NCT06049082招募中1 期
A Phase 1 Study of Inhaled KB408 for the Treatment of Alpha-1 Antitrypsin Deficiency
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 15
- 试验地点
- 3
- 主要终点
- To evaluate safety and tolerability of KB408 based upon assessment of adverse events (frequency, severity, relatedness), and changes from baseline in vital signs, ECG, spirometry, and clinical laboratory test results
研究概览
简要总结
The Sponsor is developing KB408, a replication-defective, non-integrating herpes simplex virus type 1 (HSV-1)-derived vector engineered to deliver functional full-length human SERPINA1 to the airways of people with alpha-1 antitrypsin deficiency (AATD) via nebulization. This study is designed to evaluate safety and pharmacodynamics of KB408 in adults with AATD with a PI*ZZ or PI*ZNull genotype. Three planned dose levels of KB408 will be evaluated in single dose escalation cohorts. Repeat dosing will be evaluated at the mid dose level. Subjects taking intravenous AAT augmentation therapy are not required to wash out from IV AAT in the low and mid dose cohorts. In the repeat dose and the high dose cohorts, subjects must wash out from IV AAT for at least 10 days, as applicable.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subject or legally authorized representative must have read, understood, and signed an Institutional Review Board (IRB) approved Informed Consent Form and must be willing and able to comply with study procedures and instructions.
- •Subject is aged ≥18 to ≤70 years, at the time of informed consent.
- •Subject has a genetically confirmed diagnosis of AATD with a PI*ZZ or PI*ZNull genotype.
- •Cohort 2b and Cohort 3: Subjects receiving AAT augmentation therapy must be willing to washout for at least 10 days prior to Screening and be willing to remain off augmentation therapy for the duration of the study.
- •Cohort 2b and Cohort 3: Serum AAT level <11 μM at Screening.
- •Willing to remain on a stable regimen of treatment during the study.
- •Resting oxygen saturation ≥92% on room air at Screening.
- •Clinically stable and in good general health, except for AATD, as determined by the Investigator.
排除标准
- •Pulmonary function test with percent predicted forced expired volume in 1 second (ppFEV1) after inhalation of a bronchodilator is <40% at Screening.
- •Diffusing capacity of the lungs for carbon monoxide (DLCO) <30 percent predicted (historical DLCO within 2 years prior to Screening without any intervening change in clinical status since the measurement was taken, or as measured at Screening).
- •Known ongoing or history of clinically significant pulmonary impairment other than AATD.
- •A pulmonary exacerbation within six weeks (42 days) of first dose.
- •Initiation of any new chronic therapy or any change in ongoing therapy routine within 28 days of first dose.
- •Participation in another interventional clinical study or treatment with an investigational agent within 30 days or 5 half-lives, whichever is longer, of first dose. Previous treatment with a genetic therapy for AATD, where the investigational product was demonstrated to be non-efficacious, is not exclusionary.
- •History of or listed for solid organ transplantation or has undergone major lung surgery (e.g., lobectomy) within 6 months of first dose.
- •Any clinical condition or illness (including a history or current evidence of substance abuse or dependence) that, in the opinion of the Investigator, would impact a subject's ability to complete all study-related procedures and/or poses an additional risk to the assessment of safety of KB
- •An active oral herpes infection 30 days prior to the first dose.
- •Clinically significant hepatic dysfunction defined as any one of the following:
- •AST and ALT ≥3× upper limit of normal (ULN) at Screening
- •Total bilirubin ≥2× ULN at Screening (unless associated with Gilbert's syndrome)
- •Evidence of liver cirrhosis with clinical manifestations of portal hypertension (e.g., ascites, encephalopathy, variceal hemorrhage)
- •History of cigarette smoking or any other tobacco use, or use of e-cigarettes or other recreational inhalant, within 6 months of Screening.
- •Unwilling to refrain from smoking, e-cigarette use, or vaping throughout the duration of the study.
- •A positive urine cotinine result that is consistent with active smoking at Screening. (A positive cotinine test due to nicotine replacement therapy for the purpose of smoking cessation, as attested by the Investigator, is allowed.)
- •Abnormal hematology or chemistry testing at Screening as defined below, or any other clinically significant abnormalities that the Investigator believes may interfere with the assessment of safety of the study treatment.
- •Platelet count <100×10^9/L
- •Hemoglobin <9 g/dL
- •White blood cell count <3 or >15×10^9/L
- •Sodium <130 or >150 mmol/L
- •Potassium <3 or >5.5 mmol/L
- •Carbon dioxide <16 mmol/L
- •Creatinine >2 mg/dL
- •Subject is known to be noncompliant or is unlikely to comply with the requirements of the study protocol, in the opinion of the Investigator.
- •Females who are pregnant or nursing.
- •Subject who is unwilling to comply with contraception requirements per protocol
研究组 & 干预措施
Cohort 1: Low dose KB408
Experimental
Single dose of KB408 (low dose)
干预措施: KB408 (Nebulization) (Drug)
Cohort 2: Mid dose KB408
Experimental
Single dose of KB408 (mid dose)
干预措施: KB408 (Nebulization) (Drug)
Cohort 3: High dose KB408
Experimental
Single dose of KB408 (high dose)
干预措施: KB408 (Nebulization) (Drug)
Cohort 2b: Mid dose KB408
Experimental
Multiple doses of KB408 (mid dose)
干预措施: KB408 (Nebulization) (Drug)
结局指标
主要结局
To evaluate safety and tolerability of KB408 based upon assessment of adverse events (frequency, severity, relatedness), and changes from baseline in vital signs, ECG, spirometry, and clinical laboratory test results
时间窗: 2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b)
Number of subjects with treatment related adverse events as assessed by NCI-CTCAE v5
次要结局
- To assess the effect of KB408 on serum alpha-1 antitrypsin (AAT) concentration(2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b))
- To assess the effect of KB408 on plasma neutrophil elastase (NE) concentration(2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b))
- To evaluate the effect of KB408 on AAT concentration in the lung(2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b))
- To evaluate the effect of KB408 on NE concentration in the lung(2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b))
研究者
研究点 (3)
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