190-202 (300 mg) | Natural History Comparator |
|---|---|---|
| Protocol-Specified Withdrawal Criterion Met | 2 | 0 |
| Withdrawal by Subject | 1 | 0 |
| Withdrawal by Parent/ Guardian | 4 | 0 |
Analysis population for the primary outcome, as defined in the registry: BMN 190-202: 24 subjects were enrolled in 190-201 at 5 clinic sites worldwide. One subject terminated from 190-201 after a single infusion and is not included in the Intent-to-Treat (ITT) population for 190-202. Study 190-202 final efficacy results include pooled data from the complete dataset from Study 190-201 \& Study 190-202 for all subjects who received \>1 dose (N=23). NH: 42 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description below.
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: The demographic characteristics of the enrolled population are summarized for the 190-201/202 study (24 subjects). The demographic characteristics of the control group (NH comparator) which were necessary to determine the primary efficacy outcome measures, are also included (42 subjects).
| Characteristic | Unit | 190-202 (300 mg) | Natural History Comparator | Total |
|---|---|---|---|---|
| Participants analysed | 24 | 42 | 66 | |
| Age, Continuous | years | 5.0 (SD 1.29) | 4.0 (SD 0.92) | 4.3 (SD 1.17) |
| Sex: Female, Male: Female | Participants | 15 | 17 | 32 |
| Sex: Female, Male: Male | Participants | 9 | 25 | 34 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 1 | 0 | 1 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 23 | 0 | 23 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 42 | 42 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 23 | 0 | 23 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 42 | 42 |
| 300 mg Baseline ML Score | units on a scale | 3.5 (SD 1.18) | 4.5 (SD 0.77) | 4.1 (SD 1.05) |
6. Primary Endpoint
The registry lists the primary outcome as Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0, measured over Up to Week 289.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | 95% Confidence Interval |
| Unit | Probability of decline |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the probability of an unreversed 2-point decline in the Motor-language score or a score of 0, assessed over follow-up up to Week 289. The Motor and Language subscales each range from 0 to 3, with 3 representing best function and 0 representing loss of function. Their combined 0-6 score is used in the registry description as the main measure of loss of function.
The endpoint combines a decline criterion with the score-of-0 criterion. The term unreversed indicates that the qualifying decline is not subsequently reversed, as described in the endpoint name. The registry record does not provide further operational details about how reversals, timing, or incomplete assessments were handled.
The record explains that the earlier 190-201 study assessed a responder endpoint at Week 48 against an expected natural-history rate. In 190-202, the endpoint was revised to assess response over the full duration of follow-up. Because follow-up varied and extended well beyond 48 weeks, the record says the expected natural-history response rate was unclear. It describes comparison with natural-history data using Kaplan-Meier estimation and a covariate-adjusted Cox proportional hazards model. The resulting estimate and confidence interval are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The record identifies a clinically oriented time-to-event endpoint: whether an unreversed Motor-language decline meeting the stated threshold, or a score of 0, occurs during follow-up. It also identifies the planned analytic approach in broad terms. However, the registry record does not report the primary endpoint result, an estimated probability, a hazard ratio, a confidence interval, or a p-value. The direction, magnitude, and precision of the primary efficacy finding therefore cannot be assessed from the information.
The extension has a single-group, open-label design. Its primary endpoint description refers to natural-history data, but the registry record does not give the comparator data, the results of the comparison, or details sufficient to evaluate comparability between the extension participants and the natural-history population. Without a concurrent randomized control group, changes over time cannot be attributed to the intervention by a direct randomized contrast. General interpretation of an external comparison depends on whether the groups, outcome definitions, follow-up, and relevant prognostic characteristics are sufficiently aligned; the registry record does not establish that alignment.
The endpoint description says the analysis used Kaplan-Meier methods and a Cox proportional hazards model with adjustment for baseline Motor-language score and age as continuous covariates, and genotype for common alleles and sex as categorical covariates. Those details describe the stated approach, not its results. The adjusted estimates, model diagnostics, number of endpoint events, and handling of departures from model assumptions are not reported in the registry record. The primary endpoint description also notes variable follow-up, making the time-to-event framing relevant, but does not report how much follow-up was available for each participant.
The registry reports an enrollment value of 23, while the primary-outcome description refers to 24 subjects enrolled in the preceding study and one subject excluded from the 190-202 Intent-to-Treat population. The safety record reports 24 at risk. These values should not be combined or treated as interchangeable; their relationship is not reported in the registry record. The adverse-event counts and listed percentages describe the safety record, not the missing efficacy estimate.
A planning illustration based on an observed effect, if displayed with the results, is not evidence of observed power and does not replace the trial's outcome analysis. The registry does not state a sample-size justification or provide the primary effect estimate needed to assess such an illustration independently. Overall, the available information describes the design, endpoint definition, and selected safety entries, but does not establish the size or precision of the primary efficacy result.
9. Statistical Methods Explained
The registry describes a time-to-event approach for the primary endpoint, using Kaplan-Meier estimation and a Cox proportional hazards model. These methods are relevant when the outcome is defined by the time until an event and participants may have different lengths of follow-up. The registry reports covariate adjustment for baseline Motor-language score and age as continuous covariates, and genotype for common alleles and sex as categorical covariates. It does not report the model estimates or diagnostics.
What does Kaplan-Meier estimation describe?
In general, Kaplan-Meier estimation uses the observed event times and the follow-up information to estimate how the probability of remaining event-free changes over time. Participants who have not had the event by the end of their observed follow-up can still contribute information until that point; their later event status is not assumed to be known. This is why the method can accommodate differing follow-up durations, provided the censoring assumptions are reasonable. The estimate depends on the recorded event definition, event times, and censoring information. Those underlying data and details of censoring are not reported in the registry record.
For this trial, the event is described as an unreversed 2-point decline in Motor-language score or a score of 0. The endpoint timeframe is up to Week 289. A Kaplan-Meier estimate could express the cumulative event experience over follow-up, but no such estimate is reported in the registry record. The record also does not state the number of events or give the estimated probability at a particular follow-up time.
What does a Cox model add?
In general, a Cox proportional hazards model relates the rate at which an event occurs to participant characteristics. It can estimate associations while adjusting for specified covariates. A hazard ratio compares event rates over time under the model; it is not the same quantity as an event probability, and it should not be interpreted as a direct difference in probabilities. The proportional-hazards assumption concerns whether the relative event rate is adequately represented as stable over follow-up. The registry names the Cox model and covariates, but does not report a hazard ratio, its confidence interval, an assessment of the proportional-hazards assumption, or other model diagnostics.
Adjustment for baseline characteristics can account for measured differences included in the model. It cannot by itself remove bias from unmeasured factors or make an external natural-history group equivalent to a randomized concurrent control. The primary endpoint description names baseline Motor-language score and age, genotype for common alleles, and sex. It does not report how missing covariate values were handled, how categories for genotype were defined, or whether any additional adjustment or sensitivity analyses were performed.
How should the confidence interval be read?
In general, a confidence interval expresses uncertainty around an estimate under the statistical method used. A narrower interval indicates greater precision under that method, while a wider interval indicates less precision. It does not represent a range containing a fixed proportion of individual outcomes, and it does not address biases that arise from study design or measurement. The primary endpoint is described with a 95% Confidence Interval, but the interval limits are not reported in the registry record. Consequently, the precision of the primary estimate cannot be evaluated from this record.
What can planning illustrations establish?
In general, sample-size calculations use assumptions about the effect to be detected, variability or event rates, allocation, and error thresholds. The planning assumptions associated with this record describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Time-to-event planning is described as using a total event count; other illustrations are described in participants per arm. These are planning conventions, not a report of the study's own design or observed power.
This extension is described as a single-group study, and its allocation is listed as not applicable. Thus, any illustration using equal allocation between two arms does not describe the extension's actual allocation. A planning illustration based on the observed effect cannot establish that the study was adequately powered, cannot substitute for the observed efficacy result, and is not observed power. The registry does not report the study's sample-size justification. No interpretation of a planning figure can recover the missing primary endpoint estimate or its uncertainty.
The registry also reports seven outcome measures and two analyses. In general, when multiple outcomes or analyses are considered, the chance of at least one apparently unusual result can depend on how many tests are conducted and how they are selected. The record does not provide enough detail to determine the complete family of tests, the order of analyses, or whether an adjustment was used. Those issues should not be inferred from the named model alone.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists seven outcome measures and two analyses, and identifies secondary outcomes including whole brain volume, volume of cerebrospinal fluid, volume of total cortical gray matter, total white matter volume, and whole brain apparent diffusion coefficient. The full set of outcome measures and the relationship between the listed outcomes and analyses are not reported in the registry record. A multiplicity strategy, such as a prespecified hierarchy or adjustment across statistical tests, is also not reported.
In general, testing multiple outcomes or conducting multiple analyses can increase the chance of observing a nominally notable result by chance. Whether and how to address this depends on the trial's objectives and prespecified analysis plan. The registry record does not report a statistical analysis plan, the number of inferential tests, or whether multiplicity was controlled. It is therefore not possible to determine how any reported secondary results should be interpreted in relation to one another; secondary efficacy estimates are not reported in the registry record.
Information about missing outcome data, missed visits, censoring rules, imputation, or sensitivity analyses is not reported in the registry record. These details matter in a time-to-event analysis because follow-up may end before an event is observed, and in repeated measurements because incomplete observations can affect the available data. The primary endpoint description states that follow-up varied, but does not explain how incomplete or unavailable assessments were handled.
The record says one subject terminated from 190-201 after a single infusion and was not included in the 190-202 Intent-to-Treat population. It does not fully describe the analysis populations used for the primary endpoint or explain whether other analysis sets were used. The registry enrollment entry of 23 and the safety record's 24 at risk also require population-specific interpretation; reconciliation is not reported in the registry record. These limitations prevent a complete assessment of analysis-population selection and missing-data sensitivity.
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 |
|---|---|---|---|
| BMN 190-202 (300 mg) | 21 | 24 | 87.5% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| BMN 190-202 (300 mg) | 0 of 24 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| BMN 190-202 (300 mg) | 24 of 24 |
Most frequent serious adverse event terms
| Event term | Organ system | BMN 190-202 (300 mg) |
|---|---|---|
| Device end of service | Product Issues | 13 of 24 |
| Device related infection | Infections and infestations | 7 of 24 |
| Hypersensitivity | Immune system disorders | 7 of 24 |
| Upper respiratory tract infection | Infections and infestations | 5 of 24 |
| Gastroenteritis | Infections and infestations | 4 of 24 |
| Dysphagia | Gastrointestinal disorders | 4 of 24 |
| Pleocytosis | Nervous system disorders | 3 of 24 |
| Pharyngitis bacterial | Infections and infestations | 2 of 24 |
| Pyelonephritis | Infections and infestations | 2 of 24 |
| Epilepsy | Nervous system disorders | 2 of 24 |
Most frequent non-serious adverse event terms
| Event term | Organ system | BMN 190-202 (300 mg) |
|---|---|---|
| Upper respiratory tract infection | Infections and infestations | 21 of 24 |
| Pyrexia | General disorders | 20 of 24 |
| Vomiting | Gastrointestinal disorders | 19 of 24 |
| Viral upper respiratory tract infection | Infections and infestations | 19 of 24 |
| Generalised tonic-clonic seizure | Nervous system disorders | 16 of 24 |
| Seizure | Nervous system disorders | 14 of 24 |
| Epilepsy | Nervous system disorders | 13 of 24 |
| Constipation | Gastrointestinal disorders | 13 of 24 |
| Dysphagia | Gastrointestinal disorders | 13 of 24 |
| Device end of service | Product Issues | 13 of 24 |
Serious events with the highest arm-level rate: device end of service (54.2%), device related infection (29.2%), hypersensitivity (29.2%), upper respiratory tract infection (20.8%), gastroenteritis (16.7%).
The safety record lists a BMN 190-202 (300 mg) group with 24 at risk for serious adverse events and 21 affected. It also reports 24 at risk and 24 affected for other adverse events, and deaths of 0. These entries describe the registry's safety counts; they do not provide event-level timing, duration, severity beyond the serious-event classification, or causal attribution. The registry record does not report further details needed to interpret these counts fully.
The listed serious adverse-event terms and percentages are device end of service, 54.2%; device related infection, 29.2%; hypersensitivity, 29.2%; upper respiratory tract infection, 20.8%; gastroenteritis, 16.7%; and dysphagia, 16.7%. These are registry-listed terms and percentages. The record does not explain whether participants could contribute to more than one term, how repeated events were counted, or the precise denominator used for each percentage. The percentages should not be added together or treated as mutually exclusive categories.
Safety counts in an open-label extension describe reported events among the recorded study population. They do not by themselves establish whether an event was caused by treatment, and they do not allow a randomized comparison of event rates. The registry's enrollment entry is 23, whereas the safety denominator is 24; the relationship between these entries is not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The registry record establishes that 190-202 was an open-label extension study intended to assess long-term safety and efficacy of BMN 190 in patients with CLN2 disease. It describes the treatment regimen and defines a primary endpoint based on an unreversed decline in Motor-language score or a score of 0. It also states that the primary assessment used natural-history data and time-to-event methods with covariate adjustment.
Those design and methods details do not reveal the observed primary outcome. The registry record does not report the estimated probability of the endpoint, a hazard ratio, a confidence interval, a p-value, or the number of primary endpoint events. Without these results, the magnitude and precision of the primary finding cannot be described. No conclusion about the treatment's efficacy follows from the endpoint definition alone.
The record's safety entries give counts for participants affected and list serious adverse-event terms with percentages. These figures describe the entries recorded in the registry, but do not establish causation or provide a comparison with an untreated or randomized control group. The record also does not explain the counting rules behind the listed terms, or report all details about follow-up and safety-event handling.
In general, an external natural-history comparison can offer context when a concurrent control group is absent, but interpretation depends on the comparability of populations, outcome definitions, measurement schedules, and follow-up. The registry record does not provide enough information to assess those features or the results of the stated comparison. Covariate adjustment addresses only measured variables included in the model and does not eliminate every potential source of bias.
The study should therefore be read as an extension record with a specified endpoint and analysis approach, but without the primary efficacy estimate needed to judge its size or precision. The status of completed does not itself supply a result. The registry record's enrollment, safety, and design details should be kept distinct from evidence about the primary endpoint.
13. Why This Trial Matters Statistically
This study raises a central statistical issue in long-term extension research: how to describe an outcome when participants have variable follow-up and there is no concurrent randomized control group. The registry addresses the varying follow-up by naming Kaplan-Meier estimation and a Cox proportional hazards model. These methods can use time-to-event information, but their interpretation depends on event definitions, censoring, follow-up completeness, and model assumptions.
The endpoint itself reflects a longitudinal clinical measure. The registry combines the Motor and Language subscales into a 0-6 Motor-language score and defines a qualifying event using an unreversed decline or a score of 0. For a longitudinal endpoint, clear rules for measuring change, confirming reversals, handling missed assessments, and determining event time are important. Those operational details are not reported in the registry record.
The record also describes comparison with natural-history data. External comparisons can be informative in some settings, but they require careful attention to differences in participant characteristics, outcome ascertainment, follow-up, and other sources of bias. The use of covariate adjustment for specified characteristics is part of the stated approach; it does not, on its own, establish comparability or eliminate unmeasured differences.
Finally, the available registry entries illustrate why design, outcome definition, analysis method, and numerical results must be distinguished. Here, the design and primary endpoint are described, while the primary estimate and its confidence interval are not reported in the registry record. Without those results, readers cannot assess the observed efficacy effect or its precision. The listed safety counts and terms contribute separate descriptive information, but do not fill that gap.
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 registry record does not report the primary endpoint estimate, confidence interval, hazard ratio, p-value, event count, or detailed natural-history comparison results. The primary efficacy finding therefore cannot be evaluated for magnitude, precision, or statistical compatibility with a range of effects. The record also does not report the statistical analysis plan, model diagnostics, proportional-hazards assessment, or sensitivity analyses.
The extension is open label and single group, with allocation listed as not applicable. Its endpoint description refers to natural-history data, but details about that comparison and the basis for comparability are not reported in the registry record. A concurrent randomized control group is not described. The record does not report how potential differences in participant characteristics, outcome measurement, or follow-up were handled beyond naming covariate adjustment for specified characteristics.
The primary endpoint description notes variable follow-up up to Week 289, but the distribution of follow-up, censoring rules, missing assessments, and handling of incomplete observations are not reported. The record does not explain how reversals in Motor-language score were operationalized, or how endpoint timing was assigned.
There are also population-count entries that need care: registry enrollment is 23, the primary-outcome description refers to 24 subjects enrolled in 190-201 and says one was excluded from the 190-202 Intent-to-Treat population, and the safety record lists 24 at risk. Their relationship is not reported in the registry record. Safety-event counting and attribution details are also limited. These constraints restrict interpretation beyond the basic design, endpoint definition, and recorded safety entries.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease — NCT02485899.
- Registry record last updated 2022-08-24; status last verified 2022-07.
- Results first posted 2022-08-24.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT02485899 is a completed, open-label Phase 1/2 extension study of BMN 190 in patients with CLN2 disease. It is described as a single-group study intended to assess long-term safety and efficacy after study 190-201. The regimen was 300 mg by continuous intracerebroventricular infusion at 2.5 mL/hour for approximately 4 hours every 14 days.
The primary endpoint was the probability of an unreversed 2-point decline in Motor-language score or a score of 0, assessed up to Week 289. The record describes Kaplan-Meier estimation and a covariate-adjusted Cox model, with comparison to natural-history data. The primary efficacy estimate and confidence interval are not reported in the registry record.
The registry lists enrollment as 23; the primary-outcome description and safety record contain population counts of 24 with a separate exclusion statement. The safety record reports 21 affected among 24 at risk for serious adverse events, 24 affected among 24 at risk for other adverse events, and deaths of 0. The relationship among enrollment and safety populations is not reported in the registry record.