Clinical trial NCT00549744: Clinical Endpoint Trial Investigating Once Daily and Bronchodilator Dosing
Official title: A Randomized, Double-blind, Double-dummy, Placebocontrolled,Three-period, Incomplete Block, Crossover Study, to a Investigate the Effect of 14 Days Repeat Inhaled Dosing With GSK256066 in Mild/Moderate Asthmatic Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: ASTHMA
CLINICAL ENDPOINT,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-10-26
Enrollment: 78
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Subjects will attend the unit for out-patient visits on Day 1, Day 7, Day 14 and Day 15 of each treatment period. The washout period between each treatment period will be a minimum of 10 days and maximum of 28 days. Subjects will participate in 3 treatment periods.


Eligibility criteria: Inclusion Criteria:

* Subjects with clinically stable persistent mild/moderate asthma within the 4 weeks preceding the screening visit, with the exclusion of other significant pulmonary diseases (e.g. chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis or bronchopulmonary dysplasia)
* Subjects with a screening pre-bronchodilator FEV1 70% predicted (having abstained from bronchodilators for the required period). Predicted values are based on the NHanes normal ranges
* During the screening visit, subjects must demonstrate the presence of reversible airway disease, defined as an increase in FEV1 of 12.0% over the max of the three screening measures and an absolute change of 150 mL within 30 minutes following a single 400 mg salbutamol dose
* Male and females who are aged between 18 and 65 years of age.A female is eligible to enter and participate in the study if she is of:

  1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post menopausal. For the purposes of this study, post menopausal is defined as 1 year without menses (FSH/LH will be also tested to confirm menopausal status); or
  2. Child bearing potential, has a negative pregnancy test (urine) at screening and pre-dose Day 1, and agrees to one of the following acceptable contraceptive methods when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of a physician for the duration of the study - screening visit to follow-up contact):

Complete abstinence from intercourse from the screening visit, throughout the trial and for 7 (\~5 half-lives of GSK256066) days after the completion of the trial; or Male partner was sterile prior to the female subject's entry into the study, or Implants of levonorgestrel inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or Injectable progestogen administered for at least 1 month prior to the study medication administration and administered for 1 month following study completion; or Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or The contraceptive transdermal patch, Ortho Evra (if the subject is less than 89kg); or Double-barrier method - spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm.

Recent data now shows that certain double-barrier methods have a failure rate below 1% \[Trussell, 2003\]. Specifically, these are a spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm). This provides validated confirmation of the failure rate of the double-barrier method. Thus this method now meets the stated criterion for acceptable contraception in the EMEA guidelines \[CPMP/ICH/285/95, 2000\]; or Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; or An intrauterine device (IUD) or intrauterine system (IUS), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; (not all IUDs meet this criterion) Acceptable IUDs: Tcu-380A (Paragard), TCU-380 Slimline (Gyne T Slimline), Tcu-220C, MULTILOAD-250 (MLCu-250) and 375, NOVA T and CUNOVAT (Novagard), Levonorgesterol (LNG-20) Intra-uterine System (Mirena/Levonova), and FlexiGard 330/CuFix PP330 (Gynefix). The device must be inserted at least 2 weeks prior to the Screen visit, and remain throughout the study and through the follow-up phase of the study or Any other methods with published data showing that the highest expected failure rate is less than 1% per year.

* Body weight of 50 kg and Body mass index within range of 19-31 kg/m2 inclusive
* Subjects who are current non-smokers, who have not used any inhaled tobacco products (snuff is permitted) in the 12 month period preceding the screening visit and who have a pack history of £ 10 pack years
* No significant abnormality on 12-lead ECG at screening, including the following requirements:

Ventricular rate ≥ 40 beats per minute PR interval ≤ 200 ms Q waves \< 30 ms (up to 50 ms permitted in lead III only) QRS interval to be ≥ 60 ms and ≤ 110 ms QTc interval \< 450msec (QTcB or QTcF; machine or manual reading) based on a single ECG value, or an average from three ECGs obtained over a brief recording period

* Able to provide written informed consent
* The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions
* Demonstrated ability to use the inhaler device in a satisfactory and repeatable manner

Exclusion Criteria:

* As a result of medical interview, physical examination or screening investigations, the principle investigator or delegate physician deems the subject unsuitable for the study. Subjects must not have a systolic blood pressure above 145 mmHg or a diastolic pressure above 85 mmHg unless the Investigator confirms that it is satisfactory for their age
* The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness
* Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease\*, haematological disease, neurological disease, endocrine disease or pulmonary disease (including but not confined to chronic bronchitis, emphysema, bronchiectasis or pulmonary fibrosis)
* Subjects will require normal serum creatinine clearance values at screening \[calculated from serum creatinine by a predicting equation using Cockcroft-Gualt formula\]. If the creatinine clearance value is greater than the upper limit of normal as determined by the local laboratory reference range, the Investigator will determine whether this is a clinically significant finding that would preclude participation
* Subject has a history of atrial arrhythmia or ventricular arrhythmia
* Pregnant or nursing females
* Women of childbearing potential who are unwilling or unable to use an appropriate method of contraception from at least two weeks prior to the first dose of study medication; and to continue until the final pregnancy test has been performed (not less than 150 hours after treatment
* Subjects with a history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with either respiratory arrest or hypoxic seizures
* Asthma exacerbations requiring treatment with oral corticosteroids: any exacerbations within 3 months of the screening visit or two or more exacerbations within 6 months of the screening visit or admittance to hospital for an asthma exacerbation within 1 year of the screening visit
* Subjects who have suffered an upper or lower respiratory tract infection within 4 weeks of the screening visit
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation
* Subjects who are unable to washout the following protocol defined prohibited medications within the defined times at screening:

Oral corticosteroids Inhaled, intranasal and topical steroids Long acting beta agonists Short acting beta agonists

* The subject has taken prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study procedures or compromise subject safety
* History of alcohol/drug abuse or dependence within 12 months of the study
* Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). 1 unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine)
* The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day
* Donation of blood in excess of 500 mL within a 56 day period prior to dosing
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* The subject has tested positive for HIV antibodies (if tested according to site SOPs)
* The subject has a positive pre-study urine drug/ urine alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines

Primary outcomes:
measure: Change from Baseline (pre-bronchodilator and pre-dose) forced expiratory volume at 1 second (FEV1) on Day 14
timeFrame: Baseline (Day 1, pre-dose) and Day 14 of each treatment period
Secondary outcomes:
measure: Change from Baseline (pre-bronchodilator and pre-dose) FEV1 on Day 7 and at one h post-dose on Day 7 and Day 14
timeFrame: Day 1 (Baseline, pre-dose), Day 7 and Day 14 of each treatment period
measure: Change from Baseline in FEV1 over 12 h post-dose on Day 1
timeFrame: Baseline (Day 1, pre-dose) and Day 1 (0.5 h, 1 h, 2 h, 8 h and 12 h post-dose) of each treatment period
measure: Change from Baseline in FEV1 over 12 h post-dose on Day 14
timeFrame: Baseline (Day 1, pre-dose) and Day 14 (0.5 h, 1 h, 2 h, 8 h and 12 h post-dose) of each treatment period
measure: Mean change from Baseline (pre-bronchodilator and pre-dose) Peak Expiratory Flow Rate (PEFR) averaged over the 14-day period
timeFrame: Baseline (Screening, 7 days prior to Day 1 of Treatment period 1) and Day 1 to 14 of each treatment period
measure: Mean change from Baseline ratio of exhaled nitric oxide on Day 1, Day 7 and Day 14
timeFrame: Baseline (Day 1 pre-dose), Day 7 and Day 14 of each treatment period
measure: Mean provocative concentration of methacholine resulting in a 20% reduction in FEV1 (PC20) on Day 15
timeFrame: Day 15 of each treatment period
measure: Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC [0-t]) and to infinity (AUC [0-infinity]) of GSK256066 at Day 1 and Day 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: Maximum observed concentration (Cmax) of GSK256066 at Day 1 and 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: Time of occurrence of Cmax (Tmax) and time to apparent terminal elimination phase half-life (t1/2) of GSK256066 at Day 1 and Day 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: AUC (0-t) and AUC (0-infinity) of GSK614917 at Day 1 and Day 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: Cmax of GSK614917 at Day 1 and Day 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: Tmax and t1/2 of GSK614917 at Day 1 and Day 14
timeFrame: Day 1 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h) and Day 14 (pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h)
measure: Number of participants with any adverse event (AE), serious adverse event (SAE) or death
timeFrame: Up to Follow-up (18 weeks)
measure: Number of participants with abnormal both clinically non-significant (CNS) and clinically significant (CS) electrocardiograph (ECG) values
timeFrame: Up to Day 14 of each treatment period
measure: Number of participants with hematology abnormalities of potential clinical importance (PCI) during the treatment period
timeFrame: Up to Day 14 of each treatment period
measure: Number of participants with clinical chemistry abnormalities of PCI during the treatment period
timeFrame: Up to Day 14 of each treatment period
measure: Number of participants with abnormal urinalysis results
timeFrame: Up to Day 14 of each treatment period
measure: Number of participants with vital sign value of PCI during the treatment period
timeFrame: Up to Day 14 of each treatment period
measure: Number of participants with troponin results
timeFrame: Up to Day 14 of each treatment period
measure: Genetic variations of participants for relationship between genetic variants and or PK, tolerability and efficacy of GSK256066
timeFrame: At any time post-Randomization
measure: Mean phosphodiesterase-4 (PDE4) values
timeFrame: Day 7 of each treatment period
measure: Mean differential cell counts during sputum analysis
timeFrame: Day 7 of each treatment period
measure: Biomarkers of sputum analysis
timeFrame: Day 7 of each treatment period
measure: Mean interleukin-10 (IL-10), IL-13 and tumour necrosis factor alfa (TNFα) values
timeFrame: Day 7 of each treatment period
measure: Anti inflammatory activity in sputum assessed by SNF1LK Cytospin on Day 7
timeFrame: Day 7 of each treatment period
measure: Anti-inflammatory activity in sputum assessed by ratio of SNF1LK Cytospin on Day 7
timeFrame: Day 7 of each treatment period
Other outcomes:
Locations:
city: Wellington
country: New Zealand
facility: GSK Investigational Site
city: George
country: South Africa
facility: GSK Investigational Site
state: Eastern Cape
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: