A Phase 1/2, Multi-Center, Open-Label, Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of Olipudase Alfa in Pediatric Patients Aged <18 Years With Acid Sphingomyelinase Deficiency
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 6
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
Primary Objective:
To evaluate the safety and tolerability of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.
Secondary Objective:
To characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.
详细描述
The maximum study duration per participant was approximately 18 months (screening period: up to 60 days; treatment period: 64 weeks; post-treatment period: up to 37 days, not applicable if participants enrolled in a long-term extension treatment trial).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Olipudase alfa
Participants received intravenous (IV) infusion of olipudase alfa once every 2 weeks (Q2W) for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 milligram per kilogram (mg/kg). Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks.
干预措施: Olipudase alfa (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: From Baseline up to End of study (64 weeks)
TEAEs were defined as adverse events (AEs) that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product \[IMP\]) administration until end of study (i.e. up to 64 weeks).
Number of Participants With Infusion-Associated Reactions (IARs)
时间窗: Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks)
IARs were defined as AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Protocol-defined IAR: all AEs that were identified as an IAR by the investigator. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might had been judged an IAR at the discretion of the investigator or sponsor.
Number of Participants With Change in Physical Examination
时间窗: Baseline, Week 52 (last complete assessment)
Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Physical examinations included following observations/measurements: examination of the skin, head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Abnormality in physical examinations was based on investigator's discretion.
Number of Participants With Change in Neurological Examination
时间窗: Baseline, Week 52 (last assessment)
Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Neurological examination included: coordination examination, cranial nerve examination, extrapyramidal features, fundoscopy, gait and coordination examination, motor examination, tone peripheral nervous system, reflexes examination, sensory examination, strength examination, mental status.
Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study
时间窗: At End of Study (Week 64)
Abnormal values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase were reported.
Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities
时间窗: From Baseline up to End of Study (64 weeks)
* Heart Rate (HR) High: \>=120 beats per minute (bpm) (adolescents), \>=120 bpm (children), \>=140 bpm (early children), \>=175 bpm (infants) \& increase from baseline (IFB) \>=20 bpm for all age categories. * HR Low: \<=50 bpm (adolescents), \<=50 bpm (children), \<=75 bpm (early children), \<=80 bpm (infants) \& decrease from baseline (DFB) \>=20 bpm for all age categories. * Systolic BP (SBP) High: \>=119 mmHg (adolescents), 108 mmHg (children), 101 mmHg (in early children), 98 mmHg (infants) \& IFB \>=20 mmHg for all age categories. * SBP Low: \<=90 mmHg (adolescents), \<= 80mm Hg (children), \<=70 mmHg (early children), \<=70 mmHg (infants) \& DFB \>=20 mmHg for all age categories. * Diastolic BP (DBP) High:\>=78 mmHg (adolescents), \>=72 mmHg (children), \>=59 mmHg (in early children), \>=54 mmHg (infants) \& IFB \>=10 mmHg for all age categories. * DBP Low:\<=54 mmHg (adolescents), \<=48 mmHg (children), \<=34 mmHg (early children), \<=34 mmHg (infants) \& DFB \>=10 mmHg for all age categories.
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities
时间窗: From Baseline up to End of Study (64 weeks)
Criteria for potentially clinically significant ECG abnormalities: * High PR Interval: \>=180 milliseconds (ms) in adolescents, 170 ms in children, 160 ms in early children, and 140 ms in infants; * High QRS Interval: \>=110 ms in adolescents, 100 ms in children, 95 ms in early children and 85 ms in infants; * Prolonged QTc Fridericia (QTc F): \>450 ms in male adolescents, children, early children and infants or 470 ms in female adolescents, * QTc F \>500 ms; * QTc F increase from baseline \>60 ms.
Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64
时间窗: Baseline, Week 64 (pre-infusion)
Change From Baseline in Safety Biomarker: Ceramide Level at Week 64
时间窗: Baseline, Week 64 (pre-infusion)
Change From Baseline in Safety Biomarker: Iron at Week 64
时间窗: Baseline, Week 64 (pre-infusion)
Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64
时间窗: Baseline, Week 64 (pre-infusion)
Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24
时间窗: Baseline, Week 24 (pre-infusion, last assessment)
Change From Baseline in Safety Biomarker: Calcitonin at Week 64
时间窗: Baseline, Week 64 (pre-infusion)
Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52
时间窗: Baseline, Week 52 (last assessment)
Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb)
时间窗: From Baseline up to Week 64
Serum samples for immunogenicity assessment were analyzed to detect ADA. ADA response were categorized as: treatment emergent antibody i.e. treatment-induced/treatment-boosted response. A participant whose ADA status was positive anytime post-baseline and was negative or missing at baseline was considered to have treatment induced ADA. A participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher than that at baseline is considered to have treatment boosted ADA. Positive samples in the ADA assay were further analyzed in the NAb assay as positive NAb inhibition of catalytic activity and positive NAb inhibition of cellular uptake.
Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52
时间窗: Week 52 (last assessment)
Evidence of portal hypertension was assessed by portal vein direction from liver ultrasound doppler.
次要结局
- Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi)(At the end of infusion of the first 3.0 mg/kg dose and at Week 52)
- Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Percent Change From Baseline in Lipid Profile at Week 52(Baseline, Week 52)
- Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Percent Change From Baseline in Bone Biomarkers at Week 52(Baseline, Week 52)
- Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa(Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52)
- Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52(Baseline, Week 52 (last assessment))
- Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs(Baseline, Week 52 (last assessment))
- Change From Baseline in Height Z-Scores at Week 52(Baseline, Week 52 (last assessment))
- Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52(Baseline, Week 52 (last assessment))
- Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52(Baseline, Week 52 (last assessment))
- Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52(Baseline, Week 52 (last assessment))
- Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52(Week 52 (last assessment))
- Percent Change From Baseline in Efficacy Biomarkers Level at Week 52(Baseline, Week 52)
- Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52(Baseline, Week 52 (last assessment))
- Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52(Baseline, Week 52 (Pre- infusion))