28 Day Repeat Dose in Cystic Fibrosis Patients

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT00903201
• Date of registration: 14/05/2009
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: 28 Day Repeat Dose in Cystic Fibrosis Patients
• Scientific 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.
• Date of first enrolment: September 28, 2009
• Target sample size: 146
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT00903201
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Canada, France, Germany, Israel, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

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 on


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Cystic Fibrosis

Intervention(s)

Drug: SB656933

Drug: Placebo

Primary Outcome(s)

Number of Participants With Vital Signs of Potential Clinical Importance [Time Frame: Up to Follow-up (up to 42 days)]

Number of Participants With Abnormal Electrocardiogram (ECG) Findings [Time Frame: Up to Follow-up (up to 42 days)]

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [Time Frame: Up to Follow-up (up to 42 days)]

Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance [Time Frame: Up to Follow-up (up to 42 days)]

Number of Participants With Cystic Fibrosis (CF) Exacerbation [Time Frame: Day 1 to Day 42]

Number of Participants With Hematology Abnormalities of Potential Clinical Importance [Time Frame: Up to Follow-up (up to 42 days)]

Secondary Outcome(s)

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) [Time Frame: Baseline (Day 1) to Day 14 and Day 28]

Maximum Observed Plasma Drug Concentration (Cmax) [Time Frame: Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours]

Induced Sputum Neutrophil Number [Time Frame: Day 28]

Serum and Plasma Markers of Inflammation- C-reactive Protein (CRP) [Time Frame: Day 14 and Day 28]

Serum and Plasma Markers of Inflammation- Clara Cell Secretory Protein (CC-16) and CXCL8 (Interleukin-8 [IL-8]) [Time Frame: Day 14 and Day 28]

Number of Participants With Pseudomonas Aeruginosa and Staphylococcus Aureus Count in Sputum [Time Frame: Day 1 and Day 28]

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]) [Time Frame: Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours]

Serum and Plasma Markers of Inflammation- Matrix Metalloproteinase-8 (MMP8), Matrix Metalloproteinase-9 (MMP9) and Surfactant Protein D (SP-D) [Time Frame: Day 14 and Day 28]

Induced Sputum Inflammatory Markers-Myeloperoxidase and Neutrophil Elastase [Time Frame: Day 28]

Induced Sputum Neutrophil Percentage [Time Frame: Day 28]

Serum and Plasma Markers of Inflammation- Fibrinogen [Time Frame: Day 14 and Day 28]

Time to Maximum Observed Plasma Drug Concentration (Tmax) [Time Frame: Day 1: pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose and Day 28: pre-dose, 1 and 4 hours]

Secondary ID(s)

110399

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 17/11/2017
• URL: https://clinicaltrials.gov/ct2/show/results/NCT00903201