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Completed

NCT Number: NCT07272135

Selective β2-AR Antagonism in Asthma

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.

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Key information

Conditions

Asthma Bronchial Diseases Hypersensitivity Hypersensitivity, Immediate Immune System Diseases Lung Diseases Lung Diseases, Obstructive Respiratory Hypersensitivity Respiratory Tract Diseases

Age range

21 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Hammersmith Medicines Research

London, NW10 7EW, United Kingdom

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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
  • 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.

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
  • Positive polymerase chain reaction (PCR) test for SARS-CoV-2 virus
  • Subjects who have not received both doses of a COVID-19 vaccine.

Treatment and study plan

TR4

Drug

TR4 is a selective beta-2-adrenoceptor antagonist. TR4 will be weighed into opaque capsules and released for individual patients, in accordance with good manufacturing practice (GMP).

Placebo

Other

Placebo capsules will contain start in opaque capsules.

Primary outcomes

  1. Mannitol (PD15)

    Time frame: Baseline (day -1) of treatment periods 1 to 5.

    The dose of mannitol causing a 15% fall in FEV1

  2. Mannitol (PD15)

    Time frame: Day 21 of treatment period 5.

    The dose of mannitol causing a 15% fall in FEV1

  3. Spirometry (FEV1)

    Time frame: Day 1 of treatment periods 1 to 5.

    Lung function test: The forced expiratory volume in 1 second (FEV1).

  4. Spirometry (FEV1)

    Time frame: Day 2 of treatment periods 1 to 5.

    Lung function test: The forced expiratory volume in 1 second (FEV1).

  5. Spirometry (FEV1)

    Time frame: Day 21 of treatment period 5.

    Lung function test: The forced expiratory volume in 1 second (FEV1).

  6. Spirometry (FVC)

    Time frame: Day 1 of treatment periods 1 to 5

    Lung function test: forced vital capacity (FVC)

  7. Spirometry (FVC)

    Time frame: Day 2 of treatment periods 1 to 5

    Lung function test: forced vital capacity (FVC).

  8. Spirometry (FVC)

    Time frame: Day 21 of treatment period 5

    Lung function test: forced vital capacity (FVC).

  9. Spirometry (FEF 25-75)

    Time frame: Day 1 of treatment periods 1 to 5

    Lung function test: forced mid-expiratory flow (FEF 25-75) is the mean forced expiratory flow during the middle half of the FVC.

  10. Spirometry (FEF 25-75)

    Time frame: Day 2 of treatment periods 1 to 5

    Lung function test: the forced mid-expiratory flow (FEF 25-75) is the mean forced expiratory flow during the middle half of the FVC.

  11. 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

  12. Spirometry (FEV1/FVC)

    Time frame: Day 1 of treatment periods 1 to 5.

    Lung function test: FEV1 as a percentage of FVC (FEV1/FVC).

  13. Spirometry (FEV1/FVC)

    Time frame: Day 2 of treatment periods 1 to 5.

    Lung function test: FEV1 as a percentage of FVC (FEV1/FVC).

  14. Spirometry (FEV1/FVC)

    Time frame: Day 21 of treatment period 5.

    Lung function test: FEV1 as a percentage of FVC (FEV1/FVC).

  15. 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.

  16. 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.

  17. IOS (AX)

    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 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.

  18. 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.

  19. Airway nitric oxide (FeNO)

    Time frame: Change between baseline (day -1) and day 1 of treatment periods 1 to 5.

    FeNO will be measured using the NIOX Viro handheld electronic device.

  20. Airway nitric oxide (FeNO)

    Time frame: Day 21 of treatment period 5.

    FeNO will be measured using the NIOX Viro handheld electronic device.

  21. Blood eosinophils

    Time frame: Day -1 of treatment periods 1 to 5.

    Blood eosinophils concentration will be used as an inflammatory marker.

  22. Blood eosinophils

    Time frame: Day 21 of treatment period 5.

    Blood eosinophils concentration will be used as an inflammatory marker.

Secondary outcomes

  1. Vital signs (safety): Blood pressure

    Time frame: Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.

    Vital signs are assessed to determine safety and tolerability of treatment.

  2. Vital signs (safety): Heart rate

    Time frame: Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.

    Vital signs are assessed to determine safety and tolerability of treatment.

  3. Vital signs (safety): Respiratory rate

    Time frame: Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.

    Vital signs are assessed to determine safety and tolerability of treatment.

  4. Vital signs (safety): Oral temperature

    Time frame: Day 1 and 2 of treatment periods 1 to 5. Day 21 and 22 of treatment periods 3 to 5.

    Vital signs are assessed to determine safety and tolerability of treatment.

  5. Safety tests of blood and urine

    Time frame: Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.

    Blood and urine for safety tests will be collected before dosing. Blood will be taken for haematology (2 mL in EDTA), and biochemistry and serology (2 x 3.5 mL).

  6. 12-lead ECG: Ventricular rate (safety)

    Time frame: Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.

    12-lead ECG will be taken to assess safety and tolerability of treatment. Ventricular rate will be assessed.

  7. 12-lead ECG: PR interval (safety)

    Time frame: Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.

    12-lead ECG will be taken to assess safety and tolerability of treatment. The PR interval is the time from the onset of the P wave to the start of the QRS complex.

  8. 12-lead ECG: QRS (safety)

    Time frame: Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.

    12-lead ECG will be taken to assess safety and tolerability of treatment. The QRS complex is the combination of the Q, R and S waves.

  9. 12-lead ECG: QT interval (safety)

    Time frame: Day 1 of treatment periods 1 to 5 and day 22 of treatment periods 3 to 5.

    12-lead ECG will be taken to assess safety and tolerability of treatment. Corrected QT interval using the Frederica formula (QTcF).

  10. ECG telemetry: Ventricular rate (safety)

    Time frame: Day 1 of treatment periods 1 to 5.

    The ECG will be monitored continuously from 30 min before until 24h after dosing, using a SpaceLabs system.

  11. ECG telemetry: PR interval (safety)

    Time frame: Day 1 of treatment periods 1 to 5.

    The ECG will be monitored continuously from 30 min before until 24h after dosing, using a SpaceLabs system.

  12. ECG telemetry: QRS (safety)

    Time frame: Day 1 of treatment periods 1 to 5.

    The ECG will be monitored continuously from 30 min before until 24h after dosing, using a SpaceLabs system.

  13. ECG telemetry: QT interval (safety)

    Time frame: Day 1 of treatment periods 1 to 5.

    The ECG will be monitored continuously from 30 min before until 24h after dosing, using a SpaceLabs system.

  14. Peak expiratory flow rate (PEFR)

    Time frame: 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.

    Subjects will be given a PEFR meter. A drop of 20% of a subject's normal PEFR is considered in the normal range.

  15. FEV1 (safety)

    Time frame: Day -1 of treatment periods 1 to 5.

    Forced expiratory volume in 1 second.

  16. Pulse oximetry

    Time frame: Day 1 and 2 of treatment periods 1 to 5. Day 21 of treatment periods 3 to 5.

    Pulse oximetry is a non-invasive method for monitoring the saturation of oxygen in the peripheral blood, which will be measured using the SpaceLabs Patients Care Monitoring System (PCMS) and a standard HMR SOP.

Other outcomes

  1. Plasma TR4 and metabolite concentration

    Time frame: Blood samples (4 mL) will be taken on day 1 of treatment periods 1 to 5.

    Plasma concentrations of TR4 and metabolites will be listed and summarised by treatment, using descriptive statistics. Individual pharamcokinetic (PK) parameters will be calculated.

  2. Plasma annexin-A1

    Time frame: Blood samples (5 mL) will be taken on day -1 of treatment periods 1 to 5 and day 21 of treatment period 5.

    Annexin-A1 is a global anti-inflammatory protein and its receptor levels are known to be modulated in asthmatics. The investigators are using it as an inflammatory biomarker and will measure concentration in plasma using a validated ELISA method.

  3. Lymphocyte beta-2-adrenoceptor density

    Time frame: Blood samples (8 mL) will be taken on day -1 of treatment periods 1 to 5 and day 21 of treatment period 5.

    Flow-cytometry assay used to measure cell-surface density of beta-2-adrenoceptor on lymphocyte subtypes.

Sponsors and collaborators

Lead sponsor

Trio Medicines Ltd.

Industry

Collaborators

  • Hammersmith Medicines Research

Registry information

Official study title

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

Important dates

Study start
2018
Primary completion
2022
Study completion
2022
First posted
Dec 9, 2025
Registry last updated
Dec 9, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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