Clinical trial NCT03771898: A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
Official title: A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in Subjects With Late Infantile Metachromatic Leukodystrophy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metachromatic Leukodystrophy (MLD)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2018-12-11
Enrollment: 36
Sex: ALL
Minimum age (years): 6
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The main aim of the study is to determine if SHP611 given by injection into the spinal fluid that surrounds the brain and spinal cord (intrathecal; IT) prolongs the time for children with Metachromatic Leukodystrophy (MLD) to retain the ability to move from place to place. Other aims of the study are to determine the effects of intrathecal administration of SHP611 on movement and speech functions and to learn how well SHP611 injected in the spinal fluid that surrounds the brain and spinal cord is tolerated.

Study participants will receive SHP611 for about 2 years with the possibility of an extended treatment period.


Eligibility criteria: Inclusion Criteria:

* The participant must have a documented diagnosis of MLD (Groups A-F):

  1. Low ASA activity in leukocytes (compared to laboratory normal range).
  2. Elevated sulfatides in urine.
* The participant must have a gait disorder due to spastic ataxia or weakness attributable to MLD by the investigator and documented by a primary care physician or a specialist physician by 30 months of age (Groups A-C, and F), or be minimally symptomatic and greater than or equal to (\> =) 6 to less than (\<) 18 months of age (Group D) or be early symptomatic and \> =12 to \< 18 months of age (Group E). Participants in Group E must have neurological symptoms either documented by either a primary care physician or a specialist physician.
* The participant'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: \>= 6 to \< 18 months of age; Group E: \> = 12 to \< 18 months of age; Group F: 18 to 72 months of age.
* The participant's GMFC-MLD category at screening must be: Group A: GMFC-MLD category of 1 or 2; Group B: GMFC-MLD category of 3; Group C: GMFC-MLD category of 4; Group D: minimally symptomatic, \>= 6 to \< 18 months of age, with the same arylsulfatase (ASA) allelic constitution as an older sibling with confirmed late infantile or juvenile onset MLD; Group E: early symptomatic, \>= 12 to \< 18 months of age with a GMFC-MLD category of 1 or 2 with a history of achieving stable walking (defined as at least 1 month of independent walking); Group F: GMFC-MLD category of 5 or 6.
* The participant and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
* Participant'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 participant.

Exclusion Criteria:

* 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.
* 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.
* Primary presentation of MLD was behavioral or cognitive symptoms (per investigator's clinical judgment); behavioral symptoms that are secondary to motor deficits (example \[eg\], tantrums in response to loss of motor skills) are not exclusionary.
* The participant has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise.
* Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study.
* Participants 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 Takeda medical monitor.
* The participant 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.
* The participant has had prior exposure to SHP611.
* The participants must weigh \> 11 pound (lbs) (5 kilograms \[kg\]).
* The participant has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU)

  1. The participant has had, or may have, an allergic reaction to the materials of construction.
  2. The participant has shown an intolerance to an implanted device.
  3. The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port.
  4. The participant's drug therapy requires substances known to be incompatible with the materials of construction.
  5. The participant has a known or suspected local or general infection.
  6. The participant is at risk of abnormal bleeding due to a medical condition or therapy.
  7. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation.
  8. The participant has a functioning Cerebro spinal fluid(CSF) shunt device .

Matched External Control Participants for Group A from Global Leukodystrophy Initiative of Metachromatic Leukodystrophy (GLIA-MLD) The matched external control group must have data for at least baseline gross motor function evaluation. Selection of the external control participants from GLIA-MLD will follow a set of criteria as similar as possible to the inclusion criteria for Group A in the SHP611-201 study protocol.

A filtering process will be applied to select the external control participants from the GLIA-MLD database, by meeting all of the following 3 filtering criteria:

1. Filtering criterion 1: requiring documented diagnosis of MLD, based on

   * low arylsulfatase A (ASA) activity in leukocytes AND elevated sulfatides in urine. OR
   * biallelic variants in arylsulfatase A gene (ARSA) AND (either low ASA activity in leukocytes OR elevated sulfatides in urine).
2. Filtering criterion 2: requiring documented gait disorder. Participants will be considered qualifying if they present with a gait disorder before 2.5 years (30 months) of age and have a medical record reporting a gait abnormality including, but not limited to, the following terms: ataxia, spasticity, and hyper/hypotonia.
3. Filtering criterion 3: participants will be considered qualifying if they have at least 1 clinical encounter occurring between the age of 18 to 48 months with a GMFC-MLD category either 1 or 2.

Primary outcomes:
measure: Percent Probability of Free of Loss of Locomotion in the Last Time Interval Up to 2 Years (Week 106) Based on GMFC-MLD for SHP611 Group A and GLIA-MLD Matched External Control
timeFrame: Baseline up to Week 106
Secondary outcomes:
measure: Group A: Number of Participants Who Maintained Their Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106 Compared With Matched External Control Group Data
timeFrame: Baseline up to Week 106
measure: Number of Participants With Change From Baseline in Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106
timeFrame: Baseline, Week 106
measure: Group A: Number of Participants With Decline From Baseline in GMFC-LMD of More Than 2 Categories
timeFrame: Baseline, Week 106
measure: Group A: Time to Decline From Baseline in GMFC-MLD of More Than 2 Categories
timeFrame: Baseline, Week 106
measure: Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106
timeFrame: Baseline, Week 106
measure: Percent Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106
timeFrame: Baseline, Week 106
measure: Group A: Number of Participants With Maintenance of Gross Motor Function at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score
timeFrame: Baseline up to Week 106
measure: Time to Unreversed Decline From Baseline in GMFM-88 Total Score of Greater Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First
timeFrame: Baseline, Week 106
measure: Change From Baseline in GMFM-88 Total Score at Week 106
timeFrame: Baseline, Week 106
measure: Group A: Number of Participants With GMFM-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score >=40 Points at Week 106
timeFrame: Baseline, Week 106
measure: Number of Participants With Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) Scale Categories at Week 106
timeFrame: Baseline, Week 106
measure: Number of Participants With Treatment-emergent Adverse Event (TEAEs)
timeFrame: From start of study drug administration up to Week 106
measure: Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values at Week 106
timeFrame: Baseline up to Week 106
measure: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings at Week 106
timeFrame: Baseline up to Week 106
measure: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values at Week 106
timeFrame: Baseline up to Week 106
measure: Number of Participants With Clinically Significant Change From Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106
timeFrame: Baseline up to Week 106
measure: Number of Participants With Anti-Drug Antibody (ADA) Response to SHP611
timeFrame: Baseline up to Week 106
measure: Number of Participants With IDDD Implantations
timeFrame: Baseline up to Week 106
measure: Number of Participants With Any IDDD Related Malfunctions
timeFrame: Baseline up to Week 106
measure: IDDD Longevity as Assessed by Time to IDDD Failure
timeFrame: Baseline up to Week 106
measure: Number of Participants With TEAE Related to IDDD and Surgical Procedure
timeFrame: Baseline up to Week 106
Other outcomes:
Locations:
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute at Harbor-UCLA
state: California
city: Aurora
country: United States
facility: Childrens Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Rare Disease Research, LLC
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Stead Family Children's Hospital
state: Iowa
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Ciudad Autónoma Buenos Aires
country: Argentina
facility: Hospital Universitario Austral - PIN
state: Buenos Aires
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Edmonton
country: Canada
facility: Stollery Children's Hospital University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Le Kremlin-bicetre
country: France
facility: Hôpital Bicêtre - Paris Sud
city: Nice
country: France
facility: CHU Lenval
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Tubingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Chaidari
country: Greece
facility: Attikon University General Hospital
state: Attiki
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebrón
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References: