A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Dose-Response Relationship of Multiple Doses of GSK2269557 Administered as a Dry Powder to Chronic Obstructive Pulmonary Disease (COPD) Patients

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Double-Blind (Sponsor Unblind), Placebo Controlled, Randomised, Parallel Group Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Doses of GSK2269557 Administered as a Dry Powder to COPD Patients and Assessment of Dose Response Using Sputum Biomarkers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02130635
• Other study ID #: 115119
• Status: Completed
• Phase: Phase 2
• Start date: July 31, 2014
• Est. completion date: August 18, 2015

Study information

• Verified date: September 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomised, double-blind, placebo controlled, parallel group study to evaluate the safety, tolerability, pharmacokinetics and dose response of multiple doses of GSK2269557 administered as a dry powder in COPD subjects. Pharmacodynamic effects on biomarkers will also be assessed. This study will have two parts. In Part A, subjects will be randomized to active or placebo treatment in a 3:1 ratio and in Part B, to placebo or one of the six doses of active treatment in an equal ratio. A sufficient number of COPD subjects (male and female of non-child bearing potential) will be screened to ensure that approximately 30 subjects are enrolled and at least 20 evaluable subjects are obtained for Part A and approximately 35 subjects will be enrolled for Part B. In both the parts, subjects will receive study treatment once daily for 14 consecutive days. Placebo control will be included for a valid evaluation of adverse events attributable to treatment versus those independent of treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: August 18, 2015
• Est. primary completion date: August 18, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

Inclusion Criteria:

• The subject has a confirmed and established diagnosis of COPD, as defined by the Global Initiative for Chronic Obstructive lung Disease (GOLD) guidelines.

• Male or female of non-child bearing potential between 40 and 75 years of age inclusive, at the time of signing the informed consent.

• The subject has a post-bronchodilator [400 microgram (mcg) salbutamol] Maximal amount of air FEV1/FVC <0.7 and FEV1 >=40% to <=80% of predicted (Predictions should be according to the European Community of Coal and Steel (ECCS) equations).

• Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = (cigarettes per day smoked/20) x number of years smoked)).

• The subject is able to produce >100 milligram (mg) of sputum at screening.

• Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 17 - 32 kg/square meter (m^2) (inclusive).

• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, salpingo-oophrectomy or oophrectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-International units (MIU)/millilitre (mL) and estradiol < 40 picogram (pg)/mL (<147 picomole(pmol)/Liter [L]) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.]; or has only same-sex partners, when this is her preferred and usual lifestyle.

• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.

• Based on averaged QTcF values of triplicate ECGs obtained over a brief recording period (e.g. 5 minutes): QTcF <450 millisecond (msec); or QTcF<480 msec in subjects with right bundle branch block.

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

• A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included if the investigator [in consultation with the Glaxosmithkline (GSK) medical monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

Exclusion Criteria:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones and cholecystectomy).

• Subjects who have a past or current medical condition or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension) are permitted to be entered into the study).

• Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the Investigator, compromise the safety of the subject or affect the interpretation of the results.

• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

• History of sensitivity to any of the study medications, or components (such as lactose) thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.

• A positive test for Human immunodeficiency virus (HIV) antibody - tested according to local policies.

• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include cannabinoids, amphetamines, barbiturates, cocaine and opiates. The detection of drugs (e.g. benzodiazepines, opiates) taken for a legitimate medical purpose would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.

• A positive pre-study Hepatitis B surface antigen (HBs-Ag) or positive total hepatitis B core antibody (anti-HBc IgM) or positive Hepatitis C antibody result within 3 months of screening.

• Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

• Lactating females.

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

• Subject has poorly controlled or unstable COPD, defined as the occurrence of any of the following: Either: acute worsening of COPD (an exacerbation) that is managed by the subject at home requiring treatment with corticosteroids and/or antibiotics in the 4 weeks prior to the screening visit; or more than two exacerbations in the previous 2 months prior to the screening visit that required a course of oral corticosteroids and/or antibiotics, or for which the subject was hospitalised.

• Subject has had a respiratory tract infection treated with antibiotics in the 4 weeks prior to first dose.

• Subject requires regular treatment with oral corticosteroids or has received oral or parenteral corticosteroids within 4 weeks of screening.

• Vulnerable subject (e.g., person kept in detention).

• The subject is not able to understand and communicate in German or native language.

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• GSK2269557 100 MCG
100 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device
• GSK2269557 500 MCG
500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device
• PLACEBO
Lactose administered using a matching dry powder inhaler device

Locations

Country	Name	City	State
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as 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, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.	From the start of study treatment until follow-up (assessed for approximately 19 days)
Primary	Part A: Change From Baseline in Counts of White Blood Cells (WBC), Total Neutrophils (Total Absolute Neutrophil Count [ANC]), Lymphocytes, Monocytes, Eosinophils, Basophils, and Platelets at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 h post-dose)
Primary	Part A: Change From Baseline in Hematocrit at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Albumin and Total Protein at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Primary	Part A: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline	Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). Potential clinical concern range for SBP was <85 millimeters of mercury (mmHg) (low) and >160 mmHg (high), for DBP <45 mmHg (low) and >100 mmHg (high) and for HR <40 bpm and >110 bpm. All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.	Day 1, Day 7, and Day 14
Primary	Part A: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline	Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Clinical significance was judged by the investigator. Day 7 assessments could be conducted on Day 7 or Day 8.	Day 1, Day 7, and Day 14
Primary	Part A: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points	Baseline is Day 1 pre-dose. FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded. Baseline was the maximum of the planned pre-dose measurements on Day 1. Change from Baseline at any post-dose time point was calculated as the post-dose value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 1 (1 h post-dose), Day 7 (pre-dose and 1 h post-dose), and Day 14 (24 h post-dose)
Primary	Part B: Adjusted Median Response of Cytokine (Interleukin 6 [IL6], Interleukin 8 [IL8], Tumor Necrosis Factor Alpha [TNFalpha]) Concentrations in Induced Sputum, on Day 7 and Day 14	This outcome measure was used to estimate the inhibition levels of various doses of GSK2269557 by analyzing inflammatory cytokines IL6, IL8, and TNF alpha using Bayesian methods of statistical analysis, using non-informative prior distributions for all modeling parameters. Posterior medians (adjusted median response) and 95% credible intervals are reported here as medians and 95% confidence intervals respectively. 95% credible interval is reported as 2-sided 95% confidence in the statistical analyses. Day 7 assessments could be conducted on Day 7 or Day 8.	Day 7 (pre-dose) and Day 14 (24 h post-dose)
Secondary	Part A: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose	A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Only those participants who were available at the indicated time points were analyzed (represented by n=X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.	Day 1 (Pre-dose, 5 min, 30 min, 1, 2, 4 & 6 hours post-dose)
Secondary	Part B: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose	A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Concentration measurements were log-transformed. Only those participants who were available at the indicated time points were analyzed (represented by n=X,X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.	Pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, and 6 h post-dose on Day 1
Secondary	Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7	Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Day 7 sampling could be done on Day 7 or Day 8.	Day 7 immediately after dosing
Secondary	Part B: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7	Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Concentration values were log-transformed. Day 7 sampling could be done on Day 7 or Day 8.	Day 7 immediately after dosing
Secondary	Part A: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15	Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.	Day 7 and Day 15
Secondary	Part B: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15	Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.	Day 7 and Day 15
Secondary	Part B: Number of Times Rescue Medication Was Used by Participants Daily, During the Treatment Period	Rescue medication was identified from concomitant medication records and the patient diaries which were provided to the participants to record data throughout the treatment period. Only participants who used rescue medication were analyzed. The value NA indicates that the standard deviation could not be calculated as only one participant was analyzed.	Day 1 to Day 15
Secondary	Part B: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as 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, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.	From the start of study treatment until follow-up (assessed for approximately 19 days)
Secondary	Part B: Change From Baseline in Counts of Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets, White Blood Cells (WBC), Total Neutrophils (Total ANC) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Hematocrit at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Albumin and Total Protein at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)
Secondary	Part B: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline	Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.	Day 1, Day 7, and Day 14
Secondary	Part B: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline	Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Day 7 assessments could be conducted on Day 7 or Day 8.	Day 1, Day 7, and Day 14
Secondary	Part B: Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at Screening and Follow-up	FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded.	Screening (up to 30 days prior to Day 1) and Follow-up (approximately Day 19)

External Links

•   IPD for this study will be made available via the Clinical Study Data Request site.