A Prospective, Blinded, Cross-Over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults With Asthma
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- PK: Maximum concentration (CMAX)
研究概览
简要总结
The overall aim in Part 1 is to compare the pharmacokinetic (PK)/pharmacodynamics (PD) relationship in intravenous (IV) versus subcutaneous (SQ) terbutaline sulfate to identify the optimal IV dosing range for use in Part 2.
The overall aim in Part 2 is to evaluate the optimal IV dosing of terbutaline sulfate based on PD response and safety data.
详细描述
Primary Objectives:
- Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
- Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC.
Secondary Objective: Describe all adverse events (AEs) in participants receiving terbutaline sulfate.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant has provided informed consent
- •History of physician-diagnosed asthma
- •Age ≥18 to <60 at time of consent
- •Past (within 12 months of consent) or current (at screening visit)evidence of airway reactivity, defined as:
- •Documentation of ≥10% FEV1 improvement following bronchodilator OR
- •Positive methacholine challenge (20% or more FEV1 decrease at ≤ 16 mg/mL)
- •Willing and able to undergo study procedures and attend required study visits.
- •Adequate venous access for blood draws and drug administration, as determined by study investigator, or designee
- •Weight ≥ 40kg
- •FEV1 ≥ 60% predicted on day of terbutaline sulfate dosing
- •Systolic blood pressure (BP) ≤ 150 millimeters of Mercury (mmHg) and diastolic BP ≤ 90 mmHg measured after 10 to 15 minutes of rest
- •Heart rate > 45 and < 110 beats per minute (bpm) measured after 10 to 15 minutes of rest
- •Female participants of child-bearing potential: negative pregnancy test (urine hCG) and agreement to use effective contraception (complete abstinence from vaginal intercourse, combination barrier and spermicide, partner vasectomy, bilateral tubal ligation, intrauterine device (IUD), progestin implants, or hormonal) during study participation
排除标准
- •Self-reported pregnancy or lactating or breastfeeding
- •Previous enrollment in the current study (any part)
- •Any chronic respiratory condition besides asthma (including, but not limited to Chronic Obstructive Pulmonary Disease (COPD), emphysema, or interstitial lung disease) that in the opinion of the Principal Investigator (PI) or clinical site investigator, would make the participant unsuitable for the study
- •Body Mass Index (BMI) > 35 kg/m2 (class II or III obesity)
- •Moderate to severe renal impairment, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2
- •Self-reported combustible cigarette smoking of more than 1 pack per day.
- •Greater than 20 pack-year smoking history
- •Any history of cardiac disease (e.g. coronary insufficiency, cardiac arrhythmias), non-skin cancer, hyperthyroidism, diabetes mellitus type 1, uncontrolled diabetes mellitus type II (HbA1C>7.5 documented within past 12 months of screening) uncontrolled epilepsy (2 or more seizures within the past 12 months and not taking anti-seizure medication)
- •History of ocular, brain, abdominal or thoracic surgery in the 12 months prior to screening
- •Known hypersensitivity to terbutaline sulfate or albuterol
- •Use of any medications from the following classes within 28 days prior to Visit 1: monoamine oxidase inhibitors, tricyclic antidepressants, beta blockers, non-potassium-sparing antihypertensive diuretics, or systemic corticosteroids
- •Self-reported respiratory tract infection in the 14 days prior to Visit 1
- •Any current chronic condition or past history of disease that, in the opinion of the PI would make the participant unsuitable for the study
- •Baseline prolongation of QTc (QTc ≥ 460 ms by Fridericia's formula)
- •Participation in another research study that includes use of any investigational drug treatment within the 30 days prior to Visit 1, or planned participation during the study period.
研究组 & 干预措施
Terbutaline Arm A
• Arm A: (n=6) IV bolus (0.25 mg) over 5 minutes SQ administration (0.25 mg) Participants in Part 1 Arms A and B (n=12) will be randomized to one of two treatment arms.No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
干预措施: Terbutaline (Drug)
Terbutaline Arm B
• Arm B: (n=6) SQ administration (0.25 mg) IV bolus (0.25 mg) over 5 minutes Participants in Part 1 Arms A and B (n=12) will be randomized to one of two treatment arms.No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
干预措施: Terbutaline (Drug)
Terbutaline Arm C
• Arm C: (n=6) SQ (0.25 mg) IV low dose over 5 minutes IV medium dose over 5 minutes IV high dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
干预措施: Terbutaline (Drug)
Terbutaline Arm D
• Arm D: (n=6)SQ (0.25 mg) IV medium dose over 5 minutes IV high dose over 5 minutes IV low dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
干预措施: Terbutaline (Drug)
Terbutaline Arm E
• Arm E: (n=6) SQ (0.25 mg) IV high dose over 5 minutes IV low dose over 5 minutes IV medium dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
干预措施: Terbutaline (Drug)
结局指标
主要结局
PK: Maximum concentration (CMAX)
时间窗: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and next calendar day after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
PK: Clearance (Cl)
时间窗: 5 mins, 15 mins, 30 mins, 45 mins, 1 hr, 2 hrs, 3 hrs, 4 hrs, 6 hrs, after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
Concentration Achieving Maximum FEV1 Improvement (CeMax)
时间窗: 0-6 hours
Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.
Area Under the Concentration Time Curve (AUC)
时间窗: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and next calendar day after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
Forced Expiratory Volume in 1 second (FEV1)
时间窗: 0-6 hours
Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.
PK: Time to Research Maximum Concentration (Tmax)
时间窗: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
PK: Volume of Distribution (Vd)
时间窗: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
PK: Half Life (t1/2)
时间窗: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose
Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
次要结局
- Number of Adverse Events (AEs)(From baseline through the end of study (Part I up to 60 days, Part II up to 180 days))
- Number of Serious Adverse Events (SAEs)(From baseline through the end of study (Part I up to 60 days, Part II up to 180 days))
- Number of Suspected Unexpected Serious Adverse Reactions (SUSARs)(From baseline through the end of study (Part I up to 60 days, Part II up to 180 days))
研究者
Kanecia Obie Zimmerman
Associate Professor of Pediatrics
Duke University