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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-002044-28 | EudraCT Number | ||
| U1111-1153-1422 | Other Identifier | WHO |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 (10 mg) | Experimental | 6 patients treated with HGT-1110 10 mg EOW by IT injection |
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| Cohort 2 (30 mg) | Experimental | 6 patients treated with HGT-1110 30 mg EOW by IT injection |
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| Cohort 3 (100 mg) | Experimental | 6 patients treated with HGT-1110 100 mg EOW by IT injection |
|
| Cohort 4 (100 mg) | Experimental | 6 patients treated with HGT-1110 100 mg EOW by IT injection |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Recombinant human arylsulfatase A | Biological | 6 patients treated with HGT-1110 EOW by IT injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From start of study treatment up to Week 42 |
| 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. | From start of study treatment up to Week 40 |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion
For Cohorts 1-4:
Confirmed diagnosis of metachromatic leukodystrophy by both:
Appearance of the first symptoms of disease at or before 30 months of age.
For Cohorts 1-3 only:
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.
The patient is less than 12 years of age at the time of screening.
For Cohort 4 only:
3.1 Minimum motor function requirements:
4.1 The patient is less than 8 years of age at the time of screening.
For Cohorts 1-4:
Neurological signs of MLD must be present at the screening examination.
The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
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:
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:
Mini S IDDD Instructions for Use (IFU), including:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Children's Hospital at Westmead | Westmead | 2145 | Australia | |||
| Rigshospitalet |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32792226 | Derived | 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. |
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- 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, …)
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A total of 34 participants were screened and 24 participants were enrolled in the study. Out of which 23 participants completed the study.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | SHP611 10 mg (Process A) | Participants received 10 milligram (mg) dose of SHP611 (HGT-1110, recombinant human arylsulfatase A [rhASA]) every other week (EOW) by intrathecal drug delivery device (IDDD) for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| FG001 | SHP611 30 mg (Process A) | Participants received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| FG002 | SHP611 100 mg (Process A) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| FG003 | SHP611 100 mg (Process B) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the revised drug substance manufacturing process referred to as Process B. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery.
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| ID | Title | Description |
|---|---|---|
| BG000 | SHP611 10 mg (Process A) | Participants received 10 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| BG001 | SHP611 30 mg (Process A) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 42 |
|
From start of study treatment up to safety follow up (Week 42)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | SHP611 10 mg (Process A) | Participants received 10 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Eosinophilia | Blood and lymphatic system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 25, 2015 | Jan 19, 2018 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 28, 2017 | Jan 19, 2018 | SAP_000.pdf |
| ID | Term |
|---|---|
| D007966 | Leukodystrophy, Metachromatic |
| ID | Term |
|---|---|
| D020279 | Hereditary Central Nervous System Demyelinating Diseases |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
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|
| From start of study treatment up to Week 40 |
| 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. | From start of study treatment up to Week 40 |
| 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. | From start of study treatment up to Week 40 |
| 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. | From start of study treatment up to Week 40 |
| 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. | Baseline up to Week 40 |
| Baseline, Week 40 |
| 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. | Week 40 |
| 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. | Week 40 |
| 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. | Week 40 |
| 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. | Week 40 |
| 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. | Week 40 |
| 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. | Baseline, Week 40 |
| 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, | Baseline, Week 40 |
| 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. | Baseline, Week 40 |
| 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. | Baseline, Week 40 |
| 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. | Baseline, Week 40 |
| Maximum Observed Serum Concentration (Cmax) of SHP611 | Cmax is the maximum observed serum concentration of SHP611. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| 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. | 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 |
| Concentration of SHP611 in Cerebrospinal Fluid | Concentration of SHP611 in CSF was determined using validated enzyme-linked immunosorbent assay (ELISA) method. | Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks |
| Copenhagen |
| 2100 |
| Denmark |
| Hopital de Bicetre | Le Kremlin-Bicêtre | Île-de-France Region | 94275 | France |
| Center for Pediatric Clinical Studies | Tübingen | Baden-Wurttemberg | 72076 | Germany |
| Osaka University Hospital | Suita | 565-0871 | Japan |
Participants received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| BG002 | SHP611 100 mg (Process A) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| BG003 | SHP611 100 mg (Process B) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the revised drug substance manufacturing process referred to as Process B. |
| BG004 | Total | Total of all reporting groups |
| Months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | SHP611 10 mg (Process A) | Participants received 10 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| OG001 | SHP611 30 mg (Process A) | Participants received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| OG002 | SHP611 100 mg (Process A) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the original drug substance manufacturing process referred to as Process A. |
| OG003 | SHP611 100 mg (Process B) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, participants received SHP611 produced with the revised drug substance manufacturing process referred to as Process B. |
|
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| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 40 |
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|
|
| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 40 |
|
|
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| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 40 |
|
|
|
| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 40 |
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| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | From start of study treatment up to Week 40 |
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| Primary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Baseline up to Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Least Squares Mean | Standard Error | Score on a Scale | Baseline, Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Baseline, Week 40 |
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| Secondary | 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, | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Baseline, Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. | Posted | Count of Participants | Participants | Baseline, Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. Participants from SHP611 10 mg and SHP611 30 mg were excluded from the analysis. Since, analysis was planned for participants received SHP611 100 mg with different manufacturing processes (Process A and B). | Posted | Mean | Standard Deviation | Score on a scale | Baseline, Week 40 |
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| Secondary | 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. | Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery. Participants from SHP611 10 mg and SHP611 30 mg were excluded from the analysis. Since, analysis was planned for participants received SHP611 100 mg with different manufacturing processes (Process A and B). | Posted | Mean | Standard Deviation | Score on a scale | Baseline, Week 40 |
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| Secondary | Maximum Observed Serum Concentration (Cmax) of SHP611 | Cmax is the maximum observed serum concentration of SHP611. | Pharmacokinetic (PK) set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Nanogram per milliliter (ng/mL) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Hour (h) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Hour * nanogram/milliliter (h*ng/mL) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | hour * nanogram per milliliter (h*ng/mL) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | hour * nanogram per milliliter (h*ng/mL) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Per hour (/h) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Hour (h) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Liter per hour (L/h) | 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 |
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| Secondary | 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. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Liter (L) | 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 |
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| Secondary | Concentration of SHP611 in Cerebrospinal Fluid | Concentration of SHP611 in CSF was determined using validated enzyme-linked immunosorbent assay (ELISA) method. | PK set consisted of participants who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. | Posted | Mean | Standard Deviation | Nanogram per milliliter (ng/mL) | Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks |
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|
| 0 |
| 6 |
| 5 |
| 6 |
| 6 |
| 6 |
| EG001 | SHP611 30 mg (Process A) | Participants received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. | 0 | 6 | 4 | 6 | 6 | 6 |
| EG002 | SHP611 100 mg (Process A) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. | 0 | 6 | 3 | 6 | 6 | 6 |
| EG003 | SHP611 100 mg (Process B) | Participants received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. | 0 | 6 | 2 | 6 | 6 | 6 |
| Device dislocation | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Device failure | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Device malfunction | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Device occlusion | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site effusion | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pain | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Influenza | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Respiratory tract infection viral | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Viral infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Viral pharyngitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
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| Gamma-Glutamyltransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
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| Convulsion | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Febrile convulsion | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Muscle spasticity | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Leukocytosis | Blood and lymphatic system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Lymphopenia | Blood and lymphatic system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Kyphosis | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Lordosis | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Tendinous contracture | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Tendon disorder | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Tendonitis | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Ear haemorrhage | Ear and labyrinth disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Ear pain | Ear and labyrinth disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Conjunctivitis | Eye disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Eye swelling | Eye disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Visual acuity reduced | Eye disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Anal fissure | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Dysphagia | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Gingivitis | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pancreatitis | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Salivary duct obstruction | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Salivary hypersecretion | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Asthenia | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Complication of device removal | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Crying | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Device dislocation | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Device malfunction | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Discomfort | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Disease progression | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Gait disturbance | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site cyst | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site effusion | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site pain | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pain | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Phimosis | Congenital, familial and genetic disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Talipes | Congenital, familial and genetic disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Seasonal allergy | Immune system disorders | MedDRA 15.0 | Non-systematic Assessment |
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| Acute tonsillitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Cystitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Ear infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Enterovirus infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Febrile infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Gastroenteritis viral | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Impetigo | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Implant site infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Influenza | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Lung infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Oral candidiasis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Otitis media | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Respiratory tract infection viral | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Tonsillitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
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| Viral infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
|
| Viral pharyngitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
|
| Viral upper respiratory tract infection | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Endotracheal intubation complication | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Incision site oedema | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Post procedural complication | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Post procedural oedema | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Postoperative fever | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Postoperative wound complication | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Vaccination complication | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Wrong technique in drug usage process | Injury, poisoning and procedural complications | MedDRA 15.0 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Albumin csf increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Amylase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
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| Blood iron decreased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Body temperature increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Csf lymphocyte count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Csf mononuclear cell count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Csf protein increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Csf white blood cell count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Eosinophil count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Gamma-Glutamyltransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Mean cell volume decreased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Neutrophil count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Red blood cells csf positive | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| White blood cell count increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Urinary incontinence | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Cytolytic hepatitis | Hepatobiliary disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Iron deficiency | Metabolism and nutrition disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Akathisia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Areflexia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Ataxia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Cerebellar syndrome | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Clonus | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Disturbance in attention | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Drooling | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Dysarthria | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Dystonia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Epilepsy | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Febrile convulsion | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Hypotonia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Motor dysfunction | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Muscle spasticity | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Myoclonus | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Neuralgia | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Speech disorder | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Speech disorder developmental | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Abnormal behaviour | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Decreased eye contact | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Initial insomnia | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Restlessness | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Sleep disorder | Psychiatric disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Balanitis | Reproductive system and breast disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Vulvovaginal erythema | Reproductive system and breast disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Bronchial obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Choking | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Laryngeal inflammation | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Nasal obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Pharyngeal erythema | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Sleep apnoea syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Sneezing | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Tonsillar hypertrophy | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Erythema nodosum | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Hirsutism | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Keloid scar | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA 15.0 | Non-systematic Assessment |
|
If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D052516 | Sulfatidosis |
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D056784 | Leukoencephalopathies |
| D003711 | Demyelinating Diseases |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
| Alanine aminotransferase (ALT) increased |
|
| Aspartate aminotransferase (AST) increased |
|
| Blood iron decreased |
|
| Amylase increased |
|
| Blood alkaline phosphatase increased |
|
| Blood creatine phosphokinase increased |
|
| Hepatic enzymes increased |
|
| Eosinophil count increased |
|
| Eosinophilia |
|
| Mean cell volume decreased |
|
| Neutrophil count increased |
|
| White blood cell count increased |
|
| Lymphopenia |
|
| Leukocytosis |
|
| Proteinuria |
|
| CSF Albumin Increased |
|
| Serum neutralizing anti-SHP611 antibody positive |
|
| CSF anti-SHP611 antibody positive |
|
| CSF neutralizing anti-SHP611 antibody positive |
|
| Serum or CSF anti-SHP611 antibody positive |
|
| Serum and CSF anti-SHP611 antibody positive |
|
| Serum or CSF neutralizing anti-SHP611 Ab positive |
|
| Serum and CSF neutralizing anti-SHP611 Ab positive |
|
| Thin Liquids to Thickened Liquids |
|
| Thin Liquids to Puree Texture |
|
| Thin Liquids to Solids |
|
| Thickened Liquids to Thin Liquids |
|
| Thickened Liquids to Thickened Liquids |
|
| Thickened Liquids to Puree Texture |
|
| Thickened Liquids to Solids |
|
| Puree Texture to Thin Liquids |
|
| Puree Texture to Thickened Liquids |
|
| Puree Texture to Puree Texture |
|
| Puree Texture to Solids |
|
| Solids to Thin Liquids |
|
| Solids to Thickened Liquids |
|
| Solids to Puree Texture |
|
| Solids to Solids |
|
| Normal to Without Cough (TL) |
|
| Without Cough to Without Cough (TL) |
|
| WCC to Without Cough (TL) |
|
| WCC to WCC (TL) |
|
| Normal to WCC (THL) |
|
| Without Cough to Normal (THL) |
|
| WCC to Normal (THL) |
|
| WCC to WCC (THL) |
|
| Normal to Normal (PT) |
|
| Normal to WCC (PT) |
|
| Normal to WCNC (PT) |
|
| Without Cough to Normal (PT) |
|
| Without Cough to WCC (PT) |
|
| WCC to Normal (PT) |
|
| WCC to WCC (PT) |
|
| WCNC to Normal (PT) |
|
| WCNC to Without Cough (PT) |
|
| WCC to WCC (Solids) |
|
| Without Cough to Without Cough (TL) |
|
| WCC to WCC (TL) |
|
| Normal to Normal (THL) |
|
| Without Cough to Normal (THL) |
|
| WCC to Normal (THL) |
|
| WCC to WCC (THL) |
|
| Normal to Normal (PT) |
|
| Without Cough to Normal (PT) |
|
| WCC to WCC (PT) |
|
| WCNC to Normal (PT) |
|
| WCC to WCC (Solids) |
|
| Normal to Yes (TL) |
|
| Yes to Yes (TL) |
|
| Yes to No (TL) |
|
| No to Yes (TL) |
|
| No to No (TL) |
|
| Normal to Yes (THL) |
|
| Yes to Normal (THL) |
|
| Yes to Yes (THL) |
|
| Normal to Normal (PT) |
|
| Normal to Yes (PT) |
|
| Normal to No (PT) |
|
| Yes to Normal (PT) |
|
| Yes to Yes (PT) |
|
| Yes to No (PT) |
|
| No to Normal (PT) |
|
| Yes to Yes (Solids) |
|
| Low to High (TL) |
|
| Low to Low (THL) |
|
| Low to Low (PT) |
|
| Low to High (PT) |
|
| Moderate to Low (PT) |
|
| Moderate to Moderate (PT) |
|
| Low to Low (Solids) |
|
| Median Motor Wrist Amplitude (Week 40) |
|
| Median Motor Elbow Amplitude (Baseline) |
|
| Median Motor Elbow Amplitude (Week 40) |
|
| Median Sensory Wrist Amplitude (Baseline) |
|
| Median Sensory Wrist Amplitude (Week 40) |
|
| Peroneal Motor Fibular Head Amplitude (Baseline) |
|
| Peroneal Motor Fibular Head Amplitude (Week 40) |
|
| Peroneal Motor Ankle Amplitude (Baseline) |
|
| Peroneal Motor Ankle Amplitude (Week 40) |
|
| Sural Sensory B-point (Baseline) |
|
| Sural Sensory B-point (Week 40) |
|
| Tibial Motor Ankle Amplitude (Baseline) |
|
| Tibial Motor Ankle Amplitude (Week 40) |
|
| Tibial Motor Knee Amplitude (Baseline) |
|
| Tibial Motor Knee Amplitude (Week 40) |
|
| Ulnar Motor Wrist Amplitude (Baseline) |
|
| Ulnar Motor Wrist Amplitude (Week 40) |
|
| Ulnar Motor Elbow Amplitude (Baseline) |
|
| Ulnar Motor Elbow Amplitude (Week 40) |
|
| MME to WCV (Week 40) |
|
| PMA to FHCV (Baseline) |
|
| PMA to FHCV (Week 40) |
|
| TMA to KCV (Baseline) |
|
| TMA to KCV (Week 40) |
|
| UME to WCV (Baseline) |
|
| UME to WCV (Week 40) |
|
| MMW to APB distal latency (Week 40) |
|
| MSW to DDL (Baseline) |
|
| MSW to DDL (Week 40) |
|
| PMA to EDB Distal Latency (Baseline) |
|
| PMA to EDB Distal Latency (Week 40) |
|
| SS B-Point Distal Latency (Baseline) |
|
| SS B-Point Distal Latency (Week 40) |
|
| TMA to AH Distal Latency (Baseline) |
|
| TMA to AH Distal Latency (Week 40) |
|
| UMW to ADM Distal Latency (Baseline) |
|
| UMW to ADM Distal Latency (Week 40) |
|
| Communication(Week 40) |
|
|
| Daily Living Skills(Baseline) |
|
|
| Daily Living Skills(Week 40) |
|
|
| Socialization(Baseline) |
|
|
| Socialization(Week 40) |
|
|
| Motor Skills(Baseline) |
|
|
| Motor Skills(Week 40) |
|
|
| Adaptive Behavior CSS(Baseline) |
|
|
| Adaptive Behavior CSS(Week 40) |
|
|
| Communication (Week 40) |
|
|
| Eating difficulty (Baseline) |
|
|
| Eating difficulty (Week 40) |
|
|
| Emotions (Baseline) |
|
|
| Emotions (Week 40) |
|
|
| Pain and discomfort during the day (Baseline) |
|
|
| Pain and discomfort during the day (Week 40) |
|
|
| Personal care (Baseline) |
|
|
| Personal care (Week 40) |
|
|
| Play and leisure activities (Baseline) |
|
|
| Play and leisure activities (Week 40) |
|
|
| Positioning, transfer or mobility (Baseline) |
|
|
| Positioning, transfer or mobility (Week 40) |
|
|
| Sleep (Baseline) |
|
|
| Sleep (Week 40) |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 38 |
|
|
|
| Week 4 |
|
|
| Week 8 |
|
|
| Week 12 |
|
|
| Week 16 |
|
|
| Week 20 |
|
|
| Week 24 |
|
|
| Week 28 |
|
|
| Week 32 |
|
|
| Week 36 |
|
|
| Week 40 |
|
|