A Phase 3 Multi-Center Study to Evaluate the Safety and Efficacy of Subcutaneous Injections of Pegvaliase in Adolescent Subjects (Ages 12-17) With Phenylketonuria- Open-Label Randomized Two-Arm (Active vs Diet-Only Control)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 55
- 试验地点
- 30
- 主要终点
- Change in blood Phe concentration
研究概览
简要总结
This is a Phase 3 open-label randomized controlled study enrolling approximately 54 adolescents with PKU. The study is designed to assess the safety and efficacy of pegvaliase injections.
详细描述
This Phase 3 multicenter study is designed to evaluate the safety and efficacy of pegvaliase administered daily to adolescents (ages 12 to 17 years old (US), inclusive, and 12 to 15 years old (EU), inclusive 12-17) with phenylketonuria (PKU). Participants will be randomized in a 2:1 ratio to the active (pegvaliase) and control (diet-only) treatment arms, respectively, with 36 participants receiving pegvaliase and 18 participants managing their PKU with diet alone.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Is 12 to 17 years old (US), inclusive, or 12 to 15 years (EU), inclusive, at the start of the Screening/Run-in Period (Day -28).
- •Diagnosis of PKU and failure to maintain recommended blood Phe levels on existing management (sapropterin dihydrochloride and Phe-restricted diet) demonstrated by 2 blood Phe concentration measurements > 600 μmol/L during the Screening/Run-in Period (7 to 10 days in between blood Phe assessments) and average blood Phe concentration > 600 μmol/L over the past 12 months (per available data).
- •Willing and able to maintain and adjust dietary and medical protein food intake according to the study protocol under the supervision of a study dietician or adequately trained designee per investigator discretion during study participation.
- •If on medication for ADHD, depression, or other psychiatric disorder, stable dose of medication for ≥ 8 weeks prior to enrollment and willing to maintain stable dose unless a change is medically indicated.
- •An adult (≥ 18 years of age) has been identified who is willing and competent to observe the participant during study drug administration and for a minimum of 1 hour following administration.
- •Participants must be capable of giving signed informed consent
- •If sexually active, male or female participants must not plan to become pregnant (self or partner) and must use 2 acceptable methods of contraception while participating in the study beginning at Screening and for 4 weeks after discontinuing study drug.
排除标准
- •Previous treatment with pegvaliase.
- •Use of any medication that is intended to treat PKU, including the use of large neutral amino acids, within 14 days prior to the administration of study drug on Day
- •Use or planned use of any injectable drugs containing polyethylene glycol (PEG; other than pegvaliase), including medroxyprogesterone injection, within 3 months prior to the start of Screening/Run-in and during study participation with the exception of COVID-19 vaccinations.
- •A history of organ transplantation or on chronic immunosuppressive therapy.
- •Use of any investigational product or investigational medical device within 30 days prior to Screening/Run-in or requirement for any investigational agent prior to completion of all scheduled study assessments.
- •A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody.
- •Alanine aminotransferase (ALT) concentration > 2 × the upper limit of normal (ULN).
- •Creatinine > 1.5 × ULN.
- •Inability to identify and/or communicate to others that the participant is experiencing symptoms of potential anaphylaxis due to cognitive impairment or other reasons.
研究组 & 干预措施
Diet Only
Participants will be managing their PKU with diet alone. Participants in the diet-only control arm will be required to maintain and adjust dietary and medical protein food intake through Week 72, initiating pegvaliase treatment beginning Week 73 and, from Weeks 73 through 215.
干预措施: Diet Only (Other)
Pegvaliase
Treatment Arm
干预措施: Pegvaliase (Drug)
结局指标
主要结局
Change in blood Phe concentration
时间窗: Treatment naïve baseline following 72 weeks on study
Incidence of treatment-emergent adverse events as assessed by CTCAE v5.0
时间窗: Treatment naïve baseline following 72 weeks on study
Change From Baseline in Blood Phe Concentration Following 72 Weeks (Average of the Week 69 and Week 73) on Study.
时间窗: Baseline to Week 72 (average of the Week 69 and Week 73)
The blood Phe measurement following 72 weeks on study is defined as the average of the Week 69 and Week 73 blood Phe measurements. Change from baseline in blood Phe will be compared between participants in the active (pegvaliase) and the control (diet-only) treatment arms. Baseline blood Phe concentration at Part 1 was defined as the average of 3 pre-treatment measurements collected between Screening/Run-in (2) and Day 1 pre-dose (1).
Incidence of Treatment-emergent Adverse Events (Part 1)
时间窗: Up to Week 73
Treatment-emergent adverse events (TEAE) is defined as any AE that newly appeared or worsened in severity after first dose of pegvaliase (pegvaliase arm) or on or after study day 1 (diet-only arm) until 30 days after last dose of the study. Serious adverse event (SAE).
Percentage of Participants With Positive Anti-pegvaliase Total Antibody (TAb)
时间窗: Baseline (Day 1), Week 73
The anti-pegvaliase total antibody (TAb) method captures drug-binding antibodies comprised of different isotypes and specificities. Antibody Positivity = number of subjects testing positive at any study visit / total number of subjects at study visit. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
Percentage of Participants With Positive PAL IgG Antibody
时间窗: Baseline (Day 1), Week 73
The presence of immunoglobulin G (IgG) Antibodies against phenylalanine ammonia lyase (PAL) is measured overtime. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
Percentage of Participants With Positive PAL IgM Antibody
时间窗: Baseline (Day 1), Week 73
The presence of immunoglobulin M (IgM) Antibodies against PAL (phenylalanine ammonia lyase) is measured overtime. PAL IgM was positive if the titer value was greater than or equal to the median of all baseline PAL IgM titers. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
Percentage of Participants With Positive PEG IgG Antibody
时间窗: Baseline (Day 1), Week 73
The presence of IgG Antibodies against polyethylene glycol (PEG) is measured overtime The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
Percentage of Participants With Positive PEG IgM Antibody
时间窗: Baseline (Day 1), Week 73
The presence of IgM Antibodies against PEG (polyethylene glycol) is measured overtime The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
Percentage of Participants With Positive Neutralizing Antibodies (NAb)
时间窗: Baseline (Day 1), Week 73
Neutralizing antibodies (NAbs) capable of inhibiting the enzymatic activity of pegvaliase were measured. The baseline was defined as the last non-missing measurement collected prior to the first pegvaliase dose (pegvaliase arm) or prior to or on Visit 1 date (diet-only arm)
次要结局
- Change in total dietary protein intake(Treatment naïve baseline following 72 weeks on study)
- Change From Baseline in Total Dietary Protein Intake (i.e., Medical Food and/or Intact Food) Following 72 Weeks (Average of Week 69 and Week 73) on Study(Baseline to Week 72 (average of Week 69 and week 73))
- Percentage Change From Baseline in Total Dietary Protein Intake (i.e., Medical Food and/or Intact Food) Following 72 Weeks (Average of Week 69 and Week 73) on Study(Baseline to Week 72 (average of Week 69 and week 73))
- Pegvaliase Tmax (Week 73 Intensive PK)(Week 73)
- Pegvaliase Cmax (Week 73 Intensive PK)(Week 73)
- Pegvaliase AUC0-24 (Week 73 Intensive PK)(Week 73)
- Pegvaliase Cavg (Week 73 Intensive PK)(Week 73)
- Overall: Incidence of Treatment-emergent Adverse Events (Including Part 2)(Up to Week 153)
- Part 2: Percentage of Participants With Anti-pegvaliase Total Antibody (TAb), Positive PAL IgG Antibody, Positive PAL IgM Antibody, Positive PEG IgG Antibody, Positive PEG IgM Antibody and Positive Neutralizing Antibodies (NAb)(Baseline (Day 1), Week 145)
- Part 2: Pegvaliase Tmax, Cmax, AUC0-24 and Cavg (Week 145 Intensive PK)(Week 145)