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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT01047306
First received: January 11, 2010
Last updated: February 29, 2016
Last verified: February 2016
  Purpose
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.

Condition Intervention
Sanfilippo Syndrome Type A
Other: assessment

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Longitudinal, Prospective, Natural History Study of Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Change From Baseline in Bayley Scales of Infant Development-III/Kaufman Assessment Battery for Children-II (BSID-III/KABC-II) Age-Equivalent Scores [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in BSID-III/KABC-II Developmental Quotient (DQ) Scores [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Vineland Adaptive Behavior Scales-II (VABS-II) Age-equivalent Scores [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in VABS-II Overall DQ Scores [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change From Baseline Values in Gray Matter Volume Assessed by Brain Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in The Total Disability Score (TDS) of The Four Point Scoring System (FPSS) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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).

  • Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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).

  • Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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).

  • Percent of Participants With an Abnormal Overall Test Result of Auditory Brainstem Response (ABR) at End of Study [ Time Frame: End of Study (12 months assessment or early termination) ] [ Designated as safety issue: No ]
    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).

  • Percent of Participants With Sensorineural Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Sensorineural Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Sensorineural Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Sensorineural Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: End of Study (12 months assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Conductive Hearing Loss at Baseline, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Conductive Hearing Loss at 6 Months, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Conductive Hearing Loss at 12 Months, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Conductive Hearing Loss at End of Study, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: End of Study (12 months assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Mild, Moderate, or Severe Hearing Loss at Baseline, as Assessed by The Auditory Brain Response (ABR) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Mild, Moderate, or Severe Hearing Loss at 6 Months, as Assessed by The Auditory Brain Response (ABR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Mild, Moderate, or Severe Hearing Loss at 12 Months, as Assessed by The Auditory Brain Response (ABR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Mild, Moderate, or Severe Hearing Loss at End of Study, as Assessed by The Auditory Brain Response (ABR) [ Time Frame: End of Study (12 months assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Profound Hearing Loss, as Assessed by the Auditory Brainstem Response (ABR) [ Time Frame: Baseline, 6 months, 12 months, End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With "Somewhat" or "Much" Worse Change in Health as Assessed by The Child Health Questionnaire Parent Form 50 (CHQ-PF50) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in The Infant Toddler Quality of Life Questionnaire (ITQoL) Growth And Development Subscale [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in The Total Sleep Disturbance (TSD) Score of The Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Change From Baseline in Urine Glycosaminoglycan (GAG) Levels [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    Urine GAG was measured by a dye binding assay. A negative value indicates that GAG levels decreased.

  • Change From Baseline in Total Tau Levels in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Phosphorylated Tau Levels in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline, 6 months, 12 months, and End of Study (Month 24 assessment or early termination) ] [ Designated as safety issue: No ]
    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.


Biospecimen Retention:   Samples With DNA
CSF, urine and serum

Enrollment: 25
Study Start Date: February 2010
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
No Treatment
This is a longitudinal, prospective, observational, natural history study of patients with MPS IIIA to identify potential surrogate endpoints for future ERT trials via standardized clinical, biochemical, neurocognitive, developmental, behavioral and imaging measures.
Other: assessment
Physical, developmental, neurological, behavioral, and neurocognitive assessments

  Eligibility

Ages Eligible for Study:   1 Year and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Initial patient eligibility is based on patient age and on a confirmed diagnosis of MPS IIIA by biochemical enzyme assay.
Criteria

Inclusion Criteria:

1a. Documented deficiency in HNS enzyme activity of less than or equal to 10% of the lower limit of the normal range as measured in fibroblasts or leukocytes (based on normal range for diagnosis of MPS IIIA by a laboratory that is acceptable to Shire HGT).

AND

1b. Normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes (based on normal range by a laboratory that is acceptable to Shire HGT).

2.Patient is greater than or equal to 1 year of age and developmental age greater than or equal to 1 year.

3. Patient is medically stable to accommodate the protocol requirements, including travel and assessments, without placing an undue burden on the patient/patient's family.

4. Voluntarily signed an IRB/IEC-approved informed consent (assent if applicable) form. The patient's, patient's parents or legally authorized representative(s) consent and patient's assent as appropriate, must be obtained.

Exclusion Criteria:

  1. Patient has significant non-MPS IIIA-related CNS impairment or behavioral disturbances, which would confound the scientific integrity or interpretation of study assessments, as determined by the investigator.
  2. Patients who, for MPS IIIA behavioral-related reasons,in the opinion of the investigator, would preclude performance of study neurocognitive and developmental testing procedures.
  3. Patients who are pregnant, breast feeding, or female patients of childbearing potential, who will not or cannot comply with the use of an acceptable method of birth control such as condoms, barrier method, oral contraception, etc.
  4. Patient is blind and/or deaf.
  5. Patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
  6. Patient or patient family history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
  7. The Investigator may choose to exclude patients who have had complications resulting from prior lumbar punctures.
  8. Patient history of poorly controlled seizure disorder.
  9. Patient history of an intracranial pressure (ICP) or opening CSF pressure upon lumbar puncture that exceeds 30 cm water that has not been definitively treated.
  10. Patient is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results.
  11. Patient cannot sustain absence from aspirin, non-steroidals, or medications that affect blood clotting within 1 week prior to a relevant study related procedure (eg, lumbar puncture if applicable), or has ingested such medications within 1 week before any procedures in which any change in clotting activity would be deleterious.
  12. Patient has received treatment with any investigational drug or device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently enrolled in another study that involves an investigational drug or device (enrollment through Safety follow-up contact).
  13. Patient has received a hematopoietic stem cell or bone marrow transplant.
  14. Patient's assent is unattainable, or the patient's parent(s), or patient's legally authorized representative(s) is/are unable to understand the nature, scope, and possible consequences of the study, or do/does not agree to comply with the protocol defined schedule of assessments.
  15. The patient has any item (braces, tattoos, etc.) which would exclude the patient from being able to undergo MRI according to local Institutional Policy, or the patient has any other situation that would exclude the patient from undergoing any other procedure required in this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01047306

Locations
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Shire
Investigators
Study Director: Patrick Haslett, MD Shire
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01047306     History of Changes
Other Study ID Numbers: HGT-SAN-053 
Study First Received: January 11, 2010
Results First Received: February 9, 2015
Last Updated: February 29, 2016
Health Authority: United States:Research Ethics Board

Additional relevant MeSH terms:
Mucopolysaccharidosis III
Syndrome
Disease
Pathologic Processes
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases

ClinicalTrials.gov processed this record on September 30, 2016