28 Day Repeat Dose in Cystic Fibrosis Patients

Cystic Fibrosis Clinical Trial

Official title:

A Randomized, Double Blind, Parallel Group, Placebo Controlled 28 Day Study to Investigate the Safety, Tolerability and Pharmacodynamics of SB-656933 in Patients With Cystic Fibrosis.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00903201
• Other study ID #: 110399
• Status: Completed
• Phase: Phase 2
• First received: May 14, 2009
• Last updated: October 16, 2017
• Start date: September 28, 2009
• Est. completion date: December 29, 2010

Study information

• Verified date: August 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether the safety, tolerability and pharmacodynamics of SB656933 in patients that have cystic fibrosis

Description:

This proof of mechanism study aims to evaluate the safety, tolerability and pharmacodynamics of SB-656933 following 28 days of daily administration of 20 and 50 mg SB-656933 in patients with CF compared to placebo. The primary endpoints of the study will be the effect of SB-656933 on safety and tolerability (adverse events, vital signs, clinical laboratory assessments, 12-lead electrocardiograms, and urinalysis) following 28 days of dosing. Secondary endpoints will include levels of neutrophil elastase in induced sputum and other sputum markers of inflammation (e.g. myeloperoxidase, total protein), induced sputum cells (i.e. total sputum neutrophil counts, percent sputum neutrophils) and sputum microbiology. Other assessments will include lung function measurements (spirometry); serum and plasma markers of inflammation (e.g. fibrinogen, CC-16, CRP, MMP8, MMP9, SP-D, and CXCL-8), quality of life questionnaire, and population pharmacokinetics parameters of SB-656933

Other known NCT identifiers

• NCT01051453

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: December 29, 2010
• Est. primary completion date: December 29, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of CF based on the following: sweat chloride > 60 mEq/L and/or genotype with 2 identifiable mutations consistent with CF; (?F508 homozygote, or ?F508 heterozygote with a second allele known to cause the disease, or two alleles known to cause a class I, II, or III mutation) and one or more clinical features consistent with CF.

• Male and female subjects aged =18 years of age

• A female subject is eligible to participate if she is of:

• Non-childbearing 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 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].

• Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one week after the last dose.

• Patients are non-smokers or former smokers by history. Former smokers will be defined as those who have not smoked for =6 months. Subjects who only use chewing tobacco products may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor.

• In the judgement of the investigator the patient is clinically stable with no change in symptoms or medication, no admissions to hospital, and no intravenous antibiotic therapy for at least 1 month prior to dosing.

• Able to perform lung function tests reliably.

• FEV1 >40% and <110% predicted.

• Excluding periods of exacerbation, FEV1 has not decreased by >15% over the past 12 months

• Clinically colonized by a bacterial organism commonly seen in cystic fibrosis other than Burkholderia cepacia (i.e. Pseudomonas spp., Staphylococcus aureus, Stenotrophomonas, B. Gladioli) as evidenced by identification in sputum culture within the past year. To be eligible a CF patient must have colonization of at least one typical CF organism.

• To be eligible, female patients must have a negative pregnancy test (urine or serum) and not be nursing at screening or prior to dosing.

• Subjects must have a QTcB or QTcF < 450 msec at screening as determined by the investigators review.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within twice (2x) the upper limit of normal at screening and bilirubin within 1.25x ULN at screening. AST, ALT, alkaline phosphatase and bilirubin >2.0 xULN (isolated bilirubin >2.0xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Male subjects must agree to use one of the contraception methods listed in Section 8.1.2. This criterion must be followed from the time of the first dose of study medication until one week after the last dose.

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

• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria:

• Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG, that is not associated with cystic fibrosis.

• Neutrophil count <1.5x109 /L

• In the judgment of the PI, the patient:

• suffers from clinically unstable pancreatic function

• has clinically significant weight loss( =5% after a previously stable period).

• has recent change in pancreatic enzyme requirements in the past 2 months.

• Recent viral infection (within 4 weeks of dosing), with or without steroid or antibiotic treatment. Presumed viral infection will be determined according to the judgment of the Investigator and no specific testing for virus will be required.

• Subjects unable to produce a technically acceptable sputum sample.

• Clinically significant hepatic impairment

• Evidence of cirrhosis

• Patients with elevated INR that is due to suspected vitamin K deficiency may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor

• Blood pressure persistently >155/95 mmHg at screening.

• Positive HIV, Hepatitis B surface antigen or Hepatitis C antibody at screening.

• History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6 months of screening.

• Urinary cotinine levels indicative of smoking.

• Use of oral or parenteral corticosteroids within 4 weeks of screening; regular use (>3 x/wk) of high dose NSAIDS (e.g. >1.6g ibuprofen/day on a regular basis), within 4 weeks of screening.

• Colonization with Burkholderia cepacia

• Subjects currently being treated for mycobacterial infection

• Subjects with presumed active Allergic Bronchopulmonary Aspergillosis (ABPA)

• Subjects who have newly started therapy with azithromycin within the past 3 months.

• In the judgment of the investigator, clinically significant hemoptysis (> 30 cc per episode) within the last 6 months

• Donation of blood in excess of 500 mL within a 56-day period prior to dosing

• Participation in a trial with any drug within 30 days or 5 half-lives (whichever is longer), or participation in a trial with a new chemical entity within 2 months prior to first dose of current study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.

• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, and cannabinoids. Subjects who use benzodiazepines or other anxiolytic on a regular basis can be included at the discretion of the investigator and in consultation with the GSK medical monitor

• Patients may not be on an inhaled antibiotic during the study (i.e. must be an "off-TOBI" month; cessation of TOBI or other inhaled antibiotics commences from one week prior to dosing until final PK draw). Patients on maintenance therapy with hypertonic saline solution or inhaled DNase may continue these therapies.

• Unwillingness or inability to follow the procedures outlined in the protocol.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• SB656933
20 mg
• SB656933
50mg
• Placebo
placebo

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
France	GSK Investigational Site	Lille cedex
France	GSK Investigational Site	Montpellier Cedex 5
France	GSK Investigational Site	Paris cedex 14
France	GSK Investigational Site	Pessac Cedex
France	GSK Investigational Site	Reims Cedex
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bochum	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg
Israel	GSK Investigational Site	Haifa
Israel	GSK Investigational Site	Jerusalem
Israel	GSK Investigational Site	Petach Tikva
United States	GSK Investigational Site	Akron	Ohio
United States	GSK Investigational Site	Albany	New York
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Colchester	Vermont
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Madison	Wisconsin
United States	GSK Investigational Site	Milwaukee	Wisconsin
United States	GSK Investigational Site	Palo Alto	California
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	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.	Up to Follow-up (up to 42 days)
Primary	Number of Participants With Vital Signs of Potential Clinical Importance	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.	Up to Follow-up (up to 42 days)
Primary	Number of Participants With Hematology Abnormalities of Potential Clinical Importance	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.	Up to Follow-up (up to 42 days)
Primary	Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance	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.	Up to Follow-up (up to 42 days)
Primary	Number of Participants With Abnormal Electrocardiogram (ECG) Findings	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.	Up to Follow-up (up to 42 days)
Primary	Number of Participants With Cystic Fibrosis (CF) Exacerbation	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.	Day 1 to Day 42
Secondary	Number of Participants With Pseudomonas Aeruginosa and Staphylococcus Aureus Count in Sputum	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.	Day 1 and Day 28
Secondary	Induced Sputum Neutrophil Number	Sputum samples were taken after bronchodilation and number of neutrophils in induced sputum were reported.	Day 28
Secondary	Induced Sputum Neutrophil Percentage	Sputum samples were taken after bronchodilation and percentage of neutrophils in induced sputum are presented.	Day 28
Secondary	Induced Sputum Inflammatory Markers-Myeloperoxidase and Neutrophil Elastase	Sputum samples were taken after bronchodilation. Mean induced sputum inflammatory markers namely Myeloperoxidase and neutrophil elastase are presented.	Day 28
Secondary	Serum and Plasma Markers of Inflammation- Clara Cell Secretory Protein (CC-16) and CXCL8 (Interleukin-8 [IL-8])	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.	Day 14 and Day 28
Secondary	Serum and Plasma Markers of Inflammation- C-reactive Protein (CRP)	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.	Day 14 and Day 28
Secondary	Serum and Plasma Markers of Inflammation- Fibrinogen	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.	Day 14 and Day 28
Secondary	Serum and Plasma Markers of Inflammation- Matrix Metalloproteinase-8 (MMP8), Matrix Metalloproteinase-9 (MMP9) and Surfactant Protein D (SP-D)	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.	Day 14 and Day 28
Secondary	Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC)	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.	Baseline (Day 1) to Day 14 and Day 28
Secondary	Area Under the Plasma Drug Concentration (AUC) Versus Time Curve: AUC From Time Zero (Pre-dose) to Four Hours Post Dose (AUC[0-4]) and AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-t])	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.	Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours
Secondary	Maximum Observed Plasma Drug Concentration (Cmax)	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.	Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours
Secondary	Time to Maximum Observed Plasma Drug Concentration (Tmax)	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.	Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours

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