Trial Outcomes & Findings for An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease (NCT NCT02485899)

NCT ID: NCT02485899

Last Updated: 2022-08-24

Results Overview

Motor and Language are each 0-3 point subscales in which 3 represents best function and 0 represents loss of function. Thus, the 0-6 point ML score was used as the primary mode of evaluation of loss of function. In 190-201, the primary endpoint was a responder endpoint: unreversed ML 2-point decline or score of 0 at Week 48 compared to the 50% rate expected in natural history using the 1-sample binomial test. For 190-202, the primary endpoint was revised to assess response over the full duration of follow-up. It is not clear, given the variable follow-up much greater than 48 weeks, what response rate is expected in natural history. For this reason, the assessment of the primary endpoint is based on comparing to natural history data and using the Kaplan-Meier method and Cox proportional hazards model with covariate adjustment (i.e., baseline ML score and age as continuous covariates, and genotype \[common alleles\] and sex as categorical covariates).

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 23 participants
• Primary outcome timeframe: Up to Week 289
• Results posted on: 2022-08-24

Participant Flow

190-201 was conducted at 5 clinic sites in Germany, Italy, the United Kingdom and the United States. One subject from one of the two 190-201 sites in the United Kingdom withdrew after 1 dose of BMN 190 and therefore this site was not activated in 190-202. The comparator group for determination of the primary efficacy outcome measures in this study was comprised of 42 Natural History (NH) subjects with CLN2 disease selected from the DEM-CHILD database (NCT04613089).

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.

Participant milestones

Measure	190-202 (300 mg) 190-202 Intent to Treat (ITT)/Efficacy Population (n = 23): The 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (i.e., completed 48 weeks in Study 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). 190-202 Safety Population (n = 24): All study subjects who had an ICV access device implanted in Study 190-201.	Natural History Comparator The NH comparator population consisted of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3 years; and at least one ML score ≥3 points at age ≥3 years and further, who had at least two CLN2 assessments with values within the range 1 to 5 points and at least 6 months apart.
Overall Study STARTED	24	42
Overall Study COMPLETED	17	42
Overall Study NOT COMPLETED	7	0

Reasons for withdrawal

Measure	190-202 (300 mg) 190-202 Intent to Treat (ITT)/Efficacy Population (n = 23): The 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (i.e., completed 48 weeks in Study 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). 190-202 Safety Population (n = 24): All study subjects who had an ICV access device implanted in Study 190-201.	Natural History Comparator The NH comparator population consisted of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3 years; and at least one ML score ≥3 points at age ≥3 years and further, who had at least two CLN2 assessments with values within the range 1 to 5 points and at least 6 months apart.
Overall Study Protocol-Specified Withdrawal Criterion Met	2	0
Overall Study Withdrawal by Subject	1	0
Overall Study Withdrawal by Parent/ Guardian	4	0

Baseline Characteristics

An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease

Baseline characteristics by cohort

Measure	190-202 (300 mg) n=24 Participants 190-202 Intent to Treat (ITT)/Efficacy Population (n = 23): The 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (i.e., completed 48 weeks in Study 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). 190-202 Safety Population (n = 24): All study subjects who had an ICV access device implanted in Study 190-201.	Natural History Comparator n=42 Participants Because of practical (limited number of available patients) and ethical (neurosurgery in children with fatal neurologic disease) concerns, this study design could not involve contemporaneous, matched, randomized, blinded, or untreated control subjects. As such, data from the DEM-CHILD Multi-Center Clinical NCL Database at the University Medical Center in Hamburg, Germany (NCT04613089) was used as a control group (i.e., Natural History \[NH\] comparator) to determine the primary efficacy outcome measures for this study. The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.	Total n=66 Participants Total of all reporting groups
Race (NIH/OMB) White	23 Participants n=5 Participants	0 Participants n=7 Participants	23 Participants n=5 Participants
Age, Continuous	5.0 years STANDARD_DEVIATION 1.29 • n=5 Participants	4.0 years STANDARD_DEVIATION 0.92 • n=7 Participants	4.3 years STANDARD_DEVIATION 1.17 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	17 Participants n=7 Participants	32 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	25 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants	0 Participants n=7 Participants	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	42 Participants n=7 Participants	42 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	42 Participants n=7 Participants	42 Participants n=5 Participants
300 mg Baseline ML Score	3.5 units on a scale STANDARD_DEVIATION 1.18 • n=5 Participants	4.5 units on a scale STANDARD_DEVIATION 0.77 • n=7 Participants	4.1 units on a scale STANDARD_DEVIATION 1.05 • n=5 Participants

PRIMARY outcome

Timeframe: Up to Week 289

Population: 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.

Motor and Language are each 0-3 point subscales in which 3 represents best function and 0 represents loss of function. Thus, the 0-6 point ML score was used as the primary mode of evaluation of loss of function.

In 190-201, the primary endpoint was a responder endpoint: unreversed ML 2-point decline or score of 0 at Week 48 compared to the 50% rate expected in natural history using the 1-sample binomial test. For 190-202, the primary endpoint was revised to assess response over the full duration of follow-up. It is not clear, given the variable follow-up much greater than 48 weeks, what response rate is expected in natural history. For this reason, the assessment of the primary endpoint is based on comparing to natural history data and using the Kaplan-Meier method and Cox proportional hazards model with covariate adjustment (i.e., baseline ML score and age as continuous covariates, and genotype [common alleles] and sex as categorical covariates).

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator n=42 Participants The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 49	0.13 Probability of decline Interval 0.04 to 0.35	0.48 Probability of decline Interval 0.34 to 0.64
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 97	0.22 Probability of decline Interval 0.1 to 0.45	0.91 Probability of decline Interval 0.79 to 0.98
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 145	0.22 Probability of decline Interval 0.1 to 0.45	0.97 Probability of decline Interval 0.87 to 1.0
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 193	0.26 Probability of decline Interval 0.13 to 0.5	0.97 Probability of decline Interval 0.87 to 1.0
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 241	0.40 Probability of decline Interval 0.23 to 0.63	1.00 Probability of decline Interval 0.87 to 1.0
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0 Probability of decline: Week 289	0.54 Probability of decline Interval 0.35 to 0.75	1.00 Probability of decline Interval 0.87 to 1.0

PRIMARY outcome

Timeframe: Up to Week 289

Population: 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.

Motor and Language are each 0-3 point subscales in which 3 represents best function and 0 represents loss of function. Thus, the 0-6 point ML score was used as the primary mode of evaluation of loss of function.

In 190-201, the primary endpoint was a responder endpoint: unreversed ML 2-point decline or score of 0 at Week 48 compared to the 50% rate expected in natural history using the 1-sample binomial test. For 190-202, the primary endpoint was revised to assess response over the full duration of follow-up. It is not clear, given the variable follow-up much greater than 48 weeks, what response rate is expected in natural history. For this reason, the assessment of the primary endpoint is based on comparing to natural history data and using the Kaplan-Meier method and Cox proportional hazards model with covariate adjustment (baseline ML score, age, genotype [common alleles], and sex).

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator n=42 Participants The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 49	0.00 Probability of decline Interval 0.0 to 0.0	0.03 Probability of decline Interval 0.0 to 0.16
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 97	0.00 Probability of decline Interval 0.0 to 0.0	0.38 Probability of decline Interval 0.24 to 0.55
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 145	0.00 Probability of decline Interval 0.0 to 0.0	0.78 Probability of decline Interval 0.63 to 0.9
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 193	0.05 Probability of decline Interval 0.01 to 0.28	0.94 Probability of decline Interval 0.82 to 0.99
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 241	0.05 Probability of decline Interval 0.01 to 0.28	0.97 Probability of decline Interval 0.86 to 1.0
Probability of Unreversed Motor-language (ML) Score of Zero. Probability of decline: Week 289	0.15 Probability of decline Interval 0.05 to 0.39	1.00 Probability of decline Interval 0.86 to 1.0

SECONDARY outcome

Timeframe: Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Population: 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).

Percentage change from Baseline to Last Observation: Whole Brain volume

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Whole Brain Volume	-4.7 percentage change Standard Deviation 10.54	—

SECONDARY outcome

Timeframe: Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Population: 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).

Percentage Change from Baseline to last observation: Volume of cerebrospinal fluid

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Volume of Cerebrospinal Fluid	8.5 percentage change Standard Deviation 21.94	—

SECONDARY outcome

Timeframe: Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Population: 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).

Percentage Change from Baseline to last observation: Volume of total cortical gray matter

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Volume of Total Cortical Gray Matter	-14.7 percentage change Standard Deviation 10.25	—

SECONDARY outcome

Timeframe: Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Population: 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).

Percentage Change from Baseline to last observation: Total white matter volume

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Total White Matter Volume	-2.4 percentage change Standard Deviation 12.07	—

SECONDARY outcome

Timeframe: Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Population: 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).

Change from Baseline to last observation Whole brain apparent diffusion coefficient

Outcome measures

Measure	BMN 190-202 (300 mg) n=23 Participants All study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.	Natural History Comparator The control group (NH comparator) was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.
Whole Brain Apparent Diffusion Coefficient	0.00 mm^2/s Standard Deviation 0.030	—

Adverse Events

BMN 190-202 (300 mg)

Serious events: 21 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Measure	BMN 190-202 (300 mg) n=24 participants at risk Study 190-202 is the extension of treatment and follow-up for patients who enrolled in Study 190-201. Pooled data (Study 190-201/202; 24 subjects) are presented since adverse event data for Study 190-202 were collected starting with ICV access device implantation in Study 190-201 (prior to any dose administration).
Infections and infestations Device related infection	29.2% 7/24 • Number of events 11 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Upper respiratory tract infection	20.8% 5/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Gastroenteritis	16.7% 4/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pharyngitis bacterial	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pyelonephritis	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Adenoviral upper respiratory infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Bronchitis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Clostridium difficile colitis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Corona virus infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Influenza	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Mycoplasma infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Otitis media	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pharyngitis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pharyngotonsillitis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pneumonia	4.2% 1/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Propionibacterium infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Respiratory tract infection viral	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Rhinovirus infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Skin infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Urinary tract infection	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Viral pharyngitis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device end of service	54.2% 13/24 • Number of events 13 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device leakage	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device malfunction	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Pleocytosis	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Epilepsy	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Generalised tonic-clonic seizure	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Haemorrhage intracranial	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Hemiparesis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Lethargy	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Motor dysfunction	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Seizure	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Status epilepticus	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Immune system disorders Hypersensitivity	29.2% 7/24 • Number of events 9 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Dysphagia	16.7% 4/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Dental caries	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Device deployment issue	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Infusion related reaction	4.2% 1/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Lower limb fracture	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Post procedural haemorrhage	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Subdural haematoma	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Adenoidal hypertrophy	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Choking	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Respiratory failure	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Pyrexia	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Eye disorders Blindness	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Investigations CSF culture positive	4.2% 1/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Metabolism and nutrition disorders Acidosis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Musculoskeletal and connective tissue disorders Osteonecrosis	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Reproductive system and breast disorders Vaginal discharge	4.2% 1/24 • Number of events 1 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.

Other adverse events

Measure	BMN 190-202 (300 mg) n=24 participants at risk Study 190-202 is the extension of treatment and follow-up for patients who enrolled in Study 190-201. Pooled data (Study 190-201/202; 24 subjects) are presented since adverse event data for Study 190-202 were collected starting with ICV access device implantation in Study 190-201 (prior to any dose administration).
Vascular disorders Hypotension	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Vascular disorders Haematoma	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Surgical and medical procedures Tooth extraction	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skin papilloma	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Immune system disorders Hypersensitivity	41.7% 10/24 • Number of events 16 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Immune system disorders Seasonal allergy	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Pyrexia	83.3% 20/24 • Number of events 219 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Gait disturbance	50.0% 12/24 • Number of events 15 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Abasia	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Complication associated with device	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Developmental delay	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Pain	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
General disorders Feeling jittery	8.3% 2/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Psychiatric disorders Sleep disorder	37.5% 9/24 • Number of events 14 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Psychiatric disorders Insomnia	20.8% 5/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Psychiatric disorders Irritability	20.8% 5/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Psychiatric disorders Agitation	16.7% 4/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Psychiatric disorders Abnormal behaviour	16.7% 4/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Fall	33.3% 8/24 • Number of events 36 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Contusion	33.3% 8/24 • Number of events 11 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Head injury	12.5% 3/24 • Number of events 8 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Procedural pain	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Device deployment issue	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Device difficult to use	8.3% 2/24 • Number of events 7 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Laceration	8.3% 2/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Limb injury	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Lower limb fracture	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Procedural vomiting	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Injury, poisoning and procedural complications Stoma site reaction	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Investigations Body temperature increased	16.7% 4/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Investigations CSF red blood cell count positive	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Investigations Oxygen saturation decreased	12.5% 3/24 • Number of events 11 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Investigations CSF test abnormal	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Cardiac disorders Bradycardia	8.3% 2/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Blood and lymphatic system disorders Thrombocytopenia	20.8% 5/24 • Number of events 7 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Blood and lymphatic system disorders Anaemia	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Cough	45.8% 11/24 • Number of events 23 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Epistaxis	16.7% 4/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Respiratory, thoracic and mediastinal disorders Choking	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Generalised tonic-clonic seizure	66.7% 16/24 • Number of events 250 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Seizure	58.3% 14/24 • Number of events 201 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Epilepsy	54.2% 13/24 • Number of events 180 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Tremor	45.8% 11/24 • Number of events 13 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Extensor plantar response	37.5% 9/24 • Number of events 13 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Myoclonus	41.7% 10/24 • Number of events 24 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Petit mal epilepsy	33.3% 8/24 • Number of events 22 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Partial seizures	29.2% 7/24 • Number of events 15 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Pleocytosis	25.0% 6/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Speech disorder	25.0% 6/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Language disorder	20.8% 5/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Dyskinesia	16.7% 4/24 • Number of events 11 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Athetosis	16.7% 4/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Headache	16.7% 4/24 • Number of events 13 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Ataxia	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Atonic seizures	12.5% 3/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Myoclonic epilepsy	12.5% 3/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Muscle spasticity	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Movement disorder	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Seizure cluster	12.5% 3/24 • Number of events 7 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Clonus	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Chorea	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Balance disorder	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Drop attacks	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Hypotonia	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Status epilepticus	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Somnolence	8.3% 2/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Nervous system disorders Dystonia	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Eye disorders Visual impairment	45.8% 11/24 • Number of events 16 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Eye disorders Blindness	16.7% 4/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Constipation	54.2% 13/24 • Number of events 22 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Vomiting	79.2% 19/24 • Number of events 78 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Dysphagia	54.2% 13/24 • Number of events 26 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Dental caries	20.8% 5/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Abdominal pain	25.0% 6/24 • Number of events 10 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Diarrhoea	37.5% 9/24 • Number of events 19 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Salivary hypersecretion	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Gastrointestinal disorder	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Toothache	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Teething	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Oesophagitis	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Nausea	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Gastrointestinal disorders Gastrooesophageal reflux disease	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device end of service	54.2% 13/24 • Number of events 13 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device leakage	16.7% 4/24 • Number of events 10 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Needle issue	37.5% 9/24 • Number of events 11 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device malfunction	16.7% 4/24 • Number of events 9 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Product Issues Device issue	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Skin and subcutaneous tissue disorders Dermatitis contact	20.8% 5/24 • Number of events 6 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Skin and subcutaneous tissue disorders Rash	12.5% 3/24 • Number of events 9 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Skin and subcutaneous tissue disorders Urticaria	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Skin and subcutaneous tissue disorders Dermatitis diaper	8.3% 2/24 • Number of events 10 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Musculoskeletal and connective tissue disorders Pain in extremity	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Musculoskeletal and connective tissue disorders Muscle spasms	12.5% 3/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Metabolism and nutrition disorders Dehydration	12.5% 3/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Metabolism and nutrition disorders Decreased appetite	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Metabolism and nutrition disorders Vitamin D deficiency	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Upper respiratory tract infection	87.5% 21/24 • Number of events 73 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Gastroenteritis	37.5% 9/24 • Number of events 15 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Device related infection	37.5% 9/24 • Number of events 14 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Viral upper respiratory tract infection	79.2% 19/24 • Number of events 46 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Rhinitis	54.2% 13/24 • Number of events 22 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Conjunctivitis	25.0% 6/24 • Number of events 7 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Viral infection	37.5% 9/24 • Number of events 16 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pharyngitis	29.2% 7/24 • Number of events 14 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Respiratory tract infection	25.0% 6/24 • Number of events 9 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Influenza	20.8% 5/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Rhinovirus infection	16.7% 4/24 • Number of events 8 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Bronchitis	12.5% 3/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Lower respiratory tract infection	12.5% 3/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Urinary tract infection	12.5% 3/24 • Number of events 8 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Corona virus infection	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Cystitis	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Oral herpes	8.3% 2/24 • Number of events 7 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Gastroenteritis viral	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Epstein-Barr virus infection	8.3% 2/24 • Number of events 4 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pharyngitis bacterial	8.3% 2/24 • Number of events 3 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pneumonia	8.3% 2/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Tonsillitis bacterial	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Respiratory tract infection viral	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Varicella	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Pyelonephritis	8.3% 2/24 • Number of events 2 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Tonsillitis	20.8% 5/24 • Number of events 12 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.
Infections and infestations Otitis media	16.7% 4/24 • Number of events 5 • Summaries of safety data were descriptive and designed to be inclusive of all adverse events reported in both the 190-201 and 190-202 studies. For each subject, adverse event (AE) data were collected from ICV access device implantation in Study 190-201, prior to any dose administration, to either 6 months after the last administration of study drug or the early termination visit in Study 190-202. 190-202 is the extension of treatment and follow-up for patients who enrolled in 190-201. Pooled data are presented since AE data for 190-202 were collected starting with ICV access device implantation in 190-201 (prior to any dose administration). Subjects who experienced more than 1 AE within a given MedDRA system organ class or preferred term were counted once within that system organ class or preferred term. Adverse events and deaths were not collected for Natural History participants.

Additional Information

Trial Specialist

BioMarin Pharmaceutical, Inc.

Phone: 1-800-983-4587

Email: medinfo@bmrn.com

Results disclosure agreements

• Principal investigator is a sponsor employee The only disclosure restrictions on the PI are that (i) they cannot publish results communications until after the multicenter dataset is published, (ii) the sponsor has an opportunity to review results communications prior to public release, and (iii) the sponsor can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days.
• Publication restrictions are in place

Restriction type: OTHER