E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Late Metachromatic Leukodystrophy (MLD) |
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E.1.1.1 | Medical condition in easily understood language |
Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067609 |
E.1.2 | Term | Metachromatic leukodystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of SHP611 on gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with MLD.
If suitable controls cannot be matched despite the sponsor's best efforts, change from baseline results of GMFC-MLD at Week 106 will be compared with a pre-specified objective threshold to evaluate primary efficacy for this study. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effects of IT administration of SHP611 on gross motor function, using the Gross Motor Function Measure 88 (GMFM-88) total score in children with MLD
- To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor functionusing GMFC-MLD
- To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFM-88
- To evaluate the effects of IT administration of SHP611 on expressive language using the Expressive Language Function Classification (ELFC
MLD)
- To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) biomarker (ie, sulfatides)
- To evaluate the effects of IT administration of SHP611 on proton magnetic resonance spectroscopy (MRS) of the brain, specifically N acetylaspartate/
Creatine (NAA/Cr) in white matter
- To evaluate the effects of IT administration of SHP611 on Eichler MLD MRI severity score |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be considered eligible for
inclusion as a subject in the study:
1. The subject must have a documented diagnosis of MLD (Groups A-E)
a. Low ASA activity in leukocytes (compared to laboratory normal range)
AND
b. Elevated sulfatides in urine
2. The subject must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by a pediatric neurologist or medical geneticist by 30 months of age (Groups A-C, and F) or be minimally symptomatic and >= 6 to <18 months of age (Group D), or be early symptomatic and >=12 to <18 months of age (Group E). Subjects in Group E must have neurological symptoms documented by a pediatric neurologist or medical geneticist.
3. The subject’s age at the time of informed consent, must be:
Group A: 18 to 48 months of age
Group B: 18 to 72 months of age
Group C: 18 to 72 months of age
Group D: <18 months of age
Group E: >=12 to <18 months of age
Group F: 18 to 72 months of age
4. The subject’s GMFC-MLD level at screening must be:
Group A: GMFC-MLD level of 1 or 2
Group B: GMFC-MLD level of 3
Group C: GMFC-MLD level of 4
Group D: minimally symptomatic, >=6 to 18 months of age, younger siblings of enrolled subjects, and have the same ASA allelic constitution
Group E: GMFC-MLD level of 1 or 2 with a history of achieving stable walking (defined as at least 1 month of independent walking)
Group F: GMFC-MLD level of 5 or 6
5. The subject and his/her parent/representative(s) must have the ability to comply with the clinical protocol
6. Subject's parent 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 subject
Inclusion criteria for matched historical controls
Subjects must meet all of the following criteria to be considered eligible for inclusion as a matched historical control:
1. The subject must have a documented diagnosis of MLD
a. Low ASA activity in leukocytes (compared to laboratory normal range)
AND
b. Elevated sulfatides in urine
2. Subjects must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by 30 months of
age
3. Subjects must have at least 2 motor assessments by GMFC-MLD with the second assessment occurring at approximately 106 (±2) weeks after the first assessment or else a second assessment measured before Week 100 with a GMFC-MLD level 5 or 6. Subjects with GMFC-MLD data (pro or retrospectively determined) must have the earliest observation of level 1 or 2 (walking with support) in the data source-verified medical record
4. Subjects must be 18 to 48 months of age at the earliest assessment |
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E.4 | Principal exclusion criteria |
1. Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory’s normal range) or a known genetic disorder other than MLD
2. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study
3. Primary presentation of MLD was behavorial or cognitive symptoms of MLD (per investigator’s clinical judgment); behavioral symptoms that are
secondary to motor deficits (eg: tantrums in response to loss of motor skills) are not exclusionary.
4. The subject has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise
5. Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study.
6. Subjects with laboratory, ECG, or vital sign abnormalities reflecting intercurrent illness that may compromise their safety during the trial should not be enrolled. Abnormal laboratory, vital sign and ECG results at screening should be reviewed with the Shire medical monitor.
7. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days or 5 half-lives (whichever is longer) prior to study enrollment or at any time during the study
8. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU)
a. The subject has had, or may have, an allergic reaction to the materials of construction
b. The subject has shown an intolerance to an implanted device
c. The subject's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port
d. The subject's drug therapy requires substances known to be incompatible with the materials of construction
e. The subject has a known or suspected local or general infection
f. The subject is at risk of abnormal bleeding due to a medical condition or therapy
g. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation
h. The subject has a functioning CSF shunt device
Exclusion criteria for matched historical controls:
1. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes BMT, HSCT, or gene therapy at any point during the study
2. Primary presentation of MLD was behavioral or cognitive symptoms of MLD (per investigator’s clinical judgment); behavioral symptoms that are
secondary to motor deficits (eg; tantrums in response to loss of motor skills) are not exclusionary.
3. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), evaluated as no greater than 2 levels decline from baseline in GMFC-MLD.
If suitable controls cannot be matched despite the sponsor's best efforts, change from baseline results of GMFC-MLD at Week 106 will be compared with a pre-specified objective threshold to evaluate primary efficacy for this study. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints of this study are:
- Response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), defined as a GMFM-88 total score >40.
- Change from baseline at Week 106 of gross motor function, using the GMFC-MLD
- Change from baseline at Week 106 of gross motor function, using the GMFM-88 total score GMFM-88 total score decline of no more than 20
points from baseline and a total score that is ≥40 at Week 106
- Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories, 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
- Time to unreversed decline from baseline in GMFM-88 total score of >20 points or unreversed decline to <40 points, whichever occurs first
- Change from baseline at Week 106 in expressive language using the ELFC-MLD
- Change from baseline at Week 106 in CSF sulfatides levels
- Change from baseline at Week 106 in MRS metabolite levels, specifically: N-acetylaspartate/Creatine
- Change from baseline at Week 106 in Eichler MLD MRI severity score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Brazil |
Canada |
France |
Germany |
Israel |
Japan |
Mexico |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 15 |