Outcome
Type |
Measure |
Description |
Time frame |
Safety issue |
Primary |
Response in Group A: Time to Loss of Locomotion Measured by Progression to Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 |
The time to loss of locomotion, measured by progression to GMFC-MLD category 5 or higher, or death, whichever occurs first, up to Week 106, evaluated on participants in Group A. The GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is from 0 (walking without support with quality of performance normal for age) to 6 (loss of any locomotion as well as loss of any head and trunk control). |
Week 106 |
|
Secondary |
Response in Group A: Maintenance of Gross Motor Function at Week 106 in Participants who do not Experience any Event within Week 106 |
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, evaluated as participants who do not experience any event within Week 106, where event is defined as a decline in GMFC-MLD to category 5 or higher, or death. The GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is from 0 (walking without support with quality of performance normal for age) to 6 (loss of any locomotion as well as loss of any head and trunk control). |
Week 106 |
|
Secondary |
Change From Baseline in Gross Motor Function Evaluated by Using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 and End of Study (EOS) |
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFC-MLD will be reported. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Number of Participants With Unreversed Decline From Baseline in Metachromatic Leukodystrophy (GMFC-LMD) of More than 2 Categories |
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Number of participants with unreversed Decline from baseline in metachromatic leukodystrophy (GMFC-LMD) of more than 2 categories evaluated on participants in Group A will be reported. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Time to Unreversed Decline From Baseline in Gross Motor Function Classification in GMFC-MLD of More Than 2 Categories |
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories is defined as any decline of more than 2-categories that has not reverted to a 2-category decline (or better) as of the last recorded observation. |
Baseline up to EOS (Week 211) |
|
Secondary |
Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106 and End of Study (EOS) |
Change from baseline in CSF sulfatides levels will be assessed. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Response in Group A: Maintenance of Gross Motor function in Participants at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score Greater than or Equal to (>=) 40 |
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, defined as a GMFM-88 total score >= 40. The GMFM-88 is a clinician-evaluated assessment of motor function across 5 dimensions: 1) lying and rolling 2) sitting 3) kneeling and crawling 4) standing and 5) walking, running, and jumping. Scoring is based on the percentage of accomplished tasks within each of the dimensions, and a total score is calculated by averaging each of the dimension scores. Each of the 88 items is rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. GMFM-88 total score range is between 100 percent and 0 percent, with 0 percent corresponding to no mobility. |
Week 106 |
|
Secondary |
Time to Unreversed Decline From Baseline in Gross Motor Function Measure (GMFM)-88 Total Score of Greater Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First |
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score of decrease of >20 points or unreversed decline to a score <40 points, whichever occurs first will be reported. |
Baseline up to EOS (Week 211) |
|
Secondary |
Change From Baseline in Gross Motor Function Evaluated by Using Gross Motor Function Measure (GMFM)-88 Total Score at Week 106 and End of Study (EOS) |
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFM-88 total score will be reported. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Number of Participants With Gross Motor Function Measure (GMFM)-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score > 40 at Week 106 and End of Study (EOS) |
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Number of participants with GMFM-88 total score decrease of <= 20 points from baseline and a total score that is >= 40 will be reported. |
Week 106, EOS (Week 211) |
|
Secondary |
Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) at Week 106 and End of Study (EOS) |
The ELFC-MLD is a 5-category rating system to describe the regression of language abilities of participant with late infantile and juvenile MLD. The scoring range is from E0 (Communicates in complete sentences at a quality and performance normal for age) to E4 (Complete loss of expressive language). Change from baseline in expressive language evaluated by using the ELFC-MLD will be reported. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Ctrough of SHP611 in CSF |
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 CSF parameters at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106 will be reported. |
Predose at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106 |
|
Secondary |
Concentrations of SHP611 in CSF Following Single and Repeat IT Dosing of SHP611 |
The concentrations of SHP611 in CSF following single and repeat IT dosing of SHP611 will be evaluated. |
Post dose at Week 0 and 106 |
|
Secondary |
Maximum Observed Plasma Concentration (Cmax) of SHP611 in Serum |
The Cmax of SHP611 in serum will be assessed. |
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106 |
|
Secondary |
Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of SHP611 in Serum |
The AUC0-inf of SHP611 in serum will be assessed. |
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106 |
|
Secondary |
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of SHP611 in Serum |
The AUC0-t of SHP611 in serum will be assessed. |
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106 |
|
Secondary |
Total Body Clearance (CL/F) of SHP611 in Serum |
The CL/F of SHP611 in serum will be assessed. |
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106 |
|
Secondary |
Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106 |
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106 will be reported. |
Predose at Weeks 0, 13, 26, 40, 53, 79, and 106 |
|
Secondary |
Number of Participants With Treatment-emergent Adverse Event (TEAEs) |
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the investigational product or medicinal product. Number of participants with TEAEs will be reported. |
From start of study drug administration up to follow-up (Week 213) |
|
Secondary |
Change from Baseline in Clinical Laboratory Result at Week 106 and End of Study (EOS) |
Clinical laboratory analysis includes serum chemistry, hematology, and urinalysis. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Change from Baseline in Physical Examination at Week 106 and End of Study (EOS) |
Physical examination includes documentation of signs and symptoms of Metachromatic Leukodystrophy (MLD) (tone, reflexes, and vision). |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Change from Baseline in Electrocardiogram (ECG) at Week 106 and End of Study (EOS) |
2-lead ECG will be recorded and measured. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Change from Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106 and End of Study (EOS) |
CSF laboratory parameters includes chemistries and cell counts. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Number of Participants With Anti-SHP611 Antibodies |
Number of participants with presence of Anti-SHP611 antibodies in CSF and serum will be reported. |
Baseline, Week 106 and EOS (Week 211) |
|
Secondary |
Number of Participants With Adverse Events Related to SOPH-A-PORT Mini S Device |
SOPH-A-PORT Mini S assessments will be evaluated using assessments of device implantation, device function, device longevity, and adverse events (AEs) associated with the implant surgery or device. |
Up to EOS (Week 211) |
|