Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Study to Evaluate the Efficacy and Safety of 15mg BID Losmapimod (GW856553) Compared to Placebo in Frequently Exacerbating Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02299375
• Other study ID #: 201496
• Status: Completed
• Phase: Phase 2
• Start date: December 9, 2014
• Est. completion date: June 30, 2016

Study information

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

Clinical Trial Summary

This is a randomised, double-blind, parallel-group, multi-centre study evaluating 15 milligram (mg) twice daily/ Bi-daily (BID) of losmapimod versus placebo, in addition to standard of care (SoC).

The primary objective of this study is to explore the therapeutic potential of losmapimod as a treatment to reduce the rate of exacerbations in the subset of participants with moderate-to-severe COPD who are at high risk of exacerbation, having experienced two or more moderate/severe exacerbations in the preceding 12 months, and who have <=2% of blood eosinophils at screening. As secondary objectives safety, effects on lung function, quality of life, pharmacokinetic (PK), biomarkers of both disease and inflammation shall be evaluated.

The duration of the treatment period is variable but will be at least 26 weeks and up to a maximum of 52 weeks, with the end of study date being established once the final participant has been randomized. The purpose of the variable dosing regimen is to enable participants to remain in the study for a longer duration, as it is anticipated that this will increase the likelihood of observing exacerbation events without increasing the overall study duration. It will also enable safety data on dosing periods beyond 6 months to be generated.

Approximately 200 participants in a 1:1 ratio between losmapimod and placebo will be randomized to the study. Sample size re-estimation will be performed during the course of the study to potentially increase the sample size up to a maximum of 600 participants.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 184
• Est. completion date: June 30, 2016
• Est. primary completion date: June 30, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• COPD diagnosis and severity: Participants with a clinical history of COPD (established by a physician) in accordance with the following definition by the American Thoracic Society/European Respiratory Society, for at least 6 months prior to enrolment. Participants must have evidence of airflow obstruction, defined as post-bronchodilator FEV1 equal to or less than 80% of predicted normal value calculated using "Third National Health and Nutrition Examination Survey" (NHANES III) reference equation at Visit 1 and a FEV1 / FVC ratio <=70% at Screening (Visit 1). Note: Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the participants has self-administered 4 inhalations (i.e., total 400/360 [microgram] mcg) of salbutamol/albuterol via a Metered Dose Inhaler (MDI) (use of spacer will be optional). The study-provided central spirometry equipment will calculate the FEV1/FVC ratio and FEV1 percent predicted values.

• Exacerbation History: A documented history (e.g., medical record verification) in the 12 months prior to Visit 1 of >=2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalisation or extended observation in a hospital emergency room or outpatient centre. Note: Prior use of antibiotics alone does not qualify as a moderate exacerbation unless the use was specifically for the treatment of worsening symptoms of COPD.

• Existing COPD maintenance treatment: Participants must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. Notes: Participants receiving only "pro re nata" or as needed (PRN) COPD medications are not eligible for inclusion in the study. All participants will continue on their current Standard of Care (SoC) COPD medications throughout the entire duration of the study.

• Tobacco use: Participants with a current or prior history of >=10 pack-years of cigarette smoking at Screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. One pack year =20 cigarettes smoked per day for 1 year or the equivalent. Number of pack years=(number of cigarettes per day/20) x number of years smoked.

• Sex: Male or female participants aged >=40 years at Screening (Visit 1). A female participant is eligible to participate if she is of non-child bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international unit/milliliter (MIU/mL) and estradiol <40 picogram/milliliter (pg/mL) (<140 [Picomoles per liter] pmol/L) is confirmatory] or if of child-bearing potential is using a highly effective method for avoidance of pregnancy from 30 days before the first dose, for the duration of dosing and until 2 weeks post last-dose.

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

• Corrected ECG QT interval (QTc)<450 milliseconds(msec) or QTc<480 msec for participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual over-read. For eligibility and withdrawal, ideally the same QT correction formula will be used for all participants. However, because this is not always possible, the same QT correction formula will be used for each individual participant to determine eligibility for and withdrawal from the study. The QTc will be based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period.

Exclusion Criteria:

• Eosinophils: >2.0% blood eosinophils at Screening (Visit 1)

• Concomitant medication: COPD Medication: Participants currently on chronic treatment with macrolides or Roflumilast; Long term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen PRN use (i.e. <=12 hours per day) is not exclusionary. Multidrug and toxin extrusion (MATE) transporter 1 (MATE1) inhibitors: cimetidine, pyrimethamine, trimethoprim (short course treatment with trimethoprim is allowed). Other medications: Chronic maintenance therapy with anti-Tumor Necrosis Factor (anti-TNF), anti-Interleukin-1 (anti-IL1), phosphodiesterase type 4 (PDE4) inhibitors, or any other immunosuppressive therapy (not including steroids) within 60 days prior to dosing. Any other investigational drug within 30 days or 5 half lives, whichever is longer prior to Screening Visit.

• Other respiratory disorders: Participants with asthma (as primary diagnosis) lung cancer, bronchiectasis, active sarcoidosis, active lung fibrosis, cystic fibrosis, idiopathic pulmonary hypertension, active interstitial lung diseases or other active pulmonary diseases. Participants with alpha-1-antitrypsin deficiency as the underlying cause of COPD.

• Participants with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device.

• Participants who require a non-invasive positive pressure ventilation (NIPPV) device (Note: Use of non invasive ventilation (NIV) in hospital as part of the medical management of an acute exacerbation is permitted.)

• Lung resection: Participants who have undergone previous lung reduction surgery (e.g. lobectomy, pneumonectomy, or lung volume reduction).

• COPD stability: Less than 30 days prior to Visit 1 have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.

• Evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD on chest X-ray (posteroanterior with lateral) or computerised tomography (CT) scan (historic data up to 1 year may be used).

• Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.

• Alanine aminotransferase (ALT) >2x Upper limits of normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

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

• Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Participants that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded).

• Other diseases/abnormalities: History or current evidence of clinically significant or uncontrolled cardiovascular, pulmonary, metabolic, neurological, endocrine (including uncontrolled diabetes or thyroid disease), renal, hepatic, haematological (including agranulocytosis) or gastrointestinal conditions that are uncontrolled on permitted therapy and in the opinion of the investigator and/or GSK Medical Monitor, places the participant at an unacceptable risk as participant in this trial or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study

• Viral infections: Presence of hepatitis B surface antigen (HBsAg), Hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase chain reaction (PCR) test is obtained.

• A positive test for human immunodeficiency virus (HIV) antibody

• Tuberculosis (TB): Participant with active TB or who have previously tested positive for latent TB and not received treatment or prophylaxis following the positive test.

• Vaccination: Participants who have received live attenuated vaccines in the 6 weeks prior to randomization. The use of live attenuated vaccines during the treatment period and in the 4 weeks post-discontinuation of investigational product is prohibited.

• Drug/food allergy: Participants with a history of hypersensitivity to any of the study medications (e.g., lactose, magnesium stearate).

• Lactating females

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

• Drug/alcohol abuse: Participants with a known or suspected history of alcohol or drug abuse within the last 2 years.

• Prior use of study medication/other investigational drugs: Participants who have received an investigational drug within 30 days of entry into this study or within 5 drug half-lives of the investigational drug, whichever is longer.

• Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.

• Inability to read: In the opinion of the investigator, any participant who is unable to read and/or would not be able to complete study related materials.

• Non-compliance: Participants at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.

• Questionable validity of consent: Participants with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Losmapimod tablets
Losmapimod tablets will be provided as 15 mg strength in a formulation containing lactose. Administered orally, twice daily approximately 12 hours apart and with food and water for the duration of the treatment period. Participants will be instructed to take their medication with a full glass of water twice-daily within 30 minutes after meals for the duration of their treatment period.
• Placebo tablets
Placebo tablets will be provided in a formulation containing lactose and visually matching the losmapimod tablets. Administered orally, twice daily approximately 12 hours apart and with food and water for the duration of the treatment period. Participants will be instructed to take their medication with a full glass of water twice-daily within 30 minutes after meals for the duration of their treatment period
• Salbutamol MDI
Salbutamol MDI will be provided as a rescue medication.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Mendoza
Argentina	GSK Investigational Site	Mendoza
Argentina	GSK Investigational Site	San Miguel de Tucumán
Brazil	GSK Investigational Site	São Paulo
Bulgaria	GSK Investigational Site	Dimitrovgrad
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Svoge
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago
Chile	GSK Investigational Site	Talca	Región Del Maule
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dueren	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Koblenz	Rheinland-Pfalz
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Potsdam	Brandenburg
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Seoul
Slovakia	GSK Investigational Site	Humenne
Slovakia	GSK Investigational Site	Poprad
Slovakia	GSK Investigational Site	Sala
Slovakia	GSK Investigational Site	Spisska Nova Ves
Slovakia	GSK Investigational Site	Vrable
Spain	GSK Investigational Site	(Barakaldo) Vizcaya
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	L'Hospitalet De Llobregat. Barcelona
Spain	GSK Investigational Site	Pozuelo De Alarcón/Madrid
Spain	GSK Investigational Site	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Argentina,  Brazil,  Bulgaria,  Chile,  Germany,  Korea, Republic of,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annual Rate of Moderate and Severe Exacerbations of COPD	An exacerbation of COPD, is defined as the worsening of 2 or more major symptoms (dyspnea, sputum volume, sputum purulence) or the worsening of any 1 major symptom together with any 1 of the minor symptoms (sore throat, cold, fever without other cause, increased cough and wheeze), for at least 2 consecutive days. Moderate-severe exacerbations were defined as use of antibiotics and/or oral steroids and/or hospitalization. Summary only included exacerbations for which a date of resolution or death was provided. Analysis was performed by using Bayesian inference assuming non-informative priors. The mean exacerbation rate was adjusted for treatment group, smoking status, ICS use and region. The adjusted posterior median was summarized per treatment group. The number of exacerbation events per participant was assumed to follow a negative binomial distribution. Modified Intent-to-Treat (mITT) Population comprised of all randomized par. who received at least one dose of study treatment.	From the start of the study treatment up to 53 Weeks
Secondary	Time to First Occurrence of Moderate or Severe COPD Exacerbation	The time to first moderate-severe COPD exacerbation in par. treated with losmapimod compared to placebo treated par. was evaluated. The time to the first on-treatment moderate-severe exacerbation was calculated as exacerbation onset date of first on-treatment exacerbation minus exposure start date plus 1. No statistical analysis was conducted. Data was summarized statistically only.	From the start of the study treatment up to 53 Weeks
Secondary	Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinaemia were categorized as SAE. AEs were considered as on-treatment If AE onset date is on or after treatment start date & on or before treatment stop date. par. having any AE or SAE were included in analysis.	From the start of the study treatment up to 53 Weeks
Secondary	Change From Baseline in Spirometry Parameters in Pre and Post Forced Expiratory Volume in 1 Second (FEV1); Pre and Post Forced Vital Capacity (FVC); Pre and Post Forced Expiratory Volume in 6 Seconds (FEV6).	Pre and post FEV1, FVC and FEV6 were performed at Screening, Day 1 pre-dose and Weeks 2, 4, 8, 12, 18, 26, 39 and 52. Par. were asked to withheld all bronchodilator therapy included ipratropiumn bromide and salbutamol/albuterol for at least 4 hours prior to prebronchodilator spirometric test. Post-bronchodilator spirometric assessment was performed after inhalation of 400/360 micograms (µg) of salbutamol/albuterol in 10-15 minutes. Day 1 (pre-dose) values were considered as Baseline values. Change from Baseline was calculated as value at the indicated time point minus Baseline value. The maximum value of the 3 replicate assessments were used. Analysis performed using a mixed-effects repeated measures model. The adjusted mean values were summarized per treatment group. Par. were included in the analysis if they had at least one post-baseline measurement. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 52
Secondary	Change From Baseline in Spirometry Parameters in Pre and Post FEV1/FVC, Percent Predicted (PP) FEV1, PP FEV6 and PP FVC	Pre and post FEV1/FVC, PP FEV1, PP FEV6 and PP FVC were assessed at Screening, Day 1 pre-dose and Weeks 2, 4, 8, 12, 18, 26, 39 and 52. Par. were asked to withheld all bronchodilator therapy included ipratropiumn bromide and salbutamol/albuterol for at least 4 hours prior to the prebronchodilator spirometric test. Post-bronchodilator spirometric assessment was performed after inhalation of 400/360 µg of salbutamol/albuterol in 10-15 minutes. Day 1 (pre-dose) values were considered as Baseline values. Change from Baseline was calculated as value at indicated time point minus Baseline value. The maximum value of the 3 replicate assessments were used. Analysis performed using a mixed-effects repeated measures model. The adjusted mean values were summarized per treatment group. Par. were included in the analysis if they had at least one post-baseline measurement. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 52
Secondary	Number of Participants With Electrocardiogram (ECG) Findings	12-lead ECGs were obtained in triplicate at Screening then singly at Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53) using an ECG machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) or QT duration corrected for heart rate by Bazett's formula (QTcB) intervals. Change in ECG findings were categorized as normal and abnormal. Abnormal ECG values could be clinically significant (CS) or not clinically significant (NCS), as determined by the investigator. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Up to 53 Weeks
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points	SBP and DBP were taken at Screening, Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53). Measurements were taken in a semi-recumbent position after 5 minutes rest. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value of an assessment is defined as the value at day 1, pre-dose. Par. were included in the analysis if they had at least one post-baseline measurement. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Heart Rate (HR) Values at the Indicated Time Points	HR was assessed at Screening, Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53). Measurements were taken in a semi-recumbent position after 5 minutes rest. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value of an assessment is defined as the value at day 1, pre-dose. Par. were included in the analysis if they had at least one post-baseline measurement. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Plasma Losmapimod Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the End of Dosing Interval (AUC[0-tau])	Pharmacokinetics (PK) of losmapimod was evaluated in participants with COPD using PK samples collected at pre-dose at Week 2 and Week 12. At Week 26, a sample was collected at pre-dose and a second sample was collected at 2 hours post-dose. Par. of mITT population that provided at least one observed concentration data in this study were considered for PK analysis. Drug plasma concentration-time data were modelled by nonlinear mixed effects modelling. AUC[0-tau] (tau=12 hours) was estimated from the model.	Pre-dose at Weeks 2 and 12; pre-dose and at 2 hours post-dose at Week 26
Secondary	Plasma Losmapimod Maximum Concentration (Cmax) and Lowest Concentration (Ctrough) at Steady State	Pharmacokinetics of losmapimod was evaluated in participants with COPD using PK samples collected at pre-dose at Week 2 and Week 12. At Week 26, a sample was collected at pre-dose and a second sample was collected at 2 hours post-dose. Par. of mITT population that provided at least one observed concentration data in this study were considered for PK analysis (represented by n=X, X in the category titles). Drug plasma concentration-time data were modelled by nonlinear mixed effects modelling to develop a Population PK model. Cmax and Ctrough were estimated from the PK model.	Pre-dose at Weeks 2 and 12; pre-dose and at 2 hours post-dose at Week 26
Secondary	Change From Baseline in Frequency of Short Acting Beta-agonist or Anti-cholinergic Use	Use of short acting bronchodilators (short-acting beta2-agonists or short-acting anti-cholinergic) was allowed and was recorded in daily patient diary. It included inhaled short-acting beta2-agonists (e.g. Ipratropium bromide, salbutamol, Ipratropium/salbutamol (albuterol) combination product) and short-acting anti-cholinergics (e.g., ipratropium bromide3). Use of these medications was allowed throughout the study except 4 hours prior to and during each clinic visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 52
Secondary	Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total, SGRQ Symptoms Score, SGRQ Activity Score and SGRQ Impact Score Over Time	SGRQ-C is a health related quality of life questionnaire consisting of 14 questions. SGRQ-C total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. Components (Activity, Symptoms, Impacts) were calculated as 100 multiplied by summed weights from all positive items in that component divided by sum of weights for all items in that component. Score range for SGRQ-C total is 0-100. Maximum weights for Activity, Symptoms and Impacts component is 982.9, 566.2 and 1652.8 respectively. SGRQ-C was transformed to SGRQ for reporting. Higher scores indicate greater disease impact. Score at Day 1, pre-dose (Week 0) was considered as Baseline. Change from Baseline was calculated as score at indicated time point minus Baseline value. Only those par. with analyzable data at the given time points (represented by n=X, X in category titles) were included in analysis.	Baseline and up to Week 52
Secondary	Number of Participants With Abnormal Liver Events During the Treatment Period	Various liver chemistry parameters were monitored periodically to ensure the safety and tolerability of Losmapimod as compared to placebo. Study treatments were discontinued for par. if alanine aminotransferase (ALT) absolute >= 5xupper limit of normal (ULN) or; ALT >= 3xULN persists for >=4 Weeks or; ALT>=3x ULN and bilirubin >=2xULN or; ALT>=3x ULN and International normalized ratio (INR) >=1.5 or; ALT>=3x ULN and cannot be monitored weekly for 4 Weeks or; ALT>=3x ULN symptomatic.	Up to Week 53
Secondary	Change From Baseline in Hemoglobin, Total Protein, Albumin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate hemoglobin, total protein, albumin and MCHC. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Hematocrit at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate hematocrit. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Absolute White Blood Cell (WBC) Count, Total Neutrophil, Total Lymphocyte, Basophil, Eosinophil, Monocyte and Platelet Count at the Indicated Time Point	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate absolute WBC count, total neutrophil, total lymphocyte, basophil, absolute eosinophil, percentage eosinophil, monocyte and platelet count. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Eosinophil Percentage at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate eosinophil percentage. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Total Bilirubin, Direct Bilirubin, Uric Acid and Creatinine at the Indicated Time Point	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate total bilirubin, direct bilirubin, urice acid and creatinine. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase and Gamma Glutamyl Transferase at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyl transferase at the indicated time point. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Chloride, Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate calcium, chloride, glucose, potassium, sodium and blood urea nitrogenat the indicated time point. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Red Blood Cell Count at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate Red blood cell count. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate mean corpuscle hemoglobin. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53
Secondary	Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points	Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate mean corpuscle volume. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).	Baseline and up to Week 53

External Links

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