A Phase 1/2 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effects on Clinical Outcomes of Pegtibatinase (TVT-058) Administered Subcutaneously in Subjects With Cystathionine Beta Synthase-Deficient Homocystinuria (COMPOSE)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 39
- 试验地点
- 14
- 主要终点
- Incidence of AEs
研究概览
简要总结
Researchers are looking for a better way to treat people who have classical homocystinuria (HCU), a rare condition that is passed down by parents (or "genetic condition"). It is caused by changes in the cystathionine beta-synthase (or "CBS") gene and prevents an enzyme from working correctly in the body. This enzyme breaks down a substance called homocysteine (from dietary methionine found in protein) and keeps both homocysteine and methionine at normal levels. When this enzyme is not working, homocysteine and methionine build up in the blood, which spreads into different tissues of the body and stops these body tissues from working normally.
People with HCU can experience problems with vision, bones, blood vessels, and cognitive function (the ability to think, learn, and remember). Treatments available for HCU, such as a low protein diet and betaine (Cystadane®), help reduce homocysteine levels. The diet is a low methionine diet and a methionine-free protein supplement (a product that provides extra protein to help meet daily protein needs). These treatments are either not sufficient or are hard to take for many patients.
Pegtibatinase was developed by scientists to be a version of the CBS enzyme that can be given to people with HCU. Researchers believe that giving pegtibatinase to people with HCU already getting medical treatment (or "standard of care") may reduce their homocysteine levels.
This study is split into 7 different groups getting different amounts of drug. The first 6 groups have already finished the study.
Group 7 plans to enroll participants from the US (virtual and in-person), France, and Qatar.
详细描述
Primary Objective - Cohorts 1-6
Researchers are performing this study to learn if pegtibatinase is safe and tolerable (how it makes participants feel).
Researchers will use medical examination, blood tests, and urine tests to measure side effects (unwanted health problems that may or may not be related to the study treatment), changes in laboratory tests and in the electrical activity of the heart (as measured by electrocardiogram or "ECG"), and if the body makes antibodies to fight against pegtibatinase. Antibodies are proteins that the body makes that may stop pegtibatinase from working or may cause side effects.
Secondary Objectives - Cohorts 1-6
Researchers also want to learn about:
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 5 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohort 7 (currently enrolling): ≥5 to <12 years of age.
- •Completed Cohorts 1-6: ≥12 to 65 years of age.
- •Diagnosis of classical homocystinuria (HCU)
- •Cohort 7 (currently enrolling): Diagnosis based on clinical, biochemical, and/or molecular genetic testing.
- •Completed Cohorts 1-6: Genetically confirmed cystathionine beta-synthase (CBS)-deficient HCU.
- •Plasma total homocysteine (tHcy)
- •Cohort 7 (currently enrolling): Plasma tHcy ≥50 μM at Screening.
- •Completed Cohorts 1-6: Plasma tHcy ≥50 μM at Screening and documented historical plasma tHcy ≥80 μM.
- •Willing and able (or parent/legal guardian willing and able) to provide informed consent/assent and comply with study procedures.
- •Willing to maintain a generally stable standard-of-care treatment regimen, including dietary management and HCU-related therapies, unless changes are medically necessary.
- •Participants of childbearing potential must have a negative pregnancy test before study treatment and agree to use protocol-specified contraception, if applicable.
排除标准
- •Cohort 7 only:
- •Diagnosis of Marfan syndrome, methylenetetrahydrofolate reductase (MTHFR) deficiency, or a disorder of cobalamin metabolism.
- •History of a major thrombotic event within the previous 6 months.
- •Body weight <15 kg.
- •All Cohorts:
- •Previous treatment with pegtibatinase or pegtarviliase)
- •Participation in a pegtibatinase clinical study.
- •Receipt of another investigational drug or investigational medical device within 30 days before Screening or planned use during study participation.
- •Use of injectable polyethylene glycol (PEG)-containing medications (other than pegtibatinase or PEG-containing vaccines) within 3 months before Screening or during study participation.
- •Known hypersensitivity to pegtibatinase or a history of severe hypersensitivity to a PEG-containing product.
- •Active HIV, hepatitis B, or hepatitis C infection.
- •History of organ transplantation or immunosuppressive therapy.
- •Clinically significant medical conditions that could interfere with study participation or participant safety.
- •Pregnant or breastfeeding, or planning to become pregnant during study participation.
- •Major surgery planned during the study period.
- •Any condition that could prevent the participant from complying with study procedures or completing the study.
研究组 & 干预措施
Pegtibatinase (Cohort 7)
Pediatric Open-label Treatment Cohort (≥5 to <12 years)
干预措施: Pegtibatinase (Drug)
Pegtibatinase (Cohort 1-6)
Double-Blind Treatment Cohorts (≥12 to ≤65 years)
干预措施: Pegtibatinase (Drug)
Placebo (Cohort 1-6)
Double-Blind Treatment Cohorts (≥12 to ≤65 years)
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence of AEs
时间窗: Through double-blind study completion, approximately 10 months per patient
Incidence of AEs (by type, severity and relationship to study drug)
Anti-pegtibatinase antibodies
时间窗: Through double-blind study completion, approximately 10 months per patient
Presence and levels of anti-pegtibatinase antibodies in plasma as measured by antibody titers
Anti-PEG antibodies
时间窗: Through double-blind study completion, approximately 10 months per patient
Presence and levels of anti-PEG antibodies in plasma as measured by antibody titers
Incidence of AEs
时间窗: • Cohorts 1-6: Through double-blind study completion, approximately 10 months per patient • Cohort 7: First dose through End of Treatment (up to 32 weeks)
Incidence of AEs (by type, severity and relationship to study drug)
Anti-pegtibatinase antibodies
时间窗: • Cohorts 1-6: Through double-blind study completion, approximately 10 months per patient • Cohort 7: First dose through End of Treatment (up to 32 weeks)
Presence and levels of anti-pegtibatinase antibodies in plasma as measured by antibody titers
Anti-PEG antibodies
时间窗: • Cohorts 1-6: Through double-blind study completion, approximately 10 months per patient • Cohort 7: First dose through End of Treatment (up to 32 weeks)
Presence and levels of anti-PEG antibodies in plasma as measured by antibody titers
Incidence of hypermethioninemia (Cohort 7 only)
时间窗: First dose through End of Treatment (up to Week 32)
The number and percentage of participants who develop hypermethioninemia during treatment, based on plasma methionine concentrations exceeding the protocol-defined threshold. Participants meeting the protocol-defined threshold may undergo dietary management or study treatment modifications, as appropriate.
Incidence of hypomethioninemia (Cohort 7 only)
时间窗: First dose through End of Treatment (up to Week 32)
The number and percentage of participants who develop hypomethioninemia during treatment, based on plasma methionine concentrations below the protocol-defined threshold. Participants meeting the protocol-defined threshold may receive dietary protein supplementation or study treatment modifications, as appropriate.
The proportion of participants requiring dietary protein rescue (Cohort 7 only)
时间窗: First dose through End of Treatment (up to Week 32)
The proportion of participants who require initiation of dietary protein supplementation during study treatment to manage protocol-defined low plasma methionine concentrations.
次要结局
- Changes in pegtibatinase levels(Through double-blind study completion, approximately 10 months per patient)
- Bone densitometry using dual-energy X-ray absorptionmetry (DEXA) scans(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - tHcy(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - total Cys(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Cth(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Phe(Through double-blind study completion, approximately 10 months per patient)
- Descriptive ophthalmology examination findings(Through double-blind study completion, approximately 10 months per patient)
- Cognitive assessments using the National Institutes of Health Toolbox Cognition Battery score(Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life in Neurological Disorders [Neuro-QoL](Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life by 36-Item Short Form Survey [SF-36](Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Met(Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life by EuroQol 5-Dimentional Instrument [EQ 5D](Through double-blind study completion, approximately 10 months per patient)
- Cognitive assessments using the National Institutes of Health Toolbox Cognition Battery score (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Changes in pegtibatinase levels(• Cohorts 1-6: Through double-blind study completion, approximately 10 months per patient • Cohort 7: First dose through End of Treatment (up to 32 weeks))
- Changes in Met cycle metabolites levels - tHcy(• Cohorts 1-6: Through double-blind study completion, approximately 10 months per patient • Cohort 7: First dose through End of Treatment (up to 32 weeks))
- Changes in Met cycle metabolites levels - total Cys (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Me (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Cth (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Changes in Met cycle metabolites levels - Phe (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Descriptive ophthalmology examination findings (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Bone densitometry using dual-energy X-ray absorptionmetry (DEXA) scans (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life in Neurological Disorders [Neuro-QoL] (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life by 36-Item Short Form Survey [SF-36] (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)
- Patient Reported Outcome (PRO): Quality of Life by EuroQol 5-Dimentional Instrument [EQ 5D] (Cohorts 1-6 Only)(Through double-blind study completion, approximately 10 months per patient)