CClinicalTrials.gg
Sign In
CompletedNCT01510028IDEAMLDUpdated Jun 14, 2021Results posted

Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)

A Phase 1/2 interventional study of Recombinant human arylsulfatase A in Metachromatic Leukodystrophy (MLD), sponsored by Shire. Completed at 5 sites in 5 countries. Open to participants aged Up to 12 Years. Per ClinicalTrials.gov, last updated 2021-06-14.

Sponsored by Shire · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
24
Allocation
Non-randomized
Ages
Up to 12 Years
Sex
All
01

Study summary

The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD).

Read the detailed description

Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD.

This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.

02

Conditions studied

  • Metachromatic Leukodystrophy (MLD)

Keywords

  • Intrathecal Drug Delivery Device (IDDD)
  • Recombinant human arylsulfatase A (rhASA)
  • Metachromatic Leukodystrophy (MLD)
03

In context

Leukodystrophy, Metachromatic

42 studies on the registry are indexed under Leukodystrophy, Metachromatic; 10 are open to participants now.

This study's enrollment of 24 is close to the median of 22 across 24 interventional studies indexed under Leukodystrophy, Metachromatic.

Browse Leukodystrophy, Metachromatic studies →

Lead sponsor

Shire is the lead sponsor of 346 studies on the registry; 2 are open to participants now.

Of its 47 completed or terminated interventional studies of FDA-regulated products, 47 (100%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
Up to 12 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

For Cohorts 1-4:

  1. Confirmed diagnosis of metachromatic leukodystrophy by both:

    • Arylsulfatase A (ASA) deficiency by assay in leukocytes AND
    • Elevated sulfatide in urine

  2. Appearance of the first symptoms of disease at or before 30 months of age.

    For Cohorts 1-3 only:

  3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to walk forward 10 steps with one hand held.

  4. The patient is less than 12 years of age at the time of screening.

    For Cohort 4 only:

    3.1 Minimum motor function requirements:

    1. A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND
    2. GMFM-88 Dimension E: Walking, Running \& Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screening and baseline examinations (if applicable).

    4.1 The patient is less than 8 years of age at the time of screening.

    For Cohorts 1-4:

  5. Neurological signs of MLD must be present at the screening examination.
  6. The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
  7. Patient's parent(s) or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the patient.

Exclusion criteria

Exclusion Criteria:

Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening:

For Cohorts 1-4:

  1. History of hematopoietic stem cell transplantation (HSCT).
  2. The 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.
  3. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
  4. The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study.
  5. The patient is pregnant or breastfeeding.
  6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT

Mini S IDDD Instructions for Use (IFU), including:

  1. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
  2. The patient's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator.
  3. The patient has a known or suspected local or general infection.
  4. The patient is at risk of abnormal bleeding due to a medical condition or therapy.
  5. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
  6. The patient has a functioning CSF shunt device.
  7. The patient has shown an intolerance to an implanted device.
05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
24 participants (actual)

Study arms

  • Experimental
    Cohort 1 (10 mg)

    6 patients treated with HGT-1110 10 mg EOW by IT injection

    Biological: Recombinant human arylsulfatase A

  • Experimental
    Cohort 2 (30 mg)

    6 patients treated with HGT-1110 30 mg EOW by IT injection

    Biological: Recombinant human arylsulfatase A

  • Experimental
    Cohort 3 (100 mg)

    6 patients treated with HGT-1110 100 mg EOW by IT injection

    Biological: Recombinant human arylsulfatase A

  • Experimental
    Cohort 4 (100 mg)

    6 patients treated with HGT-1110 100 mg EOW by IT injection

    Biological: Recombinant human arylsulfatase A

Interventions

  • BiologicalRecombinant human arylsulfatase A

    6 patients treated with HGT-1110 EOW by IT injection

    Also known as: HGT-1110, rhASA

06

What researchers measure

Primary outcomes

  1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity

    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Drug-related and device-related types of TEAEs were analyzed and reported. The severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale. Severity of all AEs or SAEs was recorded as grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or fatal. Here SDI refers to surgical device implantation.

    Time frame: From start of study treatment up to Week 42

  2. Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

    Clinical laboratory test included serum chemistry, hematology and urinalysis. Clinical laboratory abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

    Time frame: From start of study treatment up to Week 40

  3. Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

    Vital sign assessments included blood pressure, heart rate, respiratory rate and body temperature. Vital sign abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Vital sign abnormalities included pyrexia which was considered as TEAE and was reported.

    Time frame: From start of study treatment up to Week 40

  4. Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

    12-lead ECG was recorded and measured with the participant in rested supine position for at least 10 minutes. ECG abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

    Time frame: From start of study treatment up to Week 40

  5. Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)

    Complete physical examination included evaluation of the port and catheter track. Height or length and weight were recorded and used to calculate growth. Body weight and height measurements were used to calculate the body mass index (BMI). Head circumference was measured in uniform manner for all participants. Clinical significance was defined as any variation in physical findings that had medical relevance resulting in an alteration in medical care. Clinically significant abnormalities related to physical examination were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

    Time frame: From start of study treatment up to Week 40

  6. Number of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

    CSF chemistry assessments (including cell counts, glucose and protein) was measured. CSF chemistry abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

    Time frame: From start of study treatment up to Week 40

  7. Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum

    Number of participants with positive anti-SHP611 antibody results in serum and in CSF were reported. A participant was considered positive if they had at least 1 positive result during the study.

    Time frame: Baseline up to Week 40

Secondary outcomes

  1. Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40

    The GMFM-88 was used to measure motor function. The GMFM-88 item scores were used to calculate domain-specific percent score for each of the 5 GMFM-88 dimensions (lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping), and a total GMFM-88 (percent) score was calculated based on each dimension score. Each of the 88 items was rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores ranged from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities.

    Time frame: Baseline, Week 40

  2. Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40

    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for texture utilized was evaluated. Data was presented only for the shifts observed.

    Time frame: Week 40

  3. Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40

    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for laryngeal penetration was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

    Time frame: Week 40

  4. Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40

    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for aspiration through vocal cords were assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

    Time frame: Week 40

  5. Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40

    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for dose residue clear after subsequent swallowing was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture.

    Time frame: Week 40

  6. Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40

    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for aspiration risk was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

    Time frame: Week 40

  7. Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40

    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for number of participants who reported change in amplitude greater than (\>) 0.

    Time frame: Baseline, Week 40

  8. Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40

    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized nerve conduction velocity values were assessed. Data was presented only for number of participants who reported change in nerve conduction velocity \> 0. Here MME refers to median motor elbow, WCV for wrist conduction velocity, PMA for peroneal motor ankle, FHCV to fibular head conduction velocity, TMA for tibial motor ankle, KCV for knee conduction velocity and UME for ulnar motor elbow,

    Time frame: Baseline, Week 40

  9. Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40

    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for number of participants who reported change in distal latency \> 0. Here MMW refers to median motor wrist, APB for abductor pollicis brevis, MSW for median sensory wrist, DDL for digit distal latency, PMA for peroneal motor ankle, EDB for extensor digitorum brevis, SSB-point DL for sural sensory B-point distal latency, TMA for tibial motor ankle, abductor hallucis for AH distal latency and, UMW for ulnar motor wrist.

    Time frame: Baseline, Week 40

  10. Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40

    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (ABC) (a composite of the other 4 domain). Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The 4 domain standard scores range from 20-160 and higher scores indicate a higher level of functioning. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160) and higher scores indicate a higher level of functioning. A positive change value indicates improvement in adaptive functioning.

    Time frame: Baseline, Week 40

  11. Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40

    COMFORT questionnaire was used to assess health status and the impact of disease on the ability of participants with MLD to carry out activities of daily life. The questionnaire was organized by 8 domains (ie, personal care; positioning, transfer, or mobility; eating; pain and discomfort during the day; sleep; emotions; communication; and play and leisure activities). The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning.

    Time frame: Baseline, Week 40

  12. Maximum Observed Serum Concentration (Cmax) of SHP611

    Cmax is the maximum observed serum concentration of SHP611.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  13. Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma

    Tmax is the time to reach maximum observed drug concentration of SHP611 during a dosing interval.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  14. Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611

    The AUC0-inf is the area under the concentration-time curve from time zero to infinity of SHP611.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  15. Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611

    AUC0-last is the area under the concentration-time curve from the time of dosing to the last measurable concentration of SHP611.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  16. Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611

    Area under the concentration-time curve over the interval from 0 to 24 hours after dosing of SHP611.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  17. First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611

    Lambda z is first order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  18. Terminal Elimination Half Life (t1/2) of SHP611

    The t1/2 is the time in hours required for the concentration of the drug to reach half of its original value.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  19. Total Body Clearance (CL/F) After Intrathecal Administration of SHP611

    CL/F was defined as the total body clearance of the drug for extravascular administration divided by the fraction of dose absorbed.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  20. Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611

    Volume of distribution was associated with the terminal slope following extravascular administration of SHP611 divided by the fraction of dose absorbed.

    Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose

  21. Concentration of SHP611 in Cerebrospinal Fluid

    Concentration of SHP611 in CSF was determined using validated enzyme-linked immunosorbent assay (ELISA) method.

    Time frame: Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks

07

Results

Posted Oct 15, 2018

Participant flow

The study was conducted at 5 main sites for cohorts 1 to 3 in Brazil, Denmark, Germany, France, and Australia and 3 main sites for cohort 4 in Denmark, France, and Germany between 02 February 2012 (first participant first visit) and 20 January 2017 (last participant last visit).

Participant flow — Overall Study
MilestoneSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Started6666
Completed5666
Not completed1000
Withdrew: Lack of efficacy1000

Outcome measures

PrimaryNumber of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Drug-related and device-related types of TEAEs were analyzed and reported. The severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale. Severity of all AEs or SAEs was recorded as grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or fatal. Here SDI refers to surgical device implantation.

Time frame:
From start of study treatment up to Week 42
Reported as:
Count of participants · Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
TEAE6666
SHP611-related TEAE3442
SDI-related TEAE5344
IDDD-related TEAE3340
SOPH-A-PORT IDDD-related TEAE0040
IT administration process related TEAE4311
Severe TEAE2311
Serious TEAE5432
PrimaryNumber of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

Clinical laboratory test included serum chemistry, hematology and urinalysis. Clinical laboratory abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

Time frame:
From start of study treatment up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Gamma-glutamyltransferase (GGT) increased2110
Alanine aminotransferase (ALT) increased1101
Aspartate aminotransferase (AST) increased0110
Blood iron decreased0110
Amylase increased0110
Blood alkaline phosphatase increased1000
Blood creatine phosphokinase increased0003
Hepatic enzymes increased0001
Eosinophil count increased0110
Eosinophilia0200
Mean cell volume decreased0100
Neutrophil count increased0100
White blood cell count increased0100
Lymphopenia0100
Leukocytosis0100
Proteinuria0100
PrimaryNumber of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

Vital sign assessments included blood pressure, heart rate, respiratory rate and body temperature. Vital sign abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Vital sign abnormalities included pyrexia which was considered as TEAE and was reported.

Time frame:
From start of study treatment up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)5355
PrimaryNumber of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

12-lead ECG was recorded and measured with the participant in rested supine position for at least 10 minutes. ECG abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

Time frame:
From start of study treatment up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)0000
PrimaryNumber of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)

Complete physical examination included evaluation of the port and catheter track. Height or length and weight were recorded and used to calculate growth. Body weight and height measurements were used to calculate the body mass index (BMI). Head circumference was measured in uniform manner for all participants. Clinical significance was defined as any variation in physical findings that had medical relevance resulting in an alteration in medical care. Clinically significant abnormalities related to physical examination were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

Time frame:
From start of study treatment up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)0000
PrimaryNumber of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

CSF chemistry assessments (including cell counts, glucose and protein) was measured. CSF chemistry abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

Time frame:
From start of study treatment up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
CSF Protein Increased0011
CSF Albumin Increased0010
PrimaryNumber of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum

Number of participants with positive anti-SHP611 antibody results in serum and in CSF were reported. A participant was considered positive if they had at least 1 positive result during the study.

Time frame:
Baseline up to Week 40
Reported as:
Count of participants · Participants
Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Serum anti-SHP611 antibody (Ab) positive4312
Serum neutralizing anti-SHP611 antibody positive3211
CSF anti-SHP611 antibody positive3102
CSF neutralizing anti-SHP611 antibody positive0000
Serum or CSF anti-SHP611 antibody positive4312
Serum and CSF anti-SHP611 antibody positive3102
Serum or CSF neutralizing anti-SHP611 Ab positive3211
Serum and CSF neutralizing anti-SHP611 Ab positive0000
SecondaryChange From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40

The GMFM-88 was used to measure motor function. The GMFM-88 item scores were used to calculate domain-specific percent score for each of the 5 GMFM-88 dimensions (lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping), and a total GMFM-88 (percent) score was calculated based on each dimension score. Each of the 88 items was rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores ranged from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · Score on a Scale
Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40
Score on a ScaleSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40-31.9 ± 8.76-29.0 ± 8.58-19.5 ± 8.54-18.1 ± 9.14
SecondaryNumber of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for texture utilized was evaluated. Data was presented only for the shifts observed.

Time frame:
Week 40
Reported as:
Count of participants · Participants
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Thin Liquids to Thin Liquids2224
Thin Liquids to Thickened Liquids1200
Thin Liquids to Puree Texture1214
Thin Liquids to Solids0200
Thickened Liquids to Thin Liquids1211
Thickened Liquids to Thickened Liquids0230
Thickened Liquids to Puree Texture1231
Thickened Liquids to Solids0200
Puree Texture to Thin Liquids1232
Puree Texture to Thickened Liquids1220
Puree Texture to Puree Texture3443
Puree Texture to Solids0200
Solids to Thin Liquids0201
Solids to Thickened Liquids0200
Solids to Puree Texture0201
Solids to Solids0200
SecondaryNumber of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for laryngeal penetration was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame:
Week 40
Reported as:
Count of participants · Participants
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Normal to Normal (TL)0021
Normal to Without Cough (TL)0001
Without Cough to Without Cough (TL)1000
WCC to Without Cough (TL)1000
WCC to WCC (TL)0201
Normal to WCC (THL)0010
Without Cough to Normal (THL)0010
WCC to Normal (THL)0010
WCC to WCC (THL)0200
Normal to Normal (PT)0111
Normal to WCC (PT)0010
Normal to WCNC (PT)1000
Without Cough to Normal (PT)0020
Without Cough to WCC (PT)1000
WCC to Normal (PT)0001
WCC to WCC (PT)0200
WCNC to Normal (PT)0100
WCNC to Without Cough (PT)1000
WCC to WCC (Solids)NA2NANA
SecondaryNumber of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for aspiration through vocal cords were assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame:
Week 40
Reported as:
Count of participants · Participants
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Normal to Normal (TL)0023
Without Cough to Without Cough (TL)1000
WCC to WCC (TL)0200
Normal to Normal (THL)0010
Without Cough to Normal (THL)0010
WCC to Normal (THL)0010
WCC to WCC (THL)0200
Normal to Normal (PT)0222
Without Cough to Normal (PT)0020
WCC to WCC (PT)0200
WCNC to Normal (PT)1000
WCC to WCC (Solids)NA2NANA
SecondaryNumber of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for dose residue clear after subsequent swallowing was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture.

Time frame:
Week 40
Reported as:
Count of participants · Participants
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Normal to Normal (TL)0010
Normal to Yes (TL)0010
Yes to Yes (TL)1201
Yes to No (TL)0001
No to Yes (TL)0001
No to No (TL)1000
Normal to Yes (THL)0020
Yes to Normal (THL)0010
Yes to Yes (THL)0200
Normal to Normal (PT)0101
Normal to Yes (PT)0020
Normal to No (PT)1000
Yes to Normal (PT)0010
Yes to Yes (PT)1201
Yes to No (PT)1000
No to Normal (PT)0110
Yes to Yes (Solids)NA2NANA
SecondaryNumber of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for aspiration risk was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame:
Week 40
Reported as:
Count of participants · Participants
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Low to Low (TL)2223
Low to High (TL)0001
Low to Low (THL)0230
Low to Low (PT)1333
Low to High (PT)1000
Moderate to Low (PT)0110
Moderate to Moderate (PT)1000
Low to Low (Solids)NA2NANA
SecondaryNumber of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40

Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for number of participants who reported change in amplitude greater than (\>) 0.

Time frame:
Baseline, Week 40
Reported as:
Count of participants · Participants
Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Median Motor Wrist Amplitude (Baseline)6556
Median Motor Wrist Amplitude (Week 40)3565
Median Motor Elbow Amplitude (Baseline)0246
Median Motor Elbow Amplitude (Week 40)0464
Median Sensory Wrist Amplitude (Baseline)2344
Median Sensory Wrist Amplitude (Week 40)1533
Peroneal Motor Fibular Head Amplitude (Baseline)0246
Peroneal Motor Fibular Head Amplitude (Week 40)0454
Peroneal Motor Ankle Amplitude (Baseline)6556
Peroneal Motor Ankle Amplitude (Week 40)4554
Sural Sensory B-point (Baseline)2234
Sural Sensory B-point (Week 40)2234
Tibial Motor Ankle Amplitude (Baseline)4333
Tibial Motor Ankle Amplitude (Week 40)2341
Tibial Motor Knee Amplitude (Baseline)0033
Tibial Motor Knee Amplitude (Week 40)0241
Ulnar Motor Wrist Amplitude (Baseline)4333
Ulnar Motor Wrist Amplitude (Week 40)2331
Ulnar Motor Elbow Amplitude (Baseline)0033
Ulnar Motor Elbow Amplitude (Week 40)0231
SecondaryNumber of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40

Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized nerve conduction velocity values were assessed. Data was presented only for number of participants who reported change in nerve conduction velocity \> 0. Here MME refers to median motor elbow, WCV for wrist conduction velocity, PMA for peroneal motor ankle, FHCV to fibular head conduction velocity, TMA for tibial motor ankle, KCV for knee conduction velocity and UME for ulnar motor elbow,

Time frame:
Baseline, Week 40
Reported as:
Count of participants · Participants
Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
MME to WCV (Baseline)6666
MME to WCV (Week 40)3565
PMA to FHCV (Baseline)6666
PMA to FHCV (Week 40)4554
TMA to KCV (Baseline)4443
TMA to KCV (Week 40)2341
UME to WCV (Baseline)4443
UME to WCV (Week 40)2331
SecondaryNumber of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40

Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for number of participants who reported change in distal latency \> 0. Here MMW refers to median motor wrist, APB for abductor pollicis brevis, MSW for median sensory wrist, DDL for digit distal latency, PMA for peroneal motor ankle, EDB for extensor digitorum brevis, SSB-point DL for sural sensory B-point distal latency, TMA for tibial motor ankle, abductor hallucis for AH distal latency and, UMW for ulnar motor wrist.

Time frame:
Baseline, Week 40
Reported as:
Count of participants · Participants
Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40
ParticipantsSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
MMW to APB distal latency (Baseline)6556
MMW to APB distal latency (Week 40)3565
MSW to DDL (Baseline)0123
MSW to DDL (Week 40)0323
PMA to EDB Distal Latency (Baseline)6556
PMA to EDB Distal Latency (Week 40)4553
SS B-Point Distal Latency (Baseline)2223
SS B-Point Distal Latency (Week 40)1214
TMA to AH Distal Latency (Baseline)0033
TMA to AH Distal Latency (Week 40)0240
UMW to ADM Distal Latency (Baseline)4333
UMW to ADM Distal Latency (Week 40)2331
SecondaryChange From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40

The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (ABC) (a composite of the other 4 domain). Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The 4 domain standard scores range from 20-160 and higher scores indicate a higher level of functioning. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160) and higher scores indicate a higher level of functioning. A positive change value indicates improvement in adaptive functioning.

Time frame:
Baseline, Week 40
Reported as:
Mean · Score on a scale
Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40
Score on a scaleSHP611 100 mg (Process A)SHP611 100 mg (Process B)
Communication(Baseline)52.0 ± NA97.3 ± 2.52
Communication(Week 40)-10.0 ± NA-25.0 ± 18.19
Daily Living Skills(Baseline)49.0 ± 1.4180.3 ± 9.02
Daily Living Skills(Week 40)-4.0 ± 5.66-27.0 ± 19.47
Socialization(Baseline)50.0 ± 1.4186.0 ± 3.61
Socialization(Week 40)-0.5 ± 0.71-18.0 ± 17.09
Motor Skills(Baseline)31.0 ± 0.0083.7 ± 24.83
Motor Skills(Week 40)6.0 ± 16.97-43.3 ± 23.18
Adaptive Behavior CSS(Baseline)43.0 ± NA84.0 ± 10.54
Adaptive Behavior CSS(Week 40)-5.0 ± NA-25.3 ± 16.44
SecondaryChange From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40

COMFORT questionnaire was used to assess health status and the impact of disease on the ability of participants with MLD to carry out activities of daily life. The questionnaire was organized by 8 domains (ie, personal care; positioning, transfer, or mobility; eating; pain and discomfort during the day; sleep; emotions; communication; and play and leisure activities). The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning.

Time frame:
Baseline, Week 40
Reported as:
Mean · Score on a scale
Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40
Score on a scaleSHP611 100 mg (Process A)SHP611 100 mg (Process B)
Communication (Baseline)27.3 ± 13.2716.9 ± 8.65
Communication (Week 40)24.7 ± 26.8121.4 ± 20.92
Eating difficulty (Baseline)21.1 ± 22.942.4 ± 5.77
Eating difficulty (Week 40)25.1 ± 22.4411.8 ± 10.29
Emotions (Baseline)60.0 ± 9.1355.6 ± 12.55
Emotions (Week 40)-15.0 ± 21.57-1.4 ± 6.27
Pain and discomfort during the day (Baseline)16.6 ± 10.166.9 ± 11.05
Pain and discomfort during the day (Week 40)13.5 ± 15.230.0 ± 11.74
Personal care (Baseline)48.0 ± 21.2636.0 ± 17.99
Personal care (Week 40)18.1 ± 37.947.3 ± 18.95
Play and leisure activities (Baseline)46.0 ± 19.8116.7 ± 16.33
Play and leisure activities (Week 40)1.0 ± 28.1530.0 ± 25.88
Positioning, transfer or mobility (Baseline)42.2 ± 19.4418.0 ± 18.80
Positioning, transfer or mobility (Week 40)6.7 ± 21.828.8 ± 13.14
Sleep (Baseline)11.9 ± 5.5218.9 ± 6.52
Sleep (Week 40)6.8 ± 17.084.5 ± 15.60
SecondaryMaximum Observed Serum Concentration (Cmax) of SHP611

Cmax is the maximum observed serum concentration of SHP611.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Nanogram per milliliter (ng/mL)
Maximum Observed Serum Concentration (Cmax) of SHP611
Nanogram per milliliter (ng/mL)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline214.53 ± 162.104500.83 ± 260.978715.17 ± 339.856799.60 ± 494.452
Week 38157.50 ± 36.062275.40 ± 156.329888.75 ± 225.4571494.83 ± 1297.295
SecondaryTime to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma

Tmax is the time to reach maximum observed drug concentration of SHP611 during a dosing interval.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Hour (h)
Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma
Hour (h)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline7.06 ± 1.0866.81 ± 3.4625.97 ± 4.8029.61 ± 8.344
Week 385.08 ± 1.45011.22 ± 1.78018.16 ± 11.6617.02 ± 3.824
SecondaryArea Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611

The AUC0-inf is the area under the concentration-time curve from time zero to infinity of SHP611.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Hour * nanogram/milliliter (h*ng/mL)
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611
Hour * nanogram/milliliter (h*ng/mL)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline4355 ± NA10105 ± 3307.422123 ± 4217.423117 ± 10380.1
Week 382767 ± NA9589 ± NA—48648 ± 6906.8
SecondaryArea Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611

AUC0-last is the area under the concentration-time curve from the time of dosing to the last measurable concentration of SHP611.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · hour * nanogram per milliliter (h*ng/mL)
Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611
hour * nanogram per milliliter (h*ng/mL)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline2532 ± 1178.48738 ± 3106.415022 ± 10755.216288 ± 10691.4
Week 381972 ± 211.56156 ± 3904.524820 ± 16954.329219 ± 21261.5
SecondaryArea Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611

Area under the concentration-time curve over the interval from 0 to 24 hours after dosing of SHP611.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · hour * nanogram per milliliter (h*ng/mL)
Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611
hour * nanogram per milliliter (h*ng/mL)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline2530 ± 1178.06258 ± 2995.311918 ± 6376.113114 ± 8012.0
Week 381960 ± 224.04596 ± 2316.118264 ± 2162.731115 ± 15805.6
SecondaryFirst Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611

Lambda z is first order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Per hour (/h)
First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611
Per hour (/h)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline0.0934 ± NA0.0561 ± 0.019000.0461 ± 0.024390.0607 ± 0.01949
Week 380.0506 ± NA0.0640 ± NA—0.0857 ± 0.04415
SecondaryTerminal Elimination Half Life (t1/2) of SHP611

The t1/2 is the time in hours required for the concentration of the drug to reach half of its original value.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Hour (h)
Terminal Elimination Half Life (t1/2) of SHP611
Hour (h)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline7.42 ± NA13.60 ± 4.93217.47 ± 9.23812.34 ± 4.373
Week 3813.70 ± NA10.83 ± NA—9.32 ± 4.800
SecondaryTotal Body Clearance (CL/F) After Intrathecal Administration of SHP611

CL/F was defined as the total body clearance of the drug for extravascular administration divided by the fraction of dose absorbed.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Liter per hour (L/h)
Total Body Clearance (CL/F) After Intrathecal Administration of SHP611
Liter per hour (L/h)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline2.30 ± NA3.25 ± 1.1854.60 ± 0.8785.28 ± 3.179
Week 383.61 ± NA3.13 ± NA—2.08 ± 0.295
SecondaryVolume of Distribution (Vz/F) After Intrathecal Administration of SHP611

Volume of distribution was associated with the terminal slope following extravascular administration of SHP611 divided by the fraction of dose absorbed.

Time frame:
Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Reported as:
Mean · Liter (L)
Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611
Liter (L)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline24.58 ± NA69.97 ± 49.912121.88 ± 83.481106.95 ± 100.026
Week 3871.41 ± NA48.88 ± NA—28.95 ± 18.345
SecondaryConcentration of SHP611 in Cerebrospinal Fluid

Concentration of SHP611 in CSF was determined using validated enzyme-linked immunosorbent assay (ELISA) method.

Time frame:
Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks
Reported as:
Mean · Nanogram per milliliter (ng/mL)
Concentration of SHP611 in Cerebrospinal Fluid
Nanogram per milliliter (ng/mL)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Baseline280.00 ± 685.8570 ± 00 ± 00 ± 0
Week 4182.93 ± 165.91378.00 ± 102.5162935.17 ± 2632.3986152.50 ± 6546.986
Week 885.47 ± 79.3161854.07 ± 2633.8584171.20 ± 4874.1223825.00 ± 2182.056
Week 1257.50 ± 57.3651556.17 ± 1557.6662310.00 ± 2544.8142304.00 ± 2155.558
Week 1693.83 ± 147.1882805.68 ± 3499.8782395.00 ± 1550.6482606.20 ± 1212.857
Week 20112.78 ± 143.2161364.65 ± 2784.4745182.50 ± 5081.0804423.33 ± 4195.406
Week 24132.57 ± 235.783802.67 ± 903.0255402.50 ± 7352.2467914.60 ± 8243.114
Week 28525.06 ± 874.7103274.62 ± 4493.2126273.83 ± 6839.1013682.58 ± 4331.130
Week 3270.12 ± 126.513573.62 ± 376.2241831.40 ± 988.2946110.00 ± 4099.500
Week 3672.40 ± 125.5741046.05 ± 1087.3213917.50 ± 4650.7913116.67 ± 336.502
Week 40659.15 ± 1602.414243.60 ± 313.1072931.83 ± 4098.3896663.75 ± 7947.148

Adverse events

Collected over From start of study treatment up to safety follow up (Week 42). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
SHP611 10 mg (Process A)0/6 (0%)5/6 (83.3%)6/6 (100%)
SHP611 30 mg (Process A)0/6 (0%)4/6 (66.7%)6/6 (100%)
SHP611 100 mg (Process A)0/6 (0%)3/6 (50%)6/6 (100%)
SHP611 100 mg (Process B)0/6 (0%)2/6 (33.3%)6/6 (100%)
Most frequent serious events
Showing 10 of 26
Most frequent serious events
EventSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
Device failureGeneral disorders2/60/61/60/6
NasopharyngitisInfections and infestations2/61/60/60/6
Viral upper respiratory tract infectionInfections and infestations0/60/62/60/6
VomitingGastrointestinal disorders0/61/60/60/6
Device dislocationGeneral disorders1/61/60/60/6
Device malfunctionGeneral disorders1/60/60/60/6
Device occlusionGeneral disorders1/60/60/60/6
Implant site effusionGeneral disorders1/60/61/60/6
PainGeneral disorders0/61/60/60/6
PyrexiaGeneral disorders0/60/61/60/6
Most frequent other events
Showing 10 of 157
Most frequent other events
EventSHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)
VomitingGastrointestinal disorders4/65/64/62/6
PyrexiaGeneral disorders5/63/65/65/6
Procedural painInjury, poisoning and procedural complications2/62/63/65/6
ConstipationGastrointestinal disorders3/64/63/64/6
NasopharyngitisInfections and infestations4/61/61/61/6
Muscle spasticityNervous system disorders4/62/61/62/6
Pain in extremityMusculoskeletal and connective tissue disorders3/61/60/60/6
NauseaGastrointestinal disorders0/61/63/61/6
Device malfunctionGeneral disorders3/61/60/60/6
Implant site effusionGeneral disorders1/60/63/61/6

Baseline characteristics

Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery.

Age, Continuous
Age, Continuous(Months)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)Total
Mean31.5 ± 11.5047.3 ± 20.2352.2 ± 31.1748.5 ± 24.2244.9 ± 22.85
Sex: Female, Male
Sex: Female, Male(Participants)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)Total
Female33129
Male335415
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)SHP611 10 mg (Process A)SHP611 30 mg (Process A)SHP611 100 mg (Process A)SHP611 100 mg (Process B)Total
Race: White542415
Race: Asian00404
Race: Other12025
Ethnicity: Not Hispanic or Latino666624
08

Study locations

5 sites
  • The Children's Hospital at Westmead
    Westmead, 2145, Australia
  • Rigshospitalet
    København, 2100, Denmark
  • Hopital de Bicetre
    Le Kremlin Bicetre, Ile-de-France 94275, France
  • Center for Pediatric Clinical Studies
    Tubingen, Baden-Wuerttemberg 72076, Germany
  • Osaka University Hospital
    Suita, 565-0871, Japan
09

References and documents

Publications

  • I Dali C, Sevin C, Krageloh-Mann I, Giugliani R, Sakai N, Wu J, Wasilewski M. Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial. Mol Genet Metab. 2020 Sep-Oct;131(1-2):235-244. doi: 10.1016/j.ymgme.2020.07.002. Epub 2020 Jul 16. PubMed 32792226 ↗

Study documents

  • Study protocol · Aug 25, 2015
  • Statistical analysis plan · Feb 28, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — - De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites, ...)

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 14, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01510028
Lead sponsor
Shire
Responsible party
Sponsor
First posted
Jan 13, 2012
Start date
Feb 2, 2012
Primary completion
Jan 20, 2017
Completion
Jan 20, 2017
Results posted
Oct 15, 2018
Last update
Jun 14, 2021

Study contacts

Study Director
study director · Takeda

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in May 2021. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Leukodystrophy, Metachromatic→

Other studies from this sponsor

Shire

Start the discussion