A Phase 1/2, First-in-Human, Adaptive, Model-based, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Efficacy of VV-14299 and VV-14300 (Adeno-associated Virus Vector-mediated Insulin and Glucokinase) in Adults With Long-Standing Type 1 Diabetes and Suboptimal Glycemic Control Using a Continuous Subcutaneous Insulin Infusion (CSII) Pump
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- Incidence and severity of adverse events, abnormal clinical laboratory values, abnormal physical exams, and abnormal vital signs
研究概览
简要总结
This study is testing VV-14299 and VV-14300 or VV-14300 alone in adults with long-standing type 1 diabetes (T1D) whose blood sugar is not well controlled despite using an automated insulin delivery (AID) system. VV-14299 and VV-14300 are investigational gene therapies that are injected into muscle and are designed to work together to help remove excess sugar from the blood.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to provide signed informed consent.
- •18 to 65 years of age (inclusive) at Screening.
- •Body mass index (BMI) of 20.0 to <30.0 kg/m².
- •Clinical diagnosis of Type 1 Diabetes (T1D) for at least 5 years prior to Screening, currently managed with an Automated Insulin Delivery (AID) system for at least 3 months prior to Screening.
- •Suboptimal glycemic control (C-peptide <0.20 ng/mL [0.667 nmol/L] during a mixed meal tolerance test; HbA1c >7% and <10%); and on a stable insulin regimen at Screening.
- •Adequate kidney function (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73m²) at Screening.
- •Females of child-bearing potential must have a negative pregnancy test at Screening and prior to dosing; participants must agree to use highly effective contraception during and for at least 12 months after study intervention administration
- •Agree to refrain from donating blood, plasma, platelets, eggs, or sperm during the 12-month Post-Treatment Follow-up Period.
- •Willing and able to complete all study visits, procedures, and required use study-provided monitoring devices for the duration of the study.
排除标准
- •Type 2 diabetes or other condition requiring exogenous insulin that is not due to autoimmunity, or when insulin delivery is not managed through an AID system.
- •Diabetic complications (e.g., severe/proliferative retinopathy or neuropathy) or a clinically significant medical, cognitive, or psychiatric condition that, in the Investigator's opinion, poses additional risk or would make consistent study follow-up unlikely.
- •Pregnant or breastfeeding.
- •History of malignancy requiring chemotherapy and/or radiation within the 12 months prior to Screening, except for successfully treated non-melanoma skin cancers (e.g., basal cell, squamous cell carcinomas), cervical intraepithelial neoplasia, and localized prostate cancer.
- •Clinically significant cardiovascular or cerebrovascular disease, uncontrolled blood pressure, family history of Long QT syndrome, or clinically significant ECG abnormality.
- •Significant history of alcohol or drug abuse, or positive alcohol breath test or urine drug screen at the Screening or Run-in visit.
- •Plans to implement new strenuous physical activity (e.g., significantly increased running pace/duration, high-intensity interval training, heavy weightlifting, vigorous cycling) during the study.
- •Impaired awareness of hypoglycemia.
- •Documented anti-AAV1 neutralizing antibody titer above the protocol-specified threshold at Screening.
- •Active hepatitis B or C infection, positive HIV serology, or any latent or active infection that would interfere with study procedures or be exacerbated by study medications.
- •Clinically significant abnormal Screening laboratory or other diagnostic findings (including hepatic, hematologic, thyroid, muscle-enzyme, or tuberculosis screening) rendering the participant unsuitable for the study.
- •Current or recent use of medications that could interfere with glucose metabolism or confound study assessments (e.g., glucocorticoids, systemic beta-blockers, growth hormone, or other antidiabetic medications [e.g., glucagon-like peptide 1 (GLP-1) receptor agonists and/or sodium-glucose cotransport 2 (SGLT2) inhibitors]).
- •Vaccination within 30 days prior to dosing or planned vaccination within 8 weeks post-dosing.
- •Screening laboratory findings indicating undue risk of a tocilizumab-related adverse event.
- •History of bariatric surgery within the 12 months prior to Screening.
- •History of trauma to, or other findings affecting the suitability of, the muscles intended for study intervention administration.
- •Participation in another investigational drug or biologic trial within 6 months prior to Screening, or participation in any previous gene therapy trial.
研究组 & 干预措施
Part 1 - Cohort 1 (VV-14300, single dose)
A single dose of VV-14300 will be administered via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300 dosing to reduce the risk of immune responses.
干预措施: VV-14300 (Genetic)
Part 1 - Cohort 2 (VV-14300, single dose + VV-14299, low dose)
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 (low dose) via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14300 (Genetic)
Part 1 - Cohort 2 (VV-14300, single dose + VV-14299, low dose)
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 (low dose) via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14299 (Genetic)
Part 1 - Cohort 3 (VV-14300, single dose + VV-14299, high dose)
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 (high dose) via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14300 (Genetic)
Part 1 - Cohort 3 (VV-14300, single dose + VV-14299, high dose)
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 (high dose) via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14299 (Genetic)
Part 2 - Dose Expansion
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 at the dose selected from Part 1 via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14300 (Genetic)
Part 2 - Dose Expansion
The same dose of VV-14300 from Cohort 1 will be co-administered with VV-14299 at the dose selected from Part 1 via ultrasound-guided intramuscular injections on Day 1. Tocilizumab will be administered subcutaneously as an auxiliary medication prior to and after VV-14300/VV-14299 dosing to reduce the risk of immune responses.
干预措施: VV-14299 (Genetic)
结局指标
主要结局
Incidence and severity of adverse events, abnormal clinical laboratory values, abnormal physical exams, and abnormal vital signs
时间窗: 52 Weeks
Safety of VV-14299 and/or VV-14300
Change from Baseline in blood glucose as measured by continuous glucose monitoring (CGM)
时间窗: 16 Weeks
Efficacy of VV-14299 and/or VV-14300 (Part 1)
Change from Baseline in blood glucose as measured by hemoglobin A1c (HBA1c) level
时间窗: 16 Weeks
Efficacy of VV-14299 and/or VV-14300 (Part 1)
Change from Baseline in blood glucose as measured by fructosamine level
时间窗: 16 Weeks
Efficacy of VV-14299 and/or VV-14300 (Part 1)
Change from Baseline in blood glucose as measured by mixed meal tolerance test (MMTT)
时间窗: 16 Weeks
Efficacy of VV-14299 and/or VV-14300 (Part 1)
Mean change from Baseline in HbA1c levels
时间窗: 26 Weeks
Efficacy of VV-14299 and/or VV-14300 (Part 2)
次要结局
- Mean change from Baseline in HbA1c levels(16, 26 (Part 1), and 52 Weeks)
- Change from Baseline in time-in-range derived from CGM data(52 Weeks)
- Change from Baseline in mean glucose concentration derived from CGM data(52 Weeks)
- Change from Baseline in Glucose Management Indicator (GMI) derived from CGM data(52 Weeks)
- Change from Baseline in glycemic variability (coefficient of variation) derived from CGM data(52 Weeks)
- Change from Baseline in total daily insulin dose (basal and bolus)(52 Weeks)
- Change from Baseline in average insulin boluses per day(52 Weeks)
- Change from Baseline in blood glucose by mixed meal tolerance test (MMTT)(52 Weeks)
- Change from Baseline in blood glucose by fructosamine level(52 Weeks)
- Change from Baseline in body weight(52 Weeks)
- Change from Baseline in fasting lipid levels(52 Weeks)
- Change from Baseline in the level of antibodies to AAV vector capsid, VV-14300-expressed transgene product, and VV-14299-expressed transgene product by enzyme-linked immunosorbent assay (ELISA)(52 Weeks)
- Change from Baseline in interferon-gamma cellular immune response to AAV1 capsid, VV-14300-expressed transgene product, and VV-14299-expressed transgene product by enzyme-linked immunosorbent spot (ELISpot) assay(52 Weeks)
- VV-14300 vector levels in biological samples(52 Weeks)
- VV-14299 vector levels in biological samples(52 Weeks)
- VV-14299 protein levels in serum(52 Weeks)