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
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Trio Medicines Ltd.
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Spirometry (FEF 25-75)
Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 21 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
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.
Intervention: TR4 (Drug)
Placebo
Three patients will take matching placebo capsules in a similar manner to TR4.
Intervention: Placebo (Other)
Outcomes
Primary Outcomes
Spirometry (FEF 25-75)
Time Frame: 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)
Time Frame: Day 21 of treatment period 5.
Lung function test: FEV1 as a percentage of FVC (FEV1/FVC).
Mannitol (PD15)
Time Frame: Day 21 of treatment period 5.
The dose of mannitol causing a 15% fall in FEV1
Spirometry (FEV1)
Time Frame: Day 21 of treatment period 5.
Lung function test: The forced expiratory volume in 1 second (FEV1).
Spirometry (FVC)
Time Frame: Day 21 of treatment period 5
Lung function test: forced vital capacity (FVC).
Impulse oscillometry (IOS) (R5, R5-R20)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: Day 21 of treatment period 5.
FeNO will be measured using the NIOX Viro handheld electronic device.
Blood eosinophils
Time Frame: Day 21 of treatment period 5.
Blood eosinophils concentration will be used as an inflammatory marker.
Secondary Outcomes
- 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.)