Trial Outcomes & Findings for A Study of Patients With Sanfilippo Syndrome Type A (MPS IIIA) (NCT NCT01047306)

NCT ID: NCT01047306

Last Updated: 2021-06-11

Results Overview

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.

• Recruitment status: COMPLETED
• Target enrollment: 25 participants
• Primary outcome timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)
• Results posted on: 2021-06-11

Participant Flow

Participant milestones

Measure	Children < 6 Years Old Children ≥1 to \< 6 years of age with Sanfilippo Syndrome Type A (mucopolysaccharidosis type IIIA; MPS IIIA) who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years Old Children ≥ 6 years of age with Sanfilippo Syndrome Type A (mucopolysaccharidosis type IIIA; MPS IIIA) who were untreated with any investigational products (drugs and/or devices).
Overall Study STARTED	19	6
Overall Study Discontinued From the Study	3	0
Overall Study COMPLETED	16	6
Overall Study NOT COMPLETED	3	0

Reasons for withdrawal

Measure	Children < 6 Years Old Children ≥1 to \< 6 years of age with Sanfilippo Syndrome Type A (mucopolysaccharidosis type IIIA; MPS IIIA) who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years Old Children ≥ 6 years of age with Sanfilippo Syndrome Type A (mucopolysaccharidosis type IIIA; MPS IIIA) who were untreated with any investigational products (drugs and/or devices).
Overall Study Withdrawal by Subject	2	0
Overall Study Lost to Follow-up	1	0

Baseline Characteristics

A Study of Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Baseline characteristics by cohort

Measure	Children < 6 Years Old n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years Old n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Total n=25 Participants Total of all reporting groups
Age, Continuous	4.29 years STANDARD_DEVIATION 1.996 • n=5 Participants	12.44 years STANDARD_DEVIATION 4.500 • n=7 Participants	6.24 years STANDARD_DEVIATION 4.452 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	3 Participants n=7 Participants	16 Participants n=5 Participants
Region of Enrollment United States	19 Participants n=5 Participants	6 Participants n=7 Participants	25 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores 6 months, n=18,6	0.17 months Standard Deviation 2.093	1.19 months Standard Deviation 3.289
Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores 12 months, n=18,6	-1.72 months Standard Deviation 4.625	1.39 months Standard Deviation 4.029
Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores End of Study, n=15,5	-1.80 months Standard Deviation 7.143	2.95 months Standard Deviation 4.652

PRIMARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores 6 months, n=18,6	-7.42 percentage of chronological age Standard Deviation 6.153	-0.03 percentage of chronological age Standard Deviation 1.960
Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores 12 months, n=18,6	-15.69 percentage of chronological age Standard Deviation 9.258	-1.66 percentage of chronological age Standard Deviation 2.977
Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores End of Study, n=15,5	-26.09 percentage of chronological age Standard Deviation 14.788	-2.94 percentage of chronological age Standard Deviation 2.588

PRIMARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores 6 months, n=17,6	-0.92 months Standard Deviation 3.966	-1.11 months Standard Deviation 5.661
Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores 12 months, n=18,6	-0.90 months Standard Deviation 8.170	-2.63 months Standard Deviation 4.847
Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores End of Study, n=16,6	-2.29 months Standard Deviation 8.321	-7.80 months Standard Deviation 15.834

PRIMARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in VABS-II Overall DQ Scores 6 months, n=17,6	-9.33 percentage of chronological age Standard Deviation 8.632	-2.78 percentage of chronological age Standard Deviation 5.971
Change From Baseline in VABS-II Overall DQ Scores 12 months, n=18,6	-12.88 percentage of chronological age Standard Deviation 15.131	-5.12 percentage of chronological age Standard Deviation 7.683
Change From Baseline in VABS-II Overall DQ Scores End of Study, n=16,6	-23.81 percentage of chronological age Standard Deviation 14.655	-9.70 percentage of chronological age Standard Deviation 11.299

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI) 12 months, n=16,6	-41.40 milliliters Standard Deviation 36.319	-11.68 milliliters Standard Deviation 13.126
Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI) 6 months, n=17,6	-15.98 milliliters Standard Deviation 21.860	1.16 milliliters Standard Deviation 14.790
Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI) End of Study, n=9,5	-80.29 milliliters Standard Deviation 45.867	-22.41 milliliters Standard Deviation 18.134

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS) 6 months, n=18,6	-0.18 units on a scale Standard Deviation 0.411	0.10 units on a scale Standard Deviation 0.245
Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS) 12 months, n=18,6	-0.31 units on a scale Standard Deviation 0.512	0.10 units on a scale Standard Deviation 0.245
Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS) End of Study, n=15,5	-0.43 units on a scale Standard Deviation 0.448	0.18 units on a scale Standard Deviation 0.164

SECONDARY outcome

Timeframe: Baseline

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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).

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at Baseline Right ear, n=11,5	57.9 percentage of participants	50.0 percentage of participants
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at Baseline Left ear, n=11,5	57.9 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: 6 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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).

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months Left ear, n=18,6	94.7 percentage of participants	66.7 percentage of participants
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months Right ear, n=18,6	94.7 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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).

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months Right ear, n=17,6	89.5 percentage of participants	66.7 percentage of participants
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months Left ear, n=17,6	89.5 percentage of participants	83.3 percentage of participants

SECONDARY outcome

Timeframe: End of Study (12 months assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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).

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study Right ear, n=15,5	73.7 percentage of participants	66.7 percentage of participants
Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study Left ear, n=15,5	78.9 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=9,3	21.1 percentage of participants	16.7 percentage of participants
Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=9,4	21.1 percentage of participants	16.7 percentage of participants

SECONDARY outcome

Timeframe: 6 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Sensorineural Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=18,4	63.2 percentage of participants	50.0 percentage of participants
Percent of Participants With Sensorineural Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=18,4	57.9 percentage of participants	50.0 percentage of participants

SECONDARY outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Sensorineural Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=17,4	84.2 percentage of participants	50.0 percentage of participants
Percent of Participants With Sensorineural Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=17,5	89.5 percentage of participants	50.0 percentage of participants

SECONDARY outcome

Timeframe: End of Study (12 months assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Sensorineural Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=14,4	68.4 percentage of participants	66.7 percentage of participants
Percent of Participants With Sensorineural Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=15,4	78.9 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Conductive Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=9,3	10.5 percentage of participants	0.0 percentage of participants
Percent of Participants With Conductive Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=9,4	10.5 percentage of participants	16.7 percentage of participants

SECONDARY outcome

Timeframe: 6 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Conductive Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=18,4	5.3 percentage of participants	0.0 percentage of participants
Percent of Participants With Conductive Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=18,4	5.3 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Conductive Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=17,4	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Conductive Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=17,5	0.0 percentage of participants	16.7 percentage of participants

SECONDARY outcome

Timeframe: End of Study (12 months assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Conductive Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) Right ear, n=14,4	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Conductive Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) Left ear, n=15,4	0.0 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Number of Participants With Mild, Moderate, or Severe Hearing Loss at Baseline, as Assessed by The Auditory Brain Response (ABR) Right ear, n=11,3	11 participants	3 participants
Number of Participants With Mild, Moderate, or Severe Hearing Loss at Baseline, as Assessed by The Auditory Brain Response (ABR) Left ear, n=11,4	11 participants	4 participants

SECONDARY outcome

Timeframe: 6 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 6 Months, as Assessed by The Auditory Brain Response (ABR) Right ear, n=18,4	18 participants	4 participants
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 6 Months, as Assessed by The Auditory Brain Response (ABR) Left ear, n=18,4	18 participants	4 participants

SECONDARY outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 12 Months, as Assessed by The Auditory Brain Response (ABR) Right ear, n=17,4	17 participants	4 participants
Number of Participants With Mild, Moderate, or Severe Hearing Loss at 12 Months, as Assessed by The Auditory Brain Response (ABR) Left ear, n=17,5	17 participants	5 participants

SECONDARY outcome

Timeframe: End of Study (12 months assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Number of Participants With Mild, Moderate, or Severe Hearing Loss at End of Study, as Assessed by The Auditory Brain Response (ABR) Right ear, n=14,4	14 participants	4 participants
Number of Participants With Mild, Moderate, or Severe Hearing Loss at End of Study, as Assessed by The Auditory Brain Response (ABR) Left ear, n=15,4	15 participants	4 participants

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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).

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR) Baseline, n=11,3	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR) 6 months, n=18,4	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR) 12 months, n=17,4	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR) End of Study, n=14,4	0.0 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50) Baseline, n=6,4	1 participants	2 participants
Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50) 6 months, n=3,5	1 participants	1 participants
Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50) 12 months, n=7,5	3 participants	1 participants
Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50) End of Study, n=11,6	2 participants	3 participants

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale 6 months, n=10	-8.50 units on a scale Standard Deviation 12.813	NA units on a scale Standard Deviation NA This scale is not used with children in this age group.
Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale 12 months, n=9	-20.56 units on a scale Standard Deviation 16.853	NA units on a scale Standard Deviation NA This scale is not used with children in this age group.
Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale End of Study, n=4	-28.13 units on a scale Standard Deviation 13.901	NA units on a scale Standard Deviation NA This scale is not used with children in this age group.

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

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.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children's Sleep Habits Questionnaire (CSHQ) 6 months, n=8,3	1.75 units on a scale Standard Deviation 9.968	3.33 units on a scale Standard Deviation 8.145
Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children's Sleep Habits Questionnaire (CSHQ) 12 months, n=8,3	-0.13 units on a scale Standard Deviation 9.862	-2.00 units on a scale Standard Deviation 1.732
Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children's Sleep Habits Questionnaire (CSHQ) End of Study, n=7,3	0.86 units on a scale Standard Deviation 16.098	0.33 units on a scale Standard Deviation 6.028

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

Urine GAG was measured by a dye binding assay. A negative value indicates that GAG levels decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Urine Glycosaminoglycan (GAG) Levels 6 months, n=18,6	0.26 mg GAG/mmol creatinine Standard Deviation 19.379	-10.23 mg GAG/mmol creatinine Standard Deviation 32.983
Change From Baseline in Urine Glycosaminoglycan (GAG) Levels 12 months, n=18,6	-0.39 mg GAG/mmol creatinine Standard Deviation 19.429	-7.95 mg GAG/mmol creatinine Standard Deviation 31.516
Change From Baseline in Urine Glycosaminoglycan (GAG) Levels End of Study, n=15,5	-0.33 mg GAG/mmol creatinine Standard Deviation 22.706	-6.34 mg GAG/mmol creatinine Standard Deviation 28.810

POST_HOC outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

ECG allows a non-invasive assessment of cardiac structure, function, and hemodynamics and can provide essential insight into mechanisms of disease and therapeutic benefit.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Thickened Heart Valves as Assessed by Echocardiography (ECG) Tricuspid Valve, n=18,6	5.3 percentage of participants	0.0 percentage of participants
Percent of Participants With Thickened Heart Valves as Assessed by Echocardiography (ECG) Pulmonary Valve, n=18,6	0.0 percentage of participants	0.0 percentage of participants
Percent of Participants With Thickened Heart Valves as Assessed by Echocardiography (ECG) Mitral Valve, n=18,6	57.9 percentage of participants	66.7 percentage of participants
Percent of Participants With Thickened Heart Valves as Assessed by Echocardiography (ECG) Aortic Valve, n=18,6	15.8 percentage of participants	16.7 percentage of participants

POST_HOC outcome

Timeframe: 12 months

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients.

ECG allows a non-invasive assessment of cardiac structure, function, and hemodynamics and can provide essential insight into mechanisms of disease and therapeutic benefit. Regurgitation indicates that blood flows backwards through the valve.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Percent of Participants With Trace Regurgitation as Assessed by ECG Tricuspid Valve, n=18,6	73.7 percentage of participants	100.0 percentage of participants
Percent of Participants With Trace Regurgitation as Assessed by ECG Pulmonary Valve, n=16,5	63.2 percentage of participants	66.7 percentage of participants
Percent of Participants With Trace Regurgitation as Assessed by ECG Mitral Valve, n=18,6	36.8 percentage of participants	16.7 percentage of participants
Percent of Participants With Trace Regurgitation as Assessed by ECG Aortic Valve, n=18,6	21.1 percentage of participants	0.0 percentage of participants

POST_HOC outcome

Timeframe: Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

ECG allows a non-invasive assessment of cardiac structure, function, and hemodynamics and can provide essential insight into mechanisms of disease and therapeutic benefit. Backwards blood flow through the tricuspid valve is measured during one heartbeat. A negative value indicates decreased velocity.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Tricuspid Valve Regurgitant Velocity End of Study, n=3,1	-0.087 meters/second Standard Deviation 0.078	2.030 meters/second Standard Deviation 0.0
Change From Baseline in Tricuspid Valve Regurgitant Velocity 6 months, n=2,1	-0.325 meters/second Standard Deviation 0.106	1.990 meters/second Standard Deviation 0.0
Change From Baseline in Tricuspid Valve Regurgitant Velocity 12 months, n=4,2	-0.013 meters/second Standard Deviation 0.210	1.210 meters/second Standard Deviation 1.428

POST_HOC outcome

Timeframe: Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

ECG allows a non-invasive assessment of cardiac structure, function, and hemodynamics and can provide essential insight into mechanisms of disease and therapeutic benefit. Blood flow through the mitral valve is measured during one heartbeat.The E/A ratio measures the relationship between early (E) and late (A) inflow velocity by dividing E by A. A positive value indicates that either early flow through the mitral valve (E) increased or late flow through the valve (A) decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in The Ratio of Mitral Valve Early Inflow Velocity (E) to Late Inflow Velocity (A) 6 months, n=4,1	0.196 quotient of E/A Standard Deviation 0.418	0.059 quotient of E/A Standard Deviation 0.0
Change From Baseline in The Ratio of Mitral Valve Early Inflow Velocity (E) to Late Inflow Velocity (A) 12 months, n=3,1	0.293 quotient of E/A Standard Deviation 0.404	-0.608 quotient of E/A Standard Deviation 0.0
Change From Baseline in The Ratio of Mitral Valve Early Inflow Velocity (E) to Late Inflow Velocity (A) End of Study, n=4,2	-0.081 quotient of E/A Standard Deviation 0.529	-0.226 quotient of E/A Standard Deviation 0.096

POST_HOC outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

Liver volume was obtained via abdominal MRI. A negative value indicates that volume decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Liver Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) 12 months, n=5,2	39.20 milliliters Standard Deviation 248.532	280.00 milliliters Standard Deviation 32.527
Change From Baseline in Liver Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) End of Study, n=4,2	356.00 milliliters Standard Deviation 197.985	188.50 milliliters Standard Deviation 41.719
Change From Baseline in Liver Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) 6 months, n=5,2	93.00 milliliters Standard Deviation 237.960	190.00 milliliters Standard Deviation 91.924

POST_HOC outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

Spleen volume was assessed via abdominal MRI. A negative value indicates that volume decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Spleen Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) 6 months, n=5,2	29.60 milliliters Standard Deviation 63.552	11.50 milliliters Standard Deviation 0.707
Change From Baseline in Spleen Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) 12 months, n=5,2	238.40 milliliters Standard Deviation 473.682	44.00 milliliters Standard Deviation 2.828
Change From Baseline in Spleen Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI) End of Study, n=4,2	128.50 milliliters Standard Deviation 71.276	13.00 milliliters Standard Deviation 28.284

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

Tau proteins are involved in the building and stabilization of axonal microtubules in the CNS. The phosphorylation of tau proteins associated with microtubules is believed to be involved in destabilizing axons and extensively phosphorylated tau (ptau) has been observed in patients with Alzheimer disease and other neurodegenerative diseases. Because MPS IIIA is a neurodegenerative disease, CSF tau levels were determined to evaluate the potential role of this process in the natural history of the disease. A negative value indicates that total tau levels decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Total Tau Levels in Cerebrospinal Fluid (CSF) 6 months, n=17,6	-88.9 picograms/milliliter Standard Deviation 236.58	54.8 picograms/milliliter Standard Deviation 177.63
Change From Baseline in Total Tau Levels in Cerebrospinal Fluid (CSF) 12 months, n=18,6	-95.8 picograms/milliliter Standard Deviation 375.45	-79.8 picograms/milliliter Standard Deviation 96.01
Change From Baseline in Total Tau Levels in Cerebrospinal Fluid (CSF) End of Study, n=14,5	-80.9 picograms/milliliter Standard Deviation 562.50	-133.2 picograms/milliliter Standard Deviation 141.82

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Population: All analyses were based on the Main Analysis Population, which included all enrolled patients. Data were not available for all patients at all time points.

Tau proteins are involved in the building and stabilization of axonal microtubules in the CNS. The phosphorylation of tau proteins associated with microtubules is believed to be involved in destabilizing axons and extensively phosphorylated tau (ptau) has been observed in patients with Alzheimer disease and other neurodegenerative diseases. Because MPS IIIA is a neurodegenerative disease, CSF phosphorylated tau levels were determined to evaluate the potential role of this process in the natural history of the disease. A negative value indicates that phosphorylated tau levels decreased.

Outcome measures

Measure	Children < 6 Years n=19 Participants Children ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 Participants Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Change From Baseline in Phosphorylated Tau Levels in Cerebrospinal Fluid (CSF) 6 months, n=17,5	-5.42 picograms/milliliter Standard Deviation 20.722	-1.56 picograms/milliliter Standard Deviation 6.518
Change From Baseline in Phosphorylated Tau Levels in Cerebrospinal Fluid (CSF) 12 months, n=18,5	-15.04 picograms/milliliter Standard Deviation 25.550	-5.42 picograms/milliliter Standard Deviation 5.508
Change From Baseline in Phosphorylated Tau Levels in Cerebrospinal Fluid (CSF) End of Study, n=14,4	-29.98 picograms/milliliter Standard Deviation 41.190	-29.45 picograms/milliliter Standard Deviation 9.963

Adverse Events

Children < 6 Years

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Children ≥ 6 Years

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Children < 6 Years n=19 participants at risk Patients ≥1 to \< 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 Years n=6 participants at risk Patients ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Gastrointestinal disorders Vomiting	31.6% 6/19 • Number of events 6	16.7% 1/6 • Number of events 1
Injury, poisoning and procedural complications Procedural nausea	10.5% 2/19 • Number of events 2	0.00% 0/6
Injury, poisoning and procedural complications Post Lumbar Puncture Syndrome	0.00% 0/19	16.7% 1/6 • Number of events 1
Injury, poisoning and procedural complications Procedural Headache	5.3% 1/19 • Number of events 1	0.00% 0/6
Injury, poisoning and procedural complications Procedural Vomiting	5.3% 1/19 • Number of events 1	0.00% 0/6
General disorders Chills	5.3% 1/19 • Number of events 1	0.00% 0/6
General disorders Pain	5.3% 1/19 • Number of events 1	0.00% 0/6
General disorders Pyrexia	5.3% 1/19 • Number of events 1	0.00% 0/6
Ear and labyrinth disorders Ear Haemorrhage	0.00% 0/19	16.7% 1/6 • Number of events 1
Nervous system disorders Headache	5.3% 1/19 • Number of events 1	0.00% 0/6
Respiratory, thoracic and mediastinal disorders Laryngospasm	5.3% 1/19 • Number of events 1	0.00% 0/6
Respiratory, thoracic and mediastinal disorders Wheezing	5.3% 1/19 • Number of events 1	0.00% 0/6

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee Shire's agreements with investigators vary. All agreements provide Shire the right to embargo communications regarding trial results prior to public release for a period ≤180 days from the time submitted to Shire for review. Shire does not prohibit publication, but can require the removal of confidential information (excluding trial results) and can request postponement of a single-center publication until after disclosure of the trial's multi-center publication.
• Publication restrictions are in place

Restriction type: OTHER