28 Day Repeat Dose in Cystic Fibrosis Patients

AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.

Vital signs included heart rate, systolic and diastolic blood pressure and body temperature. Prior to vital signs all participants rested for at least five minutes in the seated, semi-supine, or supine position. The choice of position was kept constant for the duration of the study. Any results falling outside the normal range were repeated at the discretion of the Investigator. Potential clinical concern range for systolic blood pressure: <85 and >160 millimeter of mercury (mmHg), for diastolic: <45 and >100 mmHg and heart rate: <40 and >110 beats per minute. Number of participants with vital signs of potential clinical importance are presented.

Hematology parameters were reviewed prior to participants receiving first dose of study medication. The potential clinical concern range for hematology parameters were: Red blood cell (RBC) count (low: < 3.72 * 10^12/Liters (L) and high: > 6.313 * 10^12/L), lymphocytes (low: < 0.8 gigacells/L), hematocrit (low: > 0.075 ratio change from Baseline and high: > 0.54 ratio), mean cell hemoglobin (MCH) (low: < 23.8 picograms (pg) and high: > 39.6 pg), mean cell volume (MCV) (low: <73 femtoliters (FL) and high: >110 FL), platelet count (low: < 100 gigacells/L and high: > 550 gigacells/L), white blood cell (WBC) count (low: < 3 gigacells/L and high: > 20 gigacells/L) and eosinophils (high: > 1 gigacells/L). Only those parameters for which at least one value of potential clinical concern was reported are summarized. Number of participants with hematology abnormalities of potential clinical importance are presented.

The potential clinical concern range for clinical chemistry parameters were: glucose (low: < 2.8 millimole [mmol]/L and high: > 9.4 mmol/L), creatine kinase (high: > 3 * upper limit of normal units [ULN]/L), phosphorous, inorganic (low: < 0.8 mmol/L and high: > 1.6 mmol/L), total bilirubin (high: ≥ 1.5 * ULN micromole [μmol]/L), uric acid (low: < 41.636 μmol/L and high: > 582.904 μmol/L), alkaline phosphatase (ALP) (high: ≥ 2 * ULN international units [IU/L]/L), gamma glutamyl transpeptidase (GGT) (high: ≥ 110 IU/L), carbon dioxide content (low: < 18 mmol/L and high: > 32 mmol/L), direct bilirubin (high: > 1.5 * ULN μmol/L), potassium (low: < 3.0 mmol/L and high: > 5.5 mmol/L) and aspartate aminotransferase (AST) (high: ≥ 3* ULN IU/L). Only those parameters for which at least one value of potential clinical concern was reported are summarized. Number of participants with clinical chemistry abnormalities of potential clinical importance.

Prior to ECG recordings, all participants rested for at least 5 minutes in the seated, semi-supine, or supine position. The choice of position was kept constant for the duration of the study. Participants avoided hot and cold food for at least 30 minutes prior to an ECG measurement. Any results falling outside normal range were repeated at the discretion of the Investigator. ECG Baseline values taken within 2.5 hours prior to first dose were calculated using the mean value of triplicate pre-dose readings. Triplicate readings were taken at least five minutes apart. Participants agreed to abstain from hot and cold drinks and food prior to an ECG measurement. ECG machine calculated heart rate and measured PR, QRS, QT, and QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) intervals. Number of participants with abnormal (not clinically significant [NCS] and clinically significant [CS]) electrocardiogram (ECG) findings are presented.

CF is one of the most common, lethal, autosomal recessive disease characterized by airway obstruction, bronchiectasis and infection, and exocrine pancreatic insufficiency. Number of participants with CF exacerbation are presented.

Bacterial colony count of both Pseudomonas aeruginosa and Staphylococcus aureus in sputum were performed. Participants were graded as no bacteria in sputum, 1+, 2+, 3+ and 4+, which indicated proportional concentration of Pseudomonas aeruginosa and Staphylococcus aureus in sputum, where no bacteria indicated there was no bacteria in sputum, 1+ indicated slightly positive and 4+ indicated highly positive. Higher grades (4+) indicated worst outcomes (highly infected sputum). Number of participants with Pseudomonas aeruginosa and staphylococcus aureus count in sputum are presented.

Sputum samples were taken after bronchodilation and number of neutrophils in induced sputum were reported.

Sputum samples were taken after bronchodilation and percentage of neutrophils in induced sputum are presented.

Sputum samples were taken after bronchodilation. Mean induced sputum inflammatory markers namely Myeloperoxidase and neutrophil elastase are presented.

Blood samples intended for CC-16 and CXCL8 were collected in 5.0 milliliter (mL) serum separator goldtopped blood collection tubes, then immediately mixed by gentle inversion 10 times. The samples were permitted to coagulate for 30 to 60 minutes before centrifugation at 1600 g for 15 minutes. Two 0.75 mL aliquots of serum supernatant were transferred separately into two Sarstedt tubes and frozen at -70 degree Celsius (°C). Plasma samples intended for CC-16 and CXCL8 were centrally analyzed using a commercial test kit based on enzyme-linked immunosorbent assay (ELISA) method.

Blood samples intended for C-Reactive Protein (CRP) analysis were collected in 4.0 mL plain red-topped blood collection tubes. The samples were permitted to coagulate for 30 to 60 minutes before centrifugation at 1600 gram (g) for 15 minutes. A 1 mL volume of serum supernatant was transferred via pipette into a Nunc tube and stored at room temperature. Central analysis of CRP in serum samples was measured via fixed time nephelometry on the Behring Nephelometer II.

Blood samples intended for fibrinogen analysis were collected in 4.5 mL 3.2 % sodium citrate blue-topped blood collection tubes, then immediately mixed by gentle inversion eight to ten times. Each sample was centrifuged at 1600 g for 15 minutes. A 1 mL volume of plasma supernatant was transferred via pipette into a Nunc tube, frozen at -20°C. Central analysis of fibrinogen in plasma samples was completed via photometric clot detection with automatic sample preparation.

Blood samples intended for MMP-8 and MMP-9 analyses were collected in 4.0 mL lithium heparin greentopped collection tubes, then immediately mixed by gentle inversion five times. The samples were centrifuged at 1800 g for 15 minutes within 30 minutes of collection. A 2 mL volume of supernatant was transferred into a Sarstedt tube and subsequently centrifuged at 10000 g for 10 minutes at 2 to 8°C for complete platelet removal. A 1 mL volume of plasma supernatant was transferred into a Sarstedt tube and frozen at -70°C. Blood samples intended for SP-D were collected in 5.0 mL serum separator goldtopped blood collection tubes, then immediately mixed by gentle inversion 10 times. The samples were permitted to coagulate for 30 to 60 minutes before centrifugation at 1600 g for 15 minutes. Two 0.75 mL aliquots of serum supernatant were transferred separately into two Sarstedt tubes and frozen at -70°C. Plasma samples were centrally analyzed using a commercial test kit based on ELISA method.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.

Blood samples were taken via an indwelling cannula (or by direct venepuncture), collected into a 3.0 mL Ethylenediaminetetraacetic acid (EDTA) lavender-topped collection tube, immediately mixed by gentle inversion ten times, then placed on water ice. The samples were centrifuged at 1600 g for 15 minutes at 4°C for 10 minutes. Supernatant plasma was transferred to a 1.8 mL Nunc tube and frozen at -20°C.

Blood samples were taken via an indwelling cannula (or by direct venepuncture), collected into a 3.0 mL EDTA lavender-topped collection tube, immediately mixed by gentle inversion ten times, then placed on water ice. The samples were centrifuged at 1600 g for 15 minutes at 4°C for 10 minutes. Supernatant plasma was transferred to a 1.8 mL Nunc tube and frozen at -20°C.

Blood samples were taken via an indwelling cannula (or by direct venepuncture), collected into a 3.0 mL EDTA lavender-topped collection tube, immediately mixed by gentle inversion ten times, then placed on water ice. The samples were centrifuged at 1600 g for 15 minutes at 4°C for 10 minutes. Supernatant plasma was transferred to a 1.8 mL Nunc tube and frozen at -20°C.