The purpose is to evaluate the course of disease progression in MPS IIIA patients who are untreated to identify potential surrogate endpoints that may be utilized in future ERT trials of MPS IIIA via defined assessments including standardized clinical, biochemical, neurocognitive, behavioral, developmental, and imaging measures.
Study Type
OBSERVATIONAL
Enrollment
25
Physical, developmental, neurological, behavioral, and neurocognitive assessments
University of Minnesota
Minneapolis, Minnesota, United States
Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores
Children 1 year-42 months were assessed by the BSID-III; those \>42 months and with a developmental age of \>42 months by the Vineland Adaptive Behavior Scales-II (VABS-II) were evaluated with the KABC-II. For children \>42 months, but \<42 months in developmental age, and those unable to complete at least 3 cognitive KABC-II subtests, the BSID-III was used. The BSID-III is a series of measurements to assess the motor, language, and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The KABC-II is an individually administered measure of processing/reasoning abilities. Raw scores were converted to age- equivalent scores to measure ability, skill, and knowledge, expressed as the age at which most individuals reach the same level (age norm; range: 0, unbound ). A positive value indicates improvement. The BSID-III and KABC-II age- equivalent scores were based on the cognitive domain and average non-verbal age-equivalent score, respectively.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores
The determination of whether a patient received BSID-III was based on an algorithm that includes the patient's calendar age and VABS-II age -equivalent score (See Outcome 1). The BSID-III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The KABC-II is an individually administered measure of processing and reasoning abilities. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID-III DQ score is based on the cognitive domain. The DQ score for KABC-II is calculated from the average non-verbal age-equivalent score. A positive value indicates improvement in health and cognition.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores
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The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. It is an instrument that supports the diagnosis of intellectual and developmental disabilities in patients from birth to 90 years. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The mean age-equivalent score is obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills (range: 0, unbound). A positive value indicates improvement in health and cognition
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in VABS-II Overall DQ Scores
The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. It is an instrument that supports the diagnosis of intellectual and developmental disabilities in patients from birth to 90 years. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. A positive value indicates improvement in health and cognition.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI)
Total brain cortical gray matter volume was determined by analysis of brain MRI. The analysis was performed using "Freesurfer" software, which provides completely automated parcellation of the brain cortex and subcortical structures. In some cases, manual adjustments were necessary in cases of intensity normalization failure, resulting in erroneous white matter segmentation. A negative value indicates that gray matter volume decreased.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS)
The FPSS is an MPS III-specific disability assessment that evaluates motor function, expressive language, and cognitive function on a 0- to 3- point scale and can be used for individuals of all ages. A score of 3 points is assigned for normal function, 2 points for beginning of regression, 1 point for severe level of regression, and 0 points for lost skills. The total disability score (TDS) is the average of the motor function, speech, and cognitive function scores (range: 0, 3). The scoring is based on the parent's response to a detailed questionnaire that covers several aspects of the disease. A positive value indicates improvement in function.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at Baseline
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. An abnormal value was greater than 21 decibels hearing level (dBHL).
Time frame: Baseline
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. An abnormal value was greater than 21 decibels hearing level (dBHL).
Time frame: 6 months
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. An abnormal value was greater than 21 decibels hearing level (dBHL).
Time frame: 12 months
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. An abnormal value was greater than 21 decibels hearing level (dBHL).
Time frame: End of Study (12 months assessment or early termination)
Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR)
Sensorineural hearing loss occurs from damage to the inner ear, the brain, or the nerve that runs from the ear to the brain (auditory nerve). Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: Baseline
Percent of Participants With Sensorineural Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR)
Sensorineural hearing loss occurs from damage to the inner ear, the brain, or the nerve that runs from the ear to the brain (auditory nerve). Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: 6 months
Percent of Participants With Sensorineural Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR)
Sensorineural hearing loss occurs from damage to the inner ear, the brain, or the nerve that runs from the ear to the brain (auditory nerve). Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: 12 months
Percent of Participants With Sensorineural Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR)
Sensorineural hearing loss occurs from damage to the inner ear, the brain, or the nerve that runs from the ear to the brain (auditory nerve). Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: End of Study (12 months assessment or early termination)
Percent of Participants With Conductive Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR)
Conductive hearing loss occurs when there is a problem conducting sound waves along the route through the outer ear, tympanic membrane, or middle ear. Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (number of neurons firing), latency (speed of transmission), interpeak latency (time between peaks), and interaural latency (difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: Baseline
Percent of Participants With Conductive Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR)
Conductive hearing loss occurs when there is a problem conducting sound waves along the route through the outer ear, tympanic membrane, or middle ear. Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (number of neurons firing), latency (speed of transmission), interpeak latency (time between peaks), and interaural latency (difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: 6 months
Percent of Participants With Conductive Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR)
Conductive hearing loss occurs when there is a problem conducting sound waves along the route through the outer ear, tympanic membrane, or middle ear. Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (number of neurons firing), latency (speed of transmission), interpeak latency (time between peaks), and interaural latency (difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: 12 months
Percent of Participants With Conductive Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR)
Conductive hearing loss occurs when there is a problem conducting sound waves along the route through the outer ear, tympanic membrane, or middle ear. Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (number of neurons firing), latency (speed of transmission), interpeak latency (time between peaks), and interaural latency (difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia.
Time frame: End of Study (12 months assessment or early termination)
Number of Participants With Mild, Moderate, or Severe Hearing Loss at Baseline, as Assessed by The Auditory Brain Response (ABR)
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. Mild hearing loss: 21-40 decibels hearing level (dBHL), moderate hearing loss: 41-70 dBHL, severe hearing loss: 71-90 dBHL.
Time frame: Baseline
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 6 Months, as Assessed by The Auditory Brain Response (ABR)
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. Mild hearing loss: 21-40 decibels hearing level (dBHL), moderate hearing loss: 41-70 dBHL, severe hearing loss: 71-90 dBHL.
Time frame: 6 months
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 12 Months, as Assessed by The Auditory Brain Response (ABR)
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. Mild hearing loss: 21-40 decibels hearing level (dBHL), moderate hearing loss: 41-70 dBHL, severe hearing loss: 71-90 dBHL.
Time frame: 12 months
Number of Participants With Mild, Moderate, or Severe Hearing Loss at End of Study, as Assessed by The Auditory Brain Response (ABR)
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. Mild hearing loss: 21-40 decibels hearing level (dBHL), moderate hearing loss: 41-70 dBHL, severe hearing loss: 71-90 dBHL.
Time frame: End of Study (12 months assessment or early termination)
Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR)
Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural latency (the difference in wave V latency between ears). The interpeak latency I-V interval (or central transmission time) is considered the most reliable index of brainstem function. Auditory brainstem response assessments were conducted under anesthesia. Profound hearing loss: 91+ decibels hearing level (dBHL).
Time frame: Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)
Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50)
The parent form, CHQ-PF50, is designed to measure the physical and psychosocial well-being of children 5 years and older. In this trial it was used to assess the health of children 5 to 18 years of age. It consists of 13 health concepts including 11 multi-item and 2 single-item scales: physical function, role/social-emotional/behavioral, role/social-physical, bodily pain, general behavior, mental health, self-esteem, general health perceptions, change in health, parental impact-emotional, parental impact-time, family activities, and family cohesion. The parental impact scales capture the amount of emotional distress and time limitation experienced by the parent due to the child's physical health, emotional well-being, attention/learning abilities, ability to get along with others, and general behavior. The Change in Health section assesses changes in health over the previous year.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale
The ITQoL Questionnaire is a generic, validated health status measure for children aged 2 months up to 5 years, including items and scales to measure aspects of physical functioning, development, pain, mood, behavior, general health, and impact on parents. In this study the ITQoL was also administered to patients who were developmentally functioning at or below the age of years. Growth and development is one of 12 health concepts measured by ITQoL. Transformed scores for all subscales range from 0 to 100, with a higher score indicating better health. A positive value indicates improvement.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children's Sleep Habits Questionnaire (CSHQ)
The CSHQ is a validated, retrospective, parent-reported sleep screening tool. The questionnaire consists of 35 items that yield a TSD score, as well as 8 subscale scores, including bedtime resistance, sleep duration, parasomnias, sleep disordered breathing, night wakings, daytime sleepiness, sleep anxiety, and sleep onset delay. The questionnaire was designed for children aged 4 to 12 years. Parents were asked to think of a recent "typical" week of their child's sleep and to indicate how often sleep disturbance behaviors occurred. A 3-point scale was used for rating: "usually" if the sleep behavior occurs 5 to 7 times per week, "sometimes" for 2 to 4 times per week, and "rarely" for once or not at all during the week. The TSD score, which is the sum of all responses, included all items of the 8 subscales, but consisted of only 33 items because two on the bedtime resistance and sleep anxiety subscales were identical (range: 0, 99). A negative value indicates less sleep disturbance.
Time frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)