A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Shire
- 入组人数
- 24
- 试验地点
- 10
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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.
排除标准
- •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.
- •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.
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40(Baseline, Week 40)
- Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40(Week 40)
- Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40(Week 40)
- Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40(Week 40)
- Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40(Week 40)
- Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40(Week 40)
- Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40(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(Baseline, Week 40)
- Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40(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(Baseline, Week 40)
- Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40(Baseline, Week 40)
- Maximum Observed Serum Concentration (Cmax) 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(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(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(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(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(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(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(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(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(Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks)