Table 4.
Neurologic, CNS, and Hearing-Impairment AEs
| Eventa | Study Phase | Duration, Days | Outcome | Maximum Toxicity Grade |
|---|---|---|---|---|
| Abnormal brain MRI | pre-treatment | NR | NR | NR |
| Abnormal tympanometry | pre-treatment | NR | NR | NR |
| Alteration in periventricular white matter on brain MRI | pre-treatment | 1,121 | resolved | NR |
| Broad-based walking | pre-treatment | ongoing | not resolved | NR |
| Enlarged lateral ventricular on brain MRI | pre-treatment | NR | NR | NR |
| Low-amplitude EEG waves with poor organization | pre-treatment | ongoing | not resolved | NR |
| Psychomotor hyperactivity | pre-treatment | ∼2 years | resolved | NR |
| Sensory neural hearing loss (bilateral) | pre-treatment | ongoing | not resolved | NR |
| Hypotonia | pre-treatment | 255 | resolved | grade 3 |
| Severe mental retardation | pre-treatment | ongoing | not resolved | grade 3 |
| Cerebral hematoma | pre-treatment | 112 | resolved | grade 2 |
| Deafness (bilateral) | pre-treatment | ongoing | not resolved | grade 2 |
| Psychomotor retardation | pre-treatment | ongoing | not resolved | grade 2 |
| Psychomotor retardation | pre-treatment | ongoing | not resolved | grade 2 |
| Abnormal brain MRI | pre-treatment | 1,122 | resolved | grade 1 |
| Abnormal brain MRI | pre-treatment | ongoing | not resolved | grade 1 |
| Abnormal brain scan | pre-treatment | ongoing | not resolved | grade 1 |
| Abnormal VEP | pre-treatment | 381 | resolved | grade 1 |
| Arnold-Chiari malformation | pre-treatment | ongoing | not resolved | grade 1 |
| Attention deficit/hyperactivity disorder | pre-treatment | 1,125 | resolved | grade 1 |
| Communication disorder | pre-treatment | 1,125 | resolved | grade 1 |
| Demyelination | pre-treatment | 1,318 | resolved | grade 1 |
| Developmental delay | pre-treatment | ongoing | not resolved | grade 1 |
| Gliosis | pre-treatment | ongoing | not resolved | grade 1 |
| Hypoacusia | pre-treatment | 964 | resolved | grade 1 |
| Hypothalamo-pituitary disorder | pre-treatment | ongoing | not resolved | grade 1 |
| Hypothalamo-pituitary disorder | pre-treatment | ongoing | not resolved | grade 1 |
| Impaired psychomotor skills | pre-treatment | ongoing | not resolved | grade 1 |
| Mental retardation | pre-treatment | 3003 | resolved | grade 1 |
| Plagiocephaly | pre-treatment | NR | resolved | grade 1 |
| Psychomotor retardation | pre-treatment | ∼2.5 years | resolved | grade 1 |
| Sensorineural hypoacusia at BAER | pre-treatment | ongoing | not resolved | grade 1 |
| Sleep disorder | pre-treatment | 462 | resolved | grade 1 |
| Tympanic membrane disorder | pre-treatment | ongoing | not resolved | grade 1 |
| VEP prolonged latency | pre-treatment | 672 | resolved | grade 1 |
| Gait disturbance | treatment | 37 | resolved | grade 1 |
| Middle ear inflammation | 3-month follow-up | 5 | resolved | grade 1 |
| Guillain-Barré syndrome | 3-year follow-up | 4 | resolved | grade 3 |
| Autism | 3-year follow-up | ongoing | not resolved | grade 2 |
| Speech disorder | 3-year follow-up | ongoing | not resolved | grade 2 |
| Abnormal tympanometry | 3-year follow-up | ongoing | not resolved | grade 1 |
| Abnormal tympanometry | 3-year follow-up | 1,167 | resolved | grade 1 |
| Cognitive disorder | 3-year follow-up | ongoing | not resolved | grade 1 |
| Cognitive disorder | 3-year follow-up | ongoing | not resolved | grade 1 |
| Cognitive disorder | 3-year follow-up | ongoing | not resolved | grade 1 |
| Deafness | 3-year follow-up | 198 | resolved | grade 1 |
| Deafness | 3-year follow-up | ongoing | not resolved | grade 1 |
| Deafness (bilateral) | 3-year follow-up | ongoing | not resolved | grade 1 |
| Deafness (bilateral) | 3-year follow-up | 338 | resolved | grade 1 |
| Developmental delay | 3-year follow-up | 2,212 | resolved | grade 1 |
| Impaired psychomotor skills | 3-year follow-up | ∼1.8 years | resolved | grade 1 |
| Psychomotor hyperactivity | 3-year follow-up | ∼1.1 years | resolved | grade 1 |
| Psychomotor hyperactivity | 3-year follow-up | ongoing | not resolved | grade 1 |
| Tympanic membrane disorder | 3-year follow-up | ongoing | not resolved | grade 1 |
| Hypoacusia | 7-year follow-up | ongoing | not resolved | grade 2 |
| Abnormal tympanometry | 7-year follow-up | ongoing | not resolved | grade 1 |
| Cognitive disorder | 7-year follow-up | ongoing | not resolved | grade 1 |
| Areflexia | 7-year follow-up | 871 | resolved | grade 1 |
| Cognitive disorder | 7-year follow-up | ongoing | not resolved | grade 1 |
| Deafness | 7-year follow-up | ongoing | not resolved | grade 1 |
| Disturbance in attention | 7-year follow-up | ongoing | not resolved | grade 1 |
| Impaired hearing | ≥8-year follow-up | ongoing | not resolved | grade 3 |
| Moderate mental retardation | ≥8-year follow-up | ongoing | not resolved | grade 3 |
| Obsessive-compulsive disorder | ≥8-year follow-up | ongoing | not resolved | grade 2 |
AE, adverse event; BAER, brainstem auditory evoked response; EEG, electroencephalogram; NR, not recorded; VEP, visual evoked potential. In any given phase, only those AEs that were new or worsened after the start of a particular phase were reported.
a
Relevant medical conditions ongoing at screening, which are not reported as AEs, were identified via manual review and are included in this table for completeness.