NCT01047306

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

Completed Results posted Last updated 11 June 2021

What this trial tests

trial testing assessment in Sanfilippo Syndrome Type A in 25 participants. Completed in 10 July 2013.

Timeline

15 February 2010

Primary endpoint
10 July 2013

10 July 2013

Quick facts

Lead sponsor	Shire
Status	Completed
Study type	OBSERVATIONAL
Enrollment	25
Start date	15 February 2010
Primary completion	10 July 2013
Estimated completion	10 July 2013
Sites	1 location across United States

Drugs / interventions tested

• assessment

Conditions studied

• Sanfilippo Syndrome Type A — all drugs for Sanfilippo Syndrome Type A →

Sponsor

Shire — full company profile →

Who can join

1 and older, any sex, with Sanfilippo Syndrome Type A. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores Primary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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 processi

6 months, n=18,6

Group	Value	95% CI
Children < 6 Years	0.17	± 2.093
Children ≥ 6 Years	1.19	± 3.289

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-1.72	± 4.625
Children ≥ 6 Years	1.39	± 4.029

End of Study, n=15,5

Group	Value	95% CI
Children < 6 Years	-1.80	± 7.143
Children ≥ 6 Years	2.95	± 4.652

Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores Primary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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

6 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-7.42	± 6.153
Children ≥ 6 Years	-0.03	± 1.960

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-15.69	± 9.258
Children ≥ 6 Years	-1.66	± 2.977

End of Study, n=15,5

Group	Value	95% CI
Children < 6 Years	-26.09	± 14.788
Children ≥ 6 Years	-2.94	± 2.588

Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores Primary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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 ex

6 months, n=17,6

Group	Value	95% CI
Children < 6 Years	-0.92	± 3.966
Children ≥ 6 Years	-1.11	± 5.661

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-0.90	± 8.170
Children ≥ 6 Years	-2.63	± 4.847

End of Study, n=16,6

Group	Value	95% CI
Children < 6 Years	-2.29	± 8.321
Children ≥ 6 Years	-7.80	± 15.834

Change From Baseline in VABS-II Overall DQ Scores Primary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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

6 months, n=17,6

Group	Value	95% CI
Children < 6 Years	-9.33	± 8.632
Children ≥ 6 Years	-2.78	± 5.971

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-12.88	± 15.131
Children ≥ 6 Years	-5.12	± 7.683

End of Study, n=16,6

Group	Value	95% CI
Children < 6 Years	-23.81	± 14.655
Children ≥ 6 Years	-9.70	± 11.299

Change From Baseline in Urine Glycosaminoglycan (GAG) Levels Secondary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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

6 months, n=18,6

Group	Value	95% CI
Children < 6 Years	0.26	± 19.379
Children ≥ 6 Years	-10.23	± 32.983

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-0.39	± 19.429
Children ≥ 6 Years	-7.95	± 31.516

End of Study, n=15,5

Group	Value	95% CI
Children < 6 Years	-0.33	± 22.706
Children ≥ 6 Years	-6.34	± 28.810

Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI) Secondary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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.

6 months, n=17,6

Group	Value	95% CI
Children < 6 Years	-15.98	± 21.860
Children ≥ 6 Years	1.16	± 14.790

12 months, n=16,6

Group	Value	95% CI
Children < 6 Years	-41.40	± 36.319
Children ≥ 6 Years	-11.68	± 13.126

End of Study, n=9,5

Group	Value	95% CI
Children < 6 Years	-80.29	± 45.867
Children ≥ 6 Years	-22.41	± 18.134

Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS) Secondary · Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination)

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 diseas

6 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-0.18	± 0.411
Children ≥ 6 Years	0.10	± 0.245

12 months, n=18,6

Group	Value	95% CI
Children < 6 Years	-0.31	± 0.512
Children ≥ 6 Years	0.10	± 0.245

End of Study, n=15,5

Group	Value	95% CI
Children < 6 Years	-0.43	± 0.448
Children ≥ 6 Years	0.18	± 0.164

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

Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural

Right ear, n=11,5

Group	Value	95% CI
Children < 6 Years Old	57.9
Children ≥ 6 Years Old	50.0

Left ear, n=11,5

Group	Value	95% CI
Children < 6 Years Old	57.9
Children ≥ 6 Years Old	66.7

Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months Secondary · 6 months

Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural

Right ear, n=18,6

Group	Value	95% CI
Children < 6 Years Old	94.7
Children ≥ 6 Years Old	66.7

Left ear, n=18,6

Group	Value	95% CI
Children < 6 Years Old	94.7
Children ≥ 6 Years Old	66.7

Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months Secondary · 12 months

Hearing loss in subjects with MPS IIIA was characterized by assessing the ABR. The ABR is a voltage response evoked by acoustic stimuli as sound is processed along the auditory pathway. It consists of electrical signals resulting from the sum of sound-evoked activity along the auditory nerve and brainstem nuclei. The ABR analysis determines the sound intensity at which a neural response first appears (hearing threshold). Other parameters of interest include amplitude (the number of neurons firing), latency (the speed of transmission), interpeak latency (the time between peaks), and interaural

Right ear, n=17,6

Group	Value	95% CI
Children < 6 Years Old	89.5
Children ≥ 6 Years Old	66.7

Left ear, n=17,6

Group	Value	95% CI
Children < 6 Years Old	89.5
Children ≥ 6 Years Old	83.3

Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study Secondary · End of Study (12 months assessment or early termination)

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

Right ear, n=15,5

Group	Value	95% CI
Children < 6 Years Old	73.7
Children ≥ 6 Years Old	66.7

Left ear, n=15,5

Group	Value	95% CI
Children < 6 Years Old	78.9
Children ≥ 6 Years Old	66.7

Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) Secondary · Baseline

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 incl

Right ear, n=9,3

Group	Value	95% CI
Children < 6 Years Old	21.1
Children ≥ 6 Years Old	16.7

Left ear, n=9,4

Group	Value	95% CI
Children < 6 Years Old	21.1
Children ≥ 6 Years Old	16.7

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Children < 6 Years

Serious: 0/19 (0%)

Deaths: —

Children ≥ 6 Years

Serious: 0/6 (0%)

Deaths: —

Other adverse events (12 terms — click to expand)

Reaction	System	Children < 6 Years	Children ≥ 6 Years
Vomiting	Gastrointestinal disorders	—	—
Procedural nausea	Injury, poisoning and procedural complications	—	—
Post Lumbar Puncture Syndrome	Injury, poisoning and procedural complications	—	—
Procedural Headache	Injury, poisoning and procedural complications	—	—
Procedural Vomiting	Injury, poisoning and procedural complications	—	—
Chills	General disorders	—	—
Pain	General disorders	—	—
Pyrexia	General disorders	—	—
Ear Haemorrhage	Ear and labyrinth disorders	—	—
Headache	Nervous system disorders	—	—
Laryngospasm	Respiratory, thoracic and mediastinal disorders	—	—
Wheezing	Respiratory, thoracic and mediastinal disorders	—	—

Data from ClinicalTrials.gov NCT01047306 adverse events section.

Sponsor's own description

The purpose is to evaluate the course of disease progression in MPS IIIA patients who are untreated to identify potential surrogate endpoints that may be utilized in future ERT trials of MPS IIIA via defined assessments including standardized clinical, biochemical, neurocognitive, behavioral, developmental, and imaging measures.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA.
   Shapiro EG, Nestrasil I, Delaney KA, Rudser K, et al · · 2016 · cited 92× · PMID 26787381 · DOI 10.1016/j.jpeds.2015.11.079
2. Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome.
   Delaney KA, Rudser KR, Yund BD, Whitley CB, et al · · 2014 · cited 43× · PMID 24190801 · DOI 10.1007/8904_2013_269
3. The Neurobehavioral Phenotype in Mucopolysaccharidosis Type IIIB: an Exploratory Study.
   Shapiro E, King K, Ahmed A, Rudser K, et al · · 2016 · cited 35× · PMID 26918231 · DOI 10.1016/j.ymgmr.2016.01.003
4. Quantifying behaviors of children with Sanfilippo syndrome: the Sanfilippo Behavior Rating Scale.
   Shapiro EG, Nestrasil I, Ahmed A, Wey A, et al · · 2015 · cited 32× · PMID 25770355 · DOI 10.1016/j.ymgme.2015.02.008
5. Research challenges in central nervous system manifestations of inborn errors of metabolism.
   Dickson PI, Pariser AR, Groft SC, Ishihara RW, et al · · 2011 · cited 18× · PMID 21176882 · DOI 10.1016/j.ymgme.2010.11.164
6. Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series.
   Shapiro E, Ahmed A, Whitley C, Delaney K. · · 2018 · cited 17× · PMID 29198891 · DOI 10.1016/j.ymgme.2017.11.014
7. Anesthetic care and perioperative complications in children with Sanfilipo Syndrome Type A.
   Cingi EC, Beebe DS, Whitley CB, Belani KG. · · 2016 · cited 6× · PMID 26956723 · DOI 10.1111/pan.12876
8. Poster Presentations: ASPA 2014
   · 2014