| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to evaluate the dose response, efficacy and safety of five once daily doses of GSK573719 (15.6mcg, 31.25mcg, 62.5mcg, 125mcg and 250mcg).
compared with placebo, over a minimum 14-day treatment period, in patients with asthma. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the efficacy and safety of two twice daily regimens of GSK573719 (15.6mcg, 31.25mcg) relative to placebo and relative to the once-daily regimens of GSK573719 and to derive pharmacokinetic parameters for
GSK573719 administered once and twice daily in patients with asthma.
An additional objective is to determine whether there are differential responses to GSK573719 that can be predicted from patient characteristics. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Investigator Brochure for GSK573719, a muscarinic receptor antagonist and Inhaled Fluticasone Furoate (GW685698), a glucocorticoid receptor agonist.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in the study must meet all of the following criteria:
Informed consent: Subjects must give their signed and dated written informed consent to participate.
Type of Subject: Out-patients. However a sub-group of subjects from selected sites will remain in the clinic overnight at the end of each treatment period for serial safety, efficacy and PK blood and urine assessments over a 24 hour period.
Age: 18 years of age or older at Visit 1.
Diagnosis: diagnosis of asthma as defined by the National Institutes of Health [NIH, 2007] at least 6 months prior to Visit 1.
Gender: Male or Eligible Female, eligible being defined as of non-childbearing potential or childbearing potential using an acceptable method of birth control consistently and correctly, as defined by the following:
• Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject
• Implants of levonorgestrel or etonogestrel
• Injectable progestogen
• Oral contraceptive (either combined or progestogen alone)
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year.
• Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository)
• Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)
• Females of child-bearing potential must commit to complete abstinence from intercourse, throughout the study including the follow-up period when this is the female’s preferred and usual lifestyle
• Female subjects should not be enrolled if they are pregnant or lactating or if they plan to become pregnant during the time of study participation. A serum pregnancy test is required of all females and will be performed at the initial screening visit (Visit 1) and Visit 10 or Early Withdrawal. In addition, a urine pregnancy test will be performed as in the Table of Time and Events.
Severity of Disease: A best pre-bronchodilator AM FEV1 of 60% to 85% of the predicted normal value at the Visit 1 (screening) visit. Percent predicted normal values will be based upon:
• NHANES III (Hankinson, 1999) for the primary race/ethnicity of the subject, e.g Mexican-American, African-American/African heritage, Caucasian
• Multiethnic spirometric assessments (Hankinson, 2010) for the primary race/ethnicity of the subject,e.g Asian
Reversibility of Disease: Demonstrated by ≥12% and ≥200mL increase in FEV1 within 40 minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol at Visit 1 screening.
Current Anti-Asthma Therapy: Subjects must demonstrate a need for regular use of a non-corticosteroid controller as shown by having or received a prescription for either of the following for ≥3 months preceding Visit 1 (and with no inhaled corticosteroid used
for at least 4 weeks prior to V1):
• a non-corticosteroid controller (e.g., theophylline, cromolyn, nedocromil, leukotriene modifiers [e.g. montelukast, zafirlukast], etc.)
• short-acting beta2-agonist bronchodilator such as salbutamol/albuterol.
Short-Acting Beta2-Agonists (SABAs): All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 4 hours prior to study visits. |
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| E.4 | Principal exclusion criteria |
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
• History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 5 years.
• Asthma Exacerbation: A subject must not have a history of a severe asthma exacerbation within 4 weeks prior to Visit 1. A severe asthma exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, or injection) for at least 3 days or an inpatient hospitalization or emergency
department visit due to asthma that required systemic corticosteroids.
• Respiratory Infection expected to affect the subject’s ability to participate in the study: Within 4 weeks prior to Visit 1 a subject has had a culturedocumented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved and has led to a change in asthma management or, in the opinion of the Investigator, is expected to
affect the subject’s asthma status or the subject’s ability to participate in the study.
•Concurrent Respiratory Disease: A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma.
• Tobacco Use. Current smoker or a smoking history of ≥ 10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years].
Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
• Diseases Preventing Use of Anticholinergics: Diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator or GSK medical monitor would pose a safety risk with use of an inhaled anticholinergic.
• Other Concurrent Diseases/Abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. Examples are outlined in the
study procedure manual. The investigator is encouraged to contact the study medical monitor if further clarification is warranted.
Please refer Protocol page number: 23 and 24. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is trough FEV1 on Day 15 end of each treatment period, defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 visit of each treatment period (obtained on all subjects). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 Hours after morning dosing on day 14 visit of each treatment period. |
|
| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoints are derived from the serial FEV1 measurements (obtained in the sub-group only- see Appendix 4).
• Weighted mean FEV1 over 0-24 hours after morning dosing on Day 14 of each treatment period
• Serial FEV1 at each timepoint over 24 hours after morning dosing on Day 14 of each treatment period or from the subject diary assessments (obtained in all subjects)
• AM (pre-dose and pre-albuterol/salbutamol bronchodilator) PEF; calculated from the 7 days prior to each treatment period as baseline and the last 7 days of each treatment period
• PM (pre-dose and pre-albuterol/salbutamol bronchodilator) PEF; calculated from the 7 days prior to each treatment period as baseline and the last 7 days of each treatment period
• Rescue use albuterol/salbutamol calculated from the 7 days prior to each treatment period as baseline and the last 7 days of each treatment period. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Germany |
| Mexico |
| Peru |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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