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

• ClinicalTrials.gov Identifier: NCT01047306
• Recruitment Status: Completed
• First Posted: January 12, 2010
• Results First Posted: March 30, 2016
• Last Update Posted: March 30, 2016
• Sponsor: Shire
• Information provided by (Responsible Party): Shire

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Condition: Sanfilippo Syndrome Type A
• Intervention: Other: assessment
• Enrollment: 25

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description	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 of age with Sanfilippo Syndrome Type A (mucopolysaccharidosis type IIIA; MPS IIIA) who were untreated with any investigational products (drugs and/or devices).
Period Title: Overall Study
Started	19	6
Discontinued From the Study	3	0
Completed	16	6
Not Completed	3	0
Reason Not Completed
Withdrawal by Subject	2	0
Lost to Follow-up	1	0

Baseline Characteristics

Arm/Group Title		Children < 6 Years Old	Children ≥ 6 Years Old	Total
Arm/Group Description		Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Total of all reporting groups
Overall Number of Baseline Participants		19	6	25
Baseline Analysis Population Description		A maximum of 25 patients with MPS IIIA will be enrolled in the study to provide at least 12 patients who complete the study. This number was not based on any statistical consideration, but is expected to be adequate to describe the natural progression of Sanfilippo A syndrome.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	19 participants	6 participants	25 participants
		4.29 (1.996)	12.44 (4.500)	6.24 (4.452)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	19 participants	6 participants	25 participants
	Female	6 31.6%	3 50.0%	9 36.0%
	Male	13 68.4%	3 50.0%	16 64.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	19 participants	6 participants	25 participants
		19	6	25

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores
Description	Children 1 year-42 months were assessed by the BSID­III; those >42 months and with a developmental age of >42 months by the Vineland Adaptive Behavior Scales­II (VABS­II) were evaluated with the KABC­II. For children >42 months, but <42 months in developmental age, and those unable to complete at least 3 cognitive KABC­II subtests, the BSID­III was used. The BSID­III 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 KABC­II 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 BSID­III and KABC­II 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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: months
6 months, n=18,6	0.17 (2.093)	1.19 (3.289)
12 months, n=18,6	-1.72 (4.625)	1.39 (4.029)
End of Study, n=15,5	-1.80 (7.143)	2.95 (4.652)

2. Primary Outcome

Title	Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores
Description	The determination of whether a patient received BSID­III was based on an algorithm that includes the patient's calendar age and VABS­II age ­equivalent score (See Outcome 1). The BSID­III 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 KABC­II 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 BSID­III DQ score is based on the cognitive domain. The DQ score for KABC­II is calculated from the average non­verbal 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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: percentage of chronological age
6 months, n=18,6	-7.42 (6.153)	-0.03 (1.960)
12 months, n=18,6	-15.69 (9.258)	-1.66 (2.977)
End of Study, n=15,5	-26.09 (14.788)	-2.94 (2.588)

3. Primary Outcome

Title	Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: months
6 months, n=17,6	-0.92 (3.966)	-1.11 (5.661)
12 months, n=18,6	-0.90 (8.170)	-2.63 (4.847)
End of Study, n=16,6	-2.29 (8.321)	-7.80 (15.834)

4. Primary Outcome

Title	Change From Baseline in VABS-II Overall DQ Scores
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: percentage of chronological age
6 months, n=17,6	-9.33 (8.632)	-2.78 (5.971)
12 months, n=18,6	-12.88 (15.131)	-5.12 (7.683)
End of Study, n=16,6	-23.81 (14.655)	-9.70 (11.299)

5. Secondary Outcome

Title	Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: milliliters
6 months, n=17,6	-15.98 (21.860)	1.16 (14.790)
12 months, n=16,6	-41.40 (36.319)	-11.68 (13.126)
End of Study, n=9,5	-80.29 (45.867)	-22.41 (18.134)

6. Secondary Outcome

Title	Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: units on a scale
6 months, n=18,6	-0.18 (0.411)	0.10 (0.245)
12 months, n=18,6	-0.31 (0.512)	0.10 (0.245)
End of Study, n=15,5	-0.43 (0.448)	0.18 (0.164)

7. Secondary Outcome

Title	Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=11,5	57.9	50.0
Left ear, n=11,5	57.9	66.7

8. Secondary Outcome

Title	Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=18,6	94.7	66.7
Left ear, n=18,6	94.7	66.7

9. Secondary Outcome

Title	Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=17,6	89.5	66.7
Left ear, n=17,6	89.5	83.3

10. Secondary Outcome

Title	Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=15,5	73.7	66.7
Left ear, n=15,5	78.9	66.7

11. Secondary Outcome

Title	Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=9,3	21.1	16.7
Left ear, n=9,4	21.1	16.7

12. Secondary Outcome

Title	Percent of Participants With Sensorineural Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=18,4	63.2	50.0
Left ear, n=18,4	57.9	50.0

13. Secondary Outcome

Title	Percent of Participants With Sensorineural Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=17,4	84.2	50.0
Left ear, n=17,5	89.5	50.0

14. Secondary Outcome

Title	Percent of Participants With Sensorineural Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=14,4	68.4	66.7
Left ear, n=15,4	78.9	66.7

15. Secondary Outcome

Title	Percent of Participants With Conductive Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=9,3	10.5	0.0
Left ear, n=9,4	10.5	16.7

16. Secondary Outcome

Title	Percent of Participants With Conductive Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=18,4	5.3	0.0
Left ear, n=18,4	5.3	0.0

17. Secondary Outcome

Title	Percent of Participants With Conductive Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=17,4	0.0	0.0
Left ear, n=17,5	0.0	16.7

18. Secondary Outcome

Title	Percent of Participants With Conductive Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR)
Description	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 sound­evoked 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 I­V 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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Right ear, n=14,4	0.0	0.0
Left ear, n=15,4	0.0	0.0

19. Secondary Outcome

Title	Number of Participants With Mild, Moderate, or Severe Hearing Loss at Baseline, as Assessed by The Auditory Brain Response (ABR)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: participants
Right ear, n=11,3	11	3
Left ear, n=11,4	11	4

20. Secondary Outcome

Title	Number of Participants With Mild, Moderate, or Severe Hearing Loss at 6 Months, as Assessed by The Auditory Brain Response (ABR)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: participants
Right ear, n=18,4	18	4
Left ear, n=18,4	18	4

21. Secondary Outcome

Title	Number of Participants With Mild, Moderate, or Severe Hearing Loss at 12 Months, as Assessed by The Auditory Brain Response (ABR)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: participants
Right ear, n=17,4	17	4
Left ear, n=17,5	17	5

22. Secondary Outcome

Title	Number of Participants With Mild, Moderate, or Severe Hearing Loss at End of Study, as Assessed by The Auditory Brain Response (ABR)
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: participants
Right ear, n=14,4	14	4
Left ear, n=15,4	15	4

23. Secondary Outcome

Title	Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Baseline, n=11,3	0.0	0.0
6 months, n=18,4	0.0	0.0
12 months, n=17,4	0.0	0.0
End of Study, n=14,4	0.0	0.0

24. Secondary Outcome

Title	Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: participants
Baseline, n=6,4	1	2
6 months, n=3,5	1	1
12 months, n=7,5	3	1
End of Study, n=11,6	2	3

25. Secondary Outcome

Title	Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: units on a scale
6 months, n=10	-8.50 (12.813)	NA [1] (NA)
12 months, n=9	-20.56 (16.853)	NA [1] (NA)
End of Study, n=4	-28.13 (13.901)	NA [1] (NA)

[1]

This scale is not used with children in this age group.

26. Secondary Outcome

Title	Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children’s Sleep Habits Questionnaire (CSHQ)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: units on a scale
6 months, n=8,3	1.75 (9.968)	3.33 (8.145)
12 months, n=8,3	-0.13 (9.862)	-2.00 (1.732)
End of Study, n=7,3	0.86 (16.098)	0.33 (6.028)

27. Other Pre-specified Outcome

Title	Change From Baseline in Urine Glycosaminoglycan (GAG) Levels
Description	Urine GAG was measured by a dye binding assay. A negative value indicates that GAG levels decreased.
Time Frame	Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: mg GAG/mmol creatinine
6 months, n=18,6	0.26 (19.379)	-10.23 (32.983)
12 months, n=18,6	-0.39 (19.429)	-7.95 (31.516)
End of Study, n=15,5	-0.33 (22.706)	-6.34 (28.810)

28. Other Pre-specified Outcome

Title	Change From Baseline in Total Tau Levels in Cerebrospinal Fluid (CSF)
Description	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.
Time Frame	Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: picograms/milliliter
6 months, n=17,6	-88.9 (236.58)	54.8 (177.63)
12 months, n=18,6	-95.8 (375.45)	-79.8 (96.01)
End of Study, n=14,5	-80.9 (562.50)	-133.2 (141.82)

29. Other Pre-specified Outcome

Title	Change From Baseline in Phosphorylated Tau Levels in Cerebrospinal Fluid (CSF)
Description	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.
Time Frame	Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years	Children ≥ 6 Years
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: picograms/milliliter
6 months, n=17,5	-5.42 (20.722)	-1.56 (6.518)
12 months, n=18,5	-15.04 (25.550)	-5.42 (5.508)
End of Study, n=14,4	-29.98 (41.190)	-29.45 (9.963)

30. Post-Hoc Outcome

Title	Percent of Participants With Thickened Heart Valves as Assessed by Echocardiography (ECG)
Description	ECG allows a non-invasive assessment of cardiac structure, function, and hemodynamics and can provide essential insight into mechanisms of disease and therapeutic benefit.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Tricuspid Valve, n=18,6	5.3	0.0
Pulmonary Valve, n=18,6	0.0	0.0
Mitral Valve, n=18,6	57.9	66.7
Aortic Valve, n=18,6	15.8	16.7

31. Post-Hoc Outcome

Title	Percent of Participants With Trace Regurgitation as Assessed by ECG
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Measure Type: Number; Unit of Measure: percentage of participants
Tricuspid Valve, n=18,6	73.7	100.0
Pulmonary Valve, n=16,5	63.2	66.7
Mitral Valve, n=18,6	36.8	16.7
Aortic Valve, n=18,6	21.1	0.0

32. Post-Hoc Outcome

Title	Change From Baseline in Tricuspid Valve Regurgitant Velocity
Description	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.
Time Frame	Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: meters/second
6 months, n=2,1	-0.325 (0.106)	1.990 (0.0)
12 months, n=4,2	-0.013 (0.210)	1.210 (1.428)
End of Study, n=3,1	-0.087 (0.078)	2.030 (0.0)

33. Post-Hoc Outcome

Title	Change From Baseline in The Ratio of Mitral Valve Early Inflow Velocity (E) to Late Inflow Velocity (A)
Description	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.
Time Frame	Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: quotient of E/A
6 months, n=4,1	0.196 (0.418)	0.059 (0.0)
12 months, n=3,1	0.293 (0.404)	-0.608 (0.0)
End of Study, n=4,2	-0.081 (0.529)	-0.226 (0.096)

34. Post-Hoc Outcome

Title	Change From Baseline in Liver Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI)
Description	Liver volume was obtained via abdominal MRI. A negative value indicates that volume decreased.
Time Frame	Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: milliliters
6 months, n=5,2	93.00 (237.960)	190.00 (91.924)
12 months, n=5,2	39.20 (248.532)	280.00 (32.527)
End of Study, n=4,2	356.00 (197.985)	188.50 (41.719)

35. Post-Hoc Outcome

Title	Change From Baseline in Spleen Volume as Assessed by Abdominal Magnetic Resonance Imaging (MRI)
Description	Spleen volume was assessed via abdominal MRI. A negative value indicates that volume decreased.
Time Frame	Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Children < 6 Years Old	Children ≥ 6 Years Old
Arm/Group Description:	Children ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).	Children ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
Overall Number of Participants Analyzed	19	6
Mean (Standard Deviation); Unit of Measure: milliliters
6 months, n=5,2	29.60 (63.552)	11.50 (0.707)
12 months, n=5,2	238.40 (473.682)	44.00 (2.828)
End of Study, n=4,2	128.50 (71.276)	13.00 (28.284)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Children < 6 Years		Children ≥ 6 Years
Arm/Group Description	Patients ≥1 to < 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).		Patients ≥ 6 years of age with MPS IIIA who were untreated with any investigational products (drugs and/or devices).
All-Cause Mortality
	Children < 6 Years		Children ≥ 6 Years
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Children < 6 Years		Children ≥ 6 Years
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0.00%)		0/6 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Children < 6 Years		Children ≥ 6 Years
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/19 (42.11%)		3/6 (50.00%)
Ear and labyrinth disorders
Ear Haemorrhage † 1	0/19 (0.00%)	0	1/6 (16.67%)	1
Gastrointestinal disorders
Vomiting † 1	6/19 (31.58%)	6	1/6 (16.67%)	1
General disorders
Chills † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Pain † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Pyrexia † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Injury, poisoning and procedural complications
Procedural nausea † 1	2/19 (10.53%)	2	0/6 (0.00%)	0
Post Lumbar Puncture Syndrome † 1	0/19 (0.00%)	0	1/6 (16.67%)	1
Procedural Headache † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Procedural Vomiting † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Nervous system disorders
Headache † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Laryngospasm † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
Wheezing † 1	1/19 (5.26%)	1	0/6 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (12.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Physician
• Organization: Shire Development LLC
• Phone: +1 866 842 5335

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cingi EC, Beebe DS, Whitley CB, Belani KG. Anesthetic care and perioperative complications in children with Sanfilipo Syndrome Type A. Paediatr Anaesth. 2016 May;26(5):531-8. doi: 10.1111/pan.12876. Epub 2016 Mar 9.

Shapiro EG, Nestrasil I, Delaney KA, Rudser K, Kovac V, Nair N, Richard CW 3rd, Haslett P, Whitley CB. A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA. J Pediatr. 2016 Mar;170:278-87.e1-4. doi: 10.1016/j.jpeds.2015.11.079. Epub 2016 Jan 16.

Shapiro EG, Nestrasil I, Ahmed A, Wey A, Rudser KR, Delaney KA, Rumsey RK, Haslett PA, Whitley CB, Potegal M. Quantifying behaviors of children with Sanfilippo syndrome: the Sanfilippo Behavior Rating Scale. Mol Genet Metab. 2015 Apr;114(4):594-8. doi: 10.1016/j.ymgme.2015.02.008. Epub 2015 Mar 5.

Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB, Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014 May;164(5):1147-1151.e1. doi: 10.1016/j.jpeds.2014.01.007. Epub 2014 Feb 25.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01047306 History of Changes
• Other Study ID Numbers: HGT-SAN-053
• First Submitted: January 11, 2010
• First Posted: January 12, 2010
• Results First Submitted: February 9, 2015
• Results First Posted: March 30, 2016
• Last Update Posted: March 30, 2016