Two-part Pharmacokinetic and Pharmacodynamic Study of LAS190792 in Patients With Asthma and COPD

This study is an integrated Phase I protocol divided into 2 parts.

Part one: a single ascending dose study (6 LAS190792 dose levels) in 16 male subjects with mild asthma. LAS190792 will be administered (by the Genuair® inhaler) under supervision at the study centre, according to the randomisation scheme. One dose level will be administered per week with 2 to 3 weeks between each dose level for the safety and pharmacokinetic data review.

Part two: A 5-way , crossover, single dose study (of LAS190792 \[two doses\], indacaterol, tiotropium and placebo) in 40 male and non-childbearing potential women subjects with moderate to severe COPD. Each treatment period will be separated by a washout period of at least 7 to 14 days. The aim is to ensure at least 30 subjects complete Part 2 of the study. The primary comparison for bronchodilation will be between LAS190792 doses and placebo. Other treatment comparisons (indacaterol or tiotropium vs placebo and LAS190792 vs indacaterol or tiotropium) will be considered additional.

• LAS190792 Dose 1 (Drug)
• LAS190792 Dose 2 (Drug)
• LAS190792 Dose 3 (Drug)
• LAS190792 Dose 4 (Drug)
• LAS190792 Dose 5 (Drug)
• LAS190792 Dose 6 (Drug)
• LAS190792 Dose 1 (Part 2) (Drug)
• LAS190792 Dose 2 (Part 2) (Drug)
• Tiotropium 18 μg (Drug), also known as Spiriva
• Indacaterol 150 μg (Drug), also known as Onbrez
• Placebo (Drug)

Primary outcomes

• Subjects With ≥1 Treatment-emergent Adverse Event [30 Days]: Adverse events (AEs) are any unfavorable and unintended medical occurrence during the subject's participation in the study (including deterioration of a pre-existing medical condition, an abnormal value in a laboratory assessment, an ECG abnormality, a 12-lead 24-hour ECG-Holter abnormality, a blood pressure abnormal value, paradoxal bronchospasm or an abnormal finding in the physical examination) and will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA).
• Change From Baseline in Trough FEV1 (Forced Expiratory Volume in 1 Second) [Day 2]: Trough is defined as the mean of the FEV1 values obtained at 23 hours and at 24 hours after morning investigational product administration.

Secondary outcomes

• Maximum Observed Plasma Concentration (Cmax) [Up to 36 hours after investigational product administration]
• Time to Maximum Observed Plasma Concentration (Tmax) [Up to 36 hours after investigational product administration]
• Area Under the Concentration-time Curve From Zero to the Time of the Last Measurable Concentration [Up to 36 hours after investigational product administration]

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria (PART 1):

* Adult male subjects aged 18 to 70 years
* Body mass index (BMI) 18.5 to 30 kg/m2 at screening
* Clinical diagnosis of mild persistent asthma (according to GINA guidelines) for at least 6 months prior to screening
* Ability to change current asthma therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
* Screening FEV1 value of ≥70% of the predicted normal value after a washout of at least 5 h for short-acting beta2-agonists and 72 h for long-acting beta2-agonists
* FEV1 reversibility of ≥12% and an absolute increase of at least 200 mL over the baseline value within 30 min after inhalation of 400 µg of salbutamol
* Subjects using intermittent salbutamol and / or subjects on a stable dose or regimen of low dose ICS (as defined by the GINA guidelines) at least 4 weeks prior to screening
* Predose FEV1 value of first treatment period within the range of ±20% of the FEV1 measured at screening prior to salbutamol inhalation
* Subjects who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
* Normal blood pressure (defined as SBP between 100 and 140 mmHg, and DBP between 50 and 90 mmHg) at screening, measured after resting in supine position for 5 minutes.
* Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator
* Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis B core (HBc) antibody (IgM), hepatitis C antibody and human immunodeficiency virus (HIV) I and II antibodies at screening
* Subjects who are able and willing to provide written informed consent
* Subjects able to perform repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005 criteria at screening

Inclusion Criteria (PART 2):

* Adult male and non-childbearing potential women subjects aged ≥40 years with a clinical diagnosis of stable moderate to severe COPD according to GOLD guidelines at screening
* Females must be of non-childbearing potential, confirmed at screening
* Post-salbutamol FEV1 <80% and ≥30% of the predicted normal value and post-salbutamol FEV1 / forced vital capacity (FVC) <70%
* Ability to change current COPD therapy, to discontinue previous prescribed medications after signature of informed consent
* No evidence of clinically significant respiratory and / or cardiovascular conditions or laboratory abnormalities
* No other relevant pulmonary disease or history of thoracic surgery
* No contraindication to the use of anticholinergic drugs such as known symptomatic prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma, or beta2-agonists usage
* Subjects who are negative for HBsAg, HBc IgM, hepatitis C antibody and HIV I and II antibodies at screening
* Subjects who are able and willing to provide written informed consent
* Subjects able to perform repeatable pulmonary function testing for FEV1 according to the ATS / ERS 2005 criteria at screening

Exclusion Criteria (PART 1 and 2):

* Subjects who do not conform to the above inclusion criteria
* Current smokers, subjects with a smoking history during the last 12 months or subjects with a smoking history of more than 10 pack-years
* Other relevant pulmonary disease or history of thoracic surgery
* Subjects with a BMI ≥40 kg/m2 (only applicable for Part 2)
* Subjects with any clinically relevant history or presence of abnormality from the medical history and/or physical examination (only applicable for Part 1)
* Current evidence or recent history of any clinically significant and unstable disease (other than COPD) or abnormality that could put the subject at risk or could confound the results of the study (only applicable for Part 2)
* Subjects with a surgical history clinically relevant for the purpose of the study
* History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localised basal cell carcinoma of the skin
* Subjects with serious adverse reaction or serious hypersensitivity to Spiriva (for Part 2 only), indacaterol (for Part 2 only), or the formulation excipients (eg, lactose) or other drugs in the same pharmacologic class (for Part 1 and Part 2)
* Current diagnosis of COPD (for Part 1 only) or history of / or current diagnosis for asthma (for Part 2 only)
* Recent history of asthma / COPD exacerbation requiring hospitalisation or need for increased maintenance treatments for asthma / COPD within 6 weeks prior to screening or randomisation
* Use of daily oxygen therapy >10 h per day (for Part 2 only)
* Use of systemic steroids for respiratory reasons within 3 months prior to screening
* Lower respiratory tract infection within 6 weeks prior to screening or randomisation
* Upper respiratory tract infection requiring antibiotics within 4 weeks prior to screening or randomisation
* Current history of tuberculosis, bronchiectasis or other non-specific pulmonary disease
* QTcF interval >430 ms at screening or prior to randomisation, or history of long QT syndrome (for Part 1 only)
* QTcF interval, >450 ms for males and >470 ms for females at screening or prior to randomisation, or history of long QT syndrome (for Part 2 only)
* Subjects with a history of excessive use or abuse of alcohol or with a history of drug abuse within the past 2 years
* Subjects who are positive for drugs of abuse and alcohol tests at screening and prior to randomisation
* Donation or loss >400 ml of blood and plasma within the previous 3 months prior to screening
* Subjects consuming more than 14 (female subjects) or 21 (male subjects) units of alcohol a week
* Subjects with a significant infection or known inflammatory process at screening or prior to randomisation
* Subjects with acute gastrointestinal symptoms at the time of screening or prior to randomisation
* Subjects with an acute infection such as influenza at the time of screening or prior to randomisation
* Male subjects who do not agree to follow instructions to avoid pregnancies
* Subjects who are not able to adhere to the restrictions on prior and concomitant medications
* Subjects who intend to use any concomitant medication not permitted by the protocol or who have not undergone the required washout period for a particular prohibited medication
* Subjects who have used any investigational drug within 3 months prior to screening or within the equivalent time of 6 half-lives of receiving the last administration, whichever is longer
* Subjects who have received the last dose of investigational product more than 3 months ago but who are on an extended follow-up
* Subjects who are vegans or who have medical dietary restrictions
* Subjects unable to communicate reliably with the Investigator
* Subjects who are unlikely to co-operate with the requirements of the study

Participant flow

Outcome results

• Subjects With ≥1 Treatment-emergent Adverse Event (Primary), Number, Participants: LAS190792 5 µg (Part 1) 2; LAS190792 20 µg (Part 1) 3; LAS190792 50 µg (Part 1) 2; LAS190792 100 µg (Part 1) 2; LAS190792 200 µg (Part 1) 2; LAS190792 400 µg (Part 1) 4; Placebo (Part 1) 3; LAS190792 100 µg (Part 2) 12; LAS190792 400 µg (Part 2) 12; Tiotropium 18 μg 14; Indacaterol 150 μg 21; Placebo (Part 2) 15
• Change From Baseline in Trough FEV1 (Forced Expiratory Volume in 1 Second) (Primary), Mean, Liters: LAS190792 5 µg (Part 1) -0.013 +/- 0.333; LAS190792 20 µg (Part 1) 0.161 +/- 0.131; LAS190792 50 µg (Part 1) 0.523 +/- 0.448; LAS190792 100 µg (Part 1) 0.536 +/- 0.170; LAS190792 200 µg (Part 1) 0.371 +/- 0.333; LAS190792 400 µg (Part 1) 0.599 +/- 0.316; Placebo (Part 1) 0.029 +/- 0.144; LAS190792 100 µg (Part 2) 1.369 +/- 0.505; LAS190792 400 µg (Part 2) 1.360 +/- 0.472; Tiotropium 18 μg 1.379 +/- 0.502; Indacaterol 150 μg 1.361 +/- 0.481; Placebo (Part 2) 1.338 +/- 0.506 (p <0.0001)
• Maximum Observed Plasma Concentration (Cmax) (Secondary), Mean, pg/mL: LAS190792 5 µg (Part 1) NA +/- NA; LAS190792 20 µg (Part 1) NA +/- NA; LAS190792 50 µg (Part 1) 8.79 +/- 4.86; LAS190792 100 µg (Part 1) 19.5 +/- 8.45; LAS190792 200 µg (Part 1) 43.9 +/- 16.8; LAS190792 400 µg (Part 1) 59.7 +/- 19.2; LAS190792 100 µg (Part 2) 15.4 +/- 6.39; LAS190792 400 µg (Part 2) 56.2 +/- 10.1
• Time to Maximum Observed Plasma Concentration (Tmax) (Secondary), Median, Hours: LAS190792 5 µg (Part 1) NA (NA to NA); LAS190792 20 µg (Part 1) NA (NA to NA); LAS190792 50 µg (Part 1) 0.25 (0.25 to 0.5); LAS190792 100 µg (Part 1) 0.5 (0.28 to 0.75); LAS190792 200 µg (Part 1) 0.375 (0.25 to 0.5); LAS190792 400 µg (Part 1) 0.517 (0.25 to 0.75); LAS190792 100 µg (Part 2) 0.5 (0.25 to 0.75); LAS190792 400 µg (Part 2) 0.517 (0.317 to 1.0)
• Area Under the Concentration-time Curve From Zero to the Time of the Last Measurable Concentration (Secondary), Mean, pg.h/mL: LAS190792 5 µg (Part 1) NA +/- NA; LAS190792 20 µg (Part 1) 0.106 +/- 0.259; LAS190792 50 µg (Part 1) 5.50 +/- 3.53; LAS190792 100 µg (Part 1) 20.1 +/- 17.3; LAS190792 200 µg (Part 1) 82.7 +/- 43.3; LAS190792 400 µg (Part 1) 122 +/- 57.1; LAS190792 100 µg (Part 2) 20.5 +/- 15.4; LAS190792 400 µg (Part 2) 127 +/- 67.2

Adverse events

Time frame: Up to 14 (±2) days after the last investigational product administration or after premature discontinuation.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: In Part 1, many plasma concentrations at 50-100µg dose levels were BLOQ; thus only limited PK data were obtained for AUC(0-t), with plasma concentrations generally detected up to 1h post-administration; and at 200-400µg, up to 6 or 12h, respectively