Metachromatic Leukodystrophy (MLD)Phase 1/2IDEAMLDNCT01510028
Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)
A Phase 1/2 study testing Recombinant human arylsulfatase A in people with Metachromatic Leukodystrophy (MLD), run by Shire at 5 sites in 5 countries.
Trial summary
The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD). Read more about this study
- Who is it for?
- Ages Up to 12 years
- Conditions the study is for
- Metachromatic Leukodystrophy (MLD)
- What is being tested?
- Recombinant human arylsulfatase A
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 5 sitesin 5 countries
- Study dates
- 2 Feb 2012to 20 Jan 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 12 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- For Cohorts 1-4:
- Confirmed diagnosis of metachromatic leukodystrophy by both:
- Arylsulfatase A (ASA) deficiency by assay in leukocytes AND
- Elevated sulfatide in urine
- Appearance of the first symptoms of disease at or before 30 months of age.
- For Cohorts 1-3 only:
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- 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:
- A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND
- GMFM-88 Dimension E: Walking, Running \& Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screening and baseline examinations (if applicable).
- 4.1 The patient is less than 8 years of age at the time of screening.
- For Cohorts 1-4:
- 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.
Who cannot join
- 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:
- History of hematopoietic stem cell transplantation (HSCT).
- The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
- Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
- The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study.
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- The patient is pregnant or breastfeeding.
- The patient has a condition that is contraindicated as described in the SOPH-A-PORT
- Mini S IDDD Instructions for Use (IFU), including:
- The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
- The patient's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator.
- The patient has a known or suspected local or general infection.
- The patient is at risk of abnormal bleeding due to a medical condition or therapy.
- The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
- The patient has a functioning CSF shunt device.
- The patient has shown an intolerance to an implanted device.
Trial locations and contacts
5 sites in 5 countries.
5 sites in 5 countries
France1 site
Hopital de Bicetre
Le Kremlin-Bicêtre, Île-de-France Region, 94275
Germany1 site
Center for Pediatric Clinical Studies
Tübingen, Baden-Wurttemberg, 72076
About this study
Official title: A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy
The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD).
Read the detailed description
Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD.
This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.
- Conditions
- Metachromatic Leukodystrophy (MLD)
- Being tested
- Recombinant human arylsulfatase A
- Keywords
- Intrathecal Drug Delivery Device (IDDD), Recombinant human arylsulfatase A (rhASA), Metachromatic Leukodystrophy (MLD)
- Medical subject headings
- Leukodystrophy, Metachromatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Recombinant human arylsulfatase ABiological
Also called HGT-1110, rhASA
6 patients treated with HGT-1110 EOW by IT injection
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 (10 mg) | Experimental | 6 patients treated with HGT-1110 10 mg EOW by IT injection Receives: Biological: Recombinant human arylsulfatase A |
| Cohort 2 (30 mg) | Experimental | 6 patients treated with HGT-1110 30 mg EOW by IT injection Receives: Biological: Recombinant human arylsulfatase A |
| Cohort 3 (100 mg) | Experimental | 6 patients treated with HGT-1110 100 mg EOW by IT injection Receives: Biological: Recombinant human arylsulfatase A |
| Cohort 4 (100 mg) | Experimental | 6 patients treated with HGT-1110 100 mg EOW by IT injection Receives: Biological: Recombinant human arylsulfatase A |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline up to Week 40
Secondary outcomes (21)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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,
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 40
Maximum Observed Serum Concentration (Cmax) of SHP611
Cmax is the maximum observed serum concentration of SHP611.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2012 (estimated)
- Study start2 Feb 2012
- Primary completion20 Jan 2017
- Study completion20 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metachromatic Leukodystrophy (MLD)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shire
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Study Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01510028
- Sponsor's protocol ID
- HGT-MLD-070
- Other IDs
- 2011-002044-28, U1111-1153-1422
- Acronym
- IDEAMLD
- Status last verified
- May 2021
- First submitted
- 14 Dec 2011
- Last updated
- 14 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: \- De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites, …)
Publications
I Dali C, Sevin C, Krageloh-Mann I, Giugliani R, Sakai N, Wu J, Wasilewski M. Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial. Mol Genet Metab. 2020 Sep-Oct;131(1-2):235-244. doi: 10.1016/j.ymgme.2020.07.002. Epub 2020 Jul 16.
PubMed 32792226
Study at a glance
From the registry record, last updated by the sponsor on 14 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy
- ClinicalTrials.gov ID
- NCT01510028
- Acronym / sponsor ID
- IDEAMLD / HGT-MLD-070
- Conditions
- Metachromatic Leukodystrophy (MLD)
- Keywords
- Intrathecal Drug Delivery Device (IDDD), Recombinant human arylsulfatase A (rhASA), Metachromatic Leukodystrophy (MLD)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- ShireIndustry (pharma, biotech, devices)
- Study start
- 2 Feb 2012 (actual)
- Primary completion
- 20 Jan 2017 (actual)
- Study completion
- 20 Jan 2017 (actual)
- First posted
- 13 Jan 2012 (estimated)
- Results
- Posted 15 Oct 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD.
This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 (10 mg) | Experimental | Biological: Recombinant human arylsulfatase A6 patients treated with HGT-1110 10 mg EOW by IT injection |
| Cohort 2 (30 mg) | Experimental | Biological: Recombinant human arylsulfatase A6 patients treated with HGT-1110 30 mg EOW by IT injection |
| Cohort 3 (100 mg) | Experimental | Biological: Recombinant human arylsulfatase A6 patients treated with HGT-1110 100 mg EOW by IT injection |
| Cohort 4 (100 mg) | Experimental | Biological: Recombinant human arylsulfatase A6 patients treated with HGT-1110 100 mg EOW by IT injection |
Who may qualify
- Ages
- Up to 12 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (17 listed)
- Confirmed diagnosis of metachromatic leukodystrophy by both:
- Appearance of the first symptoms of disease at or before 30 months of age.
- 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.
- 4.1 The patient is less than 8 years of age at the time of screening.
Key exclusion criteria (16 listed)
- Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening:
- History of hematopoietic stem cell transplantation (HSCT).
- The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
- Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
- The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Recombinant human arylsulfatase AAlso: HGT-1110, rhASA6 patients treated with HGT-1110 EOW by IT injection | Biological | Cohort 1 (10 mg), Cohort 2 (30 mg), Cohort 3 (100 mg), Cohort 4 (100 mg) |
Primary outcome
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity
Time frame: From start of study treatment up to Week 42
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.
Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
Time frame: From start of study treatment up to Week 40
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.
Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
Time frame: From start of study treatment up to Week 40
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.
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
Time frame: From start of study treatment up to Week 40
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.
Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)
Time frame: From start of study treatment up to Week 40
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.
Number of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
Time frame: From start of study treatment up to Week 40
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.
Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum
Time frame: Baseline up to Week 40
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.
21 secondary outcomes
Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40
Time frame: Baseline, Week 40
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40
Time frame: Week 40
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40
Time frame: Week 40
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40
Time frame: Week 40
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40
Time frame: Week 40
Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40
Time frame: Week 40
Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40
Time frame: 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
Time frame: Baseline, Week 40
Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40
Time frame: 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
Time frame: Baseline, Week 40
Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40
Time frame: Baseline, Week 40
Maximum Observed Serum Concentration (Cmax) of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Terminal Elimination Half Life (t1/2) of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Total Body Clearance (CL/F) After Intrathecal Administration of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611
Time frame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
Concentration of SHP611 in Cerebrospinal Fluid
Time frame: Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32792226I 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.
- Individual participant dataSharing planned: No. - De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites, …)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Director study director
Takeda
5 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Recombinant human arylsulfatase A in people with Metachromatic Leukodystrophy (MLD), run by Shire at 5 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Australia, Denmark, France, Germany, Japan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity (time frame: From start of study treatment up to Week 42). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01510028, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2021.