A Double-blind, Placebo-controlled, Ascending-dose Study to Assess the Safety, Tolerability and Efficacy of TR4, a Selective β2-adrenoceptor (β2-AR) Antagonist, in Patients With Mild-to-moderate Asthma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Spirometry (FEF 25-75)
研究概览
简要总结
The objectives are to assess the safety, tolerability and effect on the airways of TR4 in patients with mild-to-moderate asthma. The Phase 1 trial is randomised, double-blind, placebo-controlled, and ascending-dose in design.
详细描述
After a run-in period of 2 weeks, 12 eligible patients will be randomised to treatment with either TR4 or placebo. Nine patients will take incremental doses of 2.5, 5, 10 and 20 mg of TR4 capsules, each dose three times daily for 7 days, and then 40 mg three times daily for 21 days, over a total period of 7 weeks. Three patients will take matching placebo capsules in a similar manner.
The number of visits and the types are as follows. There will be a maximum of 10 visits to Hammersmith Medicines Research (HMR) for those subjects who complete the whole study according to the protocol. Visit 1 is an out-patient visit for informed consent and screening. Visit 2 is a short out-patient visit at the start of a 2-week run-in period for those subjects who pass screening. After the run-in period, patients who are still eligible will be given a schedule for 8 further visits (Visits 3-10). Participants will stay on the ward for 2 nights during 5 of those visits (Visits 3-7), and for 1 night during Visit 10. Visits 8 and 9 are short out-patient visits. The study will take each subject ~10 weeks to complete. For purposes of data collection and management the study is divided into one session for screening, a run-in period and 5 treatment periods.
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
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women
- •Minimum 21 years old
- •History of mild-to-moderate asthma for at least 6 months and controlled by an inhaled SABA, as required
- •Otherwise healthy
- •Ideally have participated in previous asthma studies
- •No corticosteroid for whatever reason within 8 weeks of the start of dosing
- •No other prescription medicine within 28 days (apart from a short acting beta-agonist (SABA) or contraceptives in women)
- •No over-the-counter medicine within 7 days (apart from acetaminophen) before the start of dosing
- •Negative screen for drugs of abuse; forced expiratory volume in 1 second (FEV1) more than or equal to 70% predicted
- •Fractional exhaled nitric oxide (FeNO) more than or equal to 35 ppb
- •15% fall in FEV1 after inhaled mannitol (PD15)
- •Non-smoker or past smoker (<5 pack years)
- •Substitution of subject's SABA inhaler with an anti-cholinergic inhaler, ipratropium bromide, for use as a reliever or rescue medication during a run-in period and during dosing with TR4 or placebo.
排除标准
- •Positive test for hepatitis B & C or HIV
- •Drug or alcohol abuse
- •Airway infection or asthma exacerbation in the last 4 weeks
- •Current seasonal asthma
- •History of emergency treatment of asthma
- •Loss of more than 400 mL blood, or participation in other clinical trials of unlicensed medicines within the previous 3 months
- •Consumption of grapefruit or herbal remedies within the past 7 days
- •Objection by the subject's general practitioner (GP)
- •Subjects who are sexually active and not using reliable contraception
- •Women who are lactating, pregnant or plan to become pregnant during the study period
- •Positive polymerase chain reaction (PCR) test for SARS-CoV-2 virus
- •Subjects who have not received both doses of a COVID-19 vaccine.
研究组 & 干预措施
TR4
After a run-in period of 2 weeks, 9 patients will be randomly assigned to the TR4 treatment arm. These 9 patients will take incremental doses of 2.5, 5, 10, and 20 mg of TR4, each dose three times daily for 7 days, and then 40 mg three times daily for 21 days, over a total period of 7 weeks.
干预措施: TR4 (Drug)
Placebo
Three patients will take matching placebo capsules in a similar manner to TR4.
干预措施: Placebo (Other)
结局指标
主要结局
Spirometry (FEF 25-75)
时间窗: Day 21 of treatment period 5.
Lung function test: forced mid-expiratory flow (FEF 25-75) is the mean forced expiratory flow during the middle half of the FVC
Spirometry (FEV1/FVC)
时间窗: Day 21 of treatment period 5.
Lung function test: FEV1 as a percentage of FVC (FEV1/FVC).
Mannitol (PD15)
时间窗: Day 21 of treatment period 5.
The dose of mannitol causing a 15% fall in FEV1
Spirometry (FEV1)
时间窗: Day 21 of treatment period 5.
Lung function test: The forced expiratory volume in 1 second (FEV1).
Spirometry (FVC)
时间窗: Day 21 of treatment period 5
Lung function test: forced vital capacity (FVC).
Impulse oscillometry (IOS) (R5, R5-R20)
时间窗: Change between baseline (day -1) and day 1 of treatment periods 1 to 5.
Lung function test: A Jaeger impulse oscillometer will be used to obtain measurements according to the investigators standard operating procedure (SOP) and a published algorithm. The following settings will be used for IOS: oscillometric pressure impulses will be superimposed onto the tidal breathing of the subject, for about 30 s, with a pulse sequence of 5 per second and a frequency spectrum between 5 and 35 Hz. Resistance (R) at 5-20 Hz (R5 and R5-R20) during normal tidal breathing will be measured.
IOS (R5, R5-R20)
时间窗: Day 21 of treatment period 5.
Lung function test: A Jaeger impulse oscillometer will be used to obtain measurements according to the investigators SOP and a published algorithm. The following settings will be used for IOS: oscillometric pressure impulses will be superimposed onto the tidal breathing of the subject, for about 30 s, with a pulse sequence of 5 per second and a frequency spectrum between 5 and 35 Hz. Resistance (R) at 5-20 Hz (R5 and R5-R20) during normal tidal breathing will be measured.
IOS (AX)
时间窗: Day 21 of treatment period 5.
Lung function test: A Jaeger impulse oscillometer will be used to obtain measurements according to the investigators SOP and a published algorithm. The following settings will be used for IOS: oscillometric pressure impulses will be superimposed onto the tidal breathing of the subject, for about 30 s, with a pulse sequence of 5 per second and a frequency spectrum between 5 and 35 Hz. Reactance (X) at 5-20 Hz (AX) during normal tidal breathing will be measured.
Airway nitric oxide (FeNO)
时间窗: Day 21 of treatment period 5.
FeNO will be measured using the NIOX Viro handheld electronic device.
Blood eosinophils
时间窗: Day 21 of treatment period 5.
Blood eosinophils concentration will be used as an inflammatory marker.
次要结局
- 12-lead ECG: PR interval (safety)(Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.)
- Vital signs (safety): Blood pressure(Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.)
- Vital signs (safety): Heart rate(Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.)
- Vital signs (safety): Respiratory rate(Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.)
- Vital signs (safety): Oral temperature(Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.)
- Safety tests of blood and urine(Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.)
- 12-lead ECG: Ventricular rate (safety)(Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.)
- 12-lead ECG: QRS (safety)(Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.)
- 12-lead ECG: QT interval (safety)(Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.)
- ECG telemetry: Ventricular rate (safety)(Day 1 of treatment periods 1 to 5.)
- ECG telemetry: PR interval (safety)(Day 1 of treatment periods 1 to 5.)
- ECG telemetry: QRS (safety)(Day 1 of treatment periods 1 to 5.)
- ECG telemetry: QT interval (safety)(Day 1 of treatment periods 1 to 5.)
- Peak expiratory flow rate (PEFR)(Day -1 to 6 for treatment periods 1 and 2. Day -1 to 7 and day 8 and 16 of treatment periods 3 to 5. Day 21 of treatment period 5.)
- FEV1 (safety)(Day -1 of treatment periods 1 to 5.)
- Pulse oximetry(Day 1 and 2 of treatment periods 1 to 5. Day 21 of treatment periods 3 to 5.)