This purpose of this study is to show the superiority and long term safety and efficacy of
adding a long acting beta agonist (salmeterol) to constant dose of an inhaled corticosteroid
(fluticasone propionate) in symptomatic subjects with asthma. The 12-month assessment of
asthma control will provide key information on the efficacy and safety of the combination
therapy. The safety measure will be an assessment of adverse events
Inclusion Criteria:
- Subjects eligible for enrollment in the study must meet all of the following
criteria:
1. Consent: A signed and dated written informed consent must be obtained from the
subject and/or subject's legally acceptable representative prior to study
participation.
2. Type of Subject: Outpatient
3. Gender: Male or female Females are eligible to participate only if they are
currently non-pregnant and non-lactating.
A female is eligible to enter and participate in the study if she is:
1. of non-child-bearing potential; OR
2. of child-bearing potential but has a negative urinary pregnancy test at Screening
(Visit 1 and when specified in Appendix 1) and agrees to take contraceptive
precautions (including abstinence) which are adequate to prevent pregnancy during the
study.
Acceptable methods of contraception [Hatcher, 2004] are:
- Abstinence
- oral contraceptive (either combined or progestogen only)
- injectable progestogen
- implants of levonorgestrel
- estrogenic vaginal ring
- percutaneous contraceptive devices
- intrauterine device (IUD) or intrauterine system (IUS) with published data
showing that the lowest expected failure rate is less than 1% per year
- male partner sterilization (vasectomy with documentation of azoospermia) prior
to the female subject's entry into the study and is the sole sexual partner for
that female subject
- double barrier method: condom or occlusive cap (diaphragm or cervical/vault
caps) plus spermicidal agent
1. Age: A subject must be 12 years of age at Visit 1 (screening).
2. Asthma Diagnosis: A documented diagnosis of persistent asthma, for at
least six months, as defined by the following American Thoracic Society
definition:
Asthma is a clinical syndrome characterized by increased responsiveness of the
airways to a variety of stimuli. The major symptoms of asthma are episodes of
dyspnea, wheezing, and cough, which may vary from mild and almost undetectable to
severe and unremitting (status asthmaticus). The primary physiological manifestation
of this hyperresponsiveness is variable airway obstruction. This can take the form
of spontaneous fluctuations in the severity of obstruction, substantial improvements
in the severity of obstruction following bronchodilators or corticosteroids, or
increased obstruction caused by drugs or other stimuli [American Thoracic Society,
1987].
1. Asthma Medication History: A subject must be using a low to medium dose of an
ICS (Table 1) OR a combination of controller medications (Table 2), containing a
low (total daily) dose ICS (as defined in Table 1) for at least 4 weeks
preceding screening.
Table 1 (ICS Dosage Table) Inhaled Corticosteroid (Dosage (mcg/day))(LowMedium)
Beclomethasone dipropionate CFC (168 = 504> 504 = 840) Beclomethasone dipropionate
HFA (80 = 240>240 = 640) Triamcinolone acetonide (400 = 1000>1000 = 2000)
Flunisolide (500 = 1000> 1000 = 2000) Fluticasone propionate inhalation aerosol (176
= 220> 220 = 440) Fluticasone propionate inhalation powder (100 = 250> 250 = 500)
Budesonide1 (200 = 600> 600 =1200) Mometasone (200 = 400> 400 = 800) Ciclesonide (80
= 160>160 = 320)
1. Respules are allowed at a dosage of 250-500mcg/day.
Table 2 (Asthma Controller Medications) Asthma Controller Medication(s) Low dose ICS
+ Leukotriene modifiers Low dose ICS + Theophylline products Low Dose ICS + Inhaled
anticholinergics or combination products (e. g., Atrovent or Combivent) Low Dose ICS +
Long acting inhaled anticholinergic (e. g. Spiriva) Low dose ICS+ long acting beta
agonist or combination products containing a low dose ICS and a long-acting
beta-agonists (e. g. ADVAIR™/SERETIDE™1 100/50 mcg BID or Symbicort 160/9 mcg BID (i. e
80/4. 5 mcg two inhalations BID)
1. ADVAIR/SERETIDE =250/50 mcg BID or Symbicort 320/9 mcg BID (i. e 160/4. 5 mcg two
inhalation BID) are not permitted.
1. Pulmonary function: A pre-albuterol (salbutamol) FEV1 of 50% and 85% of
predicted normal value at screening (Visit 1) after withholding asthma
medications as detailed in the protocol (Section 6. 8.1). Predicted FEV1 will be
based on the National Health and Nutrition Examination Survey (NHANES III)
predicted normal values for ages 8 years and older [Hankinson, 1999].
2. Reversibility: An increase in FEV1 of 12% over the pre-albuterol (salbutamol)
FEV1 within 30 minutes after the inhalation of 2-4 puffs of albuterol
(salbutamol). Historical documentation of reversibility will not be permitted.
3. Asthma symptom criteria: Each subject must have experienced asthma symptoms
requiring albuterol (salbutamol) use within the 4 weeks preceding screening
(Visit 1).
Specific information regarding warnings, precautions, contraindications, adverse
events, and other pertinent information on the investigational product that may
impact subject eligibility is provided in the IB and the product labels.
Exclusion Criteria:
- Subjects meeting any of the following criteria must not be enrolled in the
study:
1. Life-Threatening Asthma: A subject must not have life-threatening asthma.
Life-threatening asthma is defined for this protocol as a history of significant
asthma episode(s) requiring intubation associated with hypercapnia, respiratory
arrest, or hypoxic seizures, or asthma-related syncopal episode(s) within the 12
months prior to screening (Visit 1).
2. Worsening of Asthma: A subject must not have experienced a worsening of asthma
which involved an ER visit, hospitalization or use of oral/parenteral
corticosteroids within 4 weeks of screening (Visit 1).
3. Intermittent, Seasonal, or Exercise-Induced Asthma Alone: Subjects with only
intermittent or seasonal or exercise-induced asthma are excluded from
participation in this study.
4. Concurrent Respiratory Disease: A subject must not have current evidence of
pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, chronic
bronchitis, emphysema, chronic obstructive pulmonary disease, or other
respiratory abnormalities other than asthma.
5. Concurrent Conditions/Diseases: A subject with historical or current evidence
of any clinically significant, co-morbid or uncontrolled condition or disease
state that, in the opinion of the investigator, would put the safety of the
subject at risk through study participation or would confound the interpretation
of the results if the condition/disease exacerbated during the study.
The list of excluded conditions/diseases includes, but is not limited to:
congestive heart failure known aortic aneurysm clinically significant coronary
clinically significant cardiac arrhythmia heart disease stroke within 3 months of
screening (Visit 1) uncontrolled hypertension coronary artery disease hematologic,
hepatic, or renal disease cystic fibrosis poorly controlled peptic ulcer dyspnea by
any other cause than asthma gastroesophageal reflux disease (GERD) not controlled by
pharmacotherapy and may be causing/contributing to subject's respiratory symptoms
thyrotoxicosis hypokalemia immunologic compromise current malignancy1 tuberculosis
(current or quiescent) Cushing's or Addison's disease pneumonia, pneumothorax,
chronic bronchitis or atelectasis uncontrolled diabetes mellitus recent history of
drug or alcohol abuse 1. history of malignancy is acceptable only if subject has been
in remission for one year prior to screening (Visit 1; remission = no treatment for
the malignancy in the 12 months prior to screening [Visit 1])
1. Drug Allergy: A subject must not have had any immediate or delayed
hypersensitivity to any beta2-agonist; sympathomimetic drug; any intranasal;
inhaled or systemic corticosteroid therapy; lactose; or have a severe milk
protein allergy.
2. Respiratory Tract Infections: A subject must not have had any sinus, middle
ear, oropharyngeal, upper or lower respiratory tract infection symptoms that
have not resolved at least 7 days immediately preceding screening (Visit 1).
3. Asthma Medications: Asthma medications listed below must not have been used
prior to screening (Visit 1) for the required exclusion period as indicated
below:
Medication (Exclusion Period Prior to screening (Visit 1)) Oral or parenteral
systemic corticosteroids (4 weeks) Omalizumab (Xolair) (6 months)
1. Concurrent Medications: A subject must not have the concurrent use of any of the
following medications that interact with any of the study drugs used in this
study, or that may affect the course of asthma or interact with sympathomimetic
amines, such as:
- beta-adrenergic receptor blocking agents
- monoamine oxidase (MAO) inhibitors
- tricyclic antidepressants
- ritonavir
- ketoconazole
2. Concurrent use of asthma medications: Concurrent use of all asthma medications
(other than protocol defined study and rescue medications and oral/parenteral
corticosteroids) are prohibited during the study.
3. Concomitant use of leukotriene modifiers (LTM) for allergies is prohibited. A
subject must not be on LTM for treatment of nasal allergies that requires
regular maintenance therapy. Substitution with any other antihistamine is
permitted.
4. Immunosuppressive Medications: A subject must not be using, or require the use
of, immunosuppressive medications during the study.
5. Immunotherapy for the treatment of allergies is not allowed during the study
unless the subject has used a constant dose for 4 weeks prior to Screening
(Visit 1) and the same dose will be continued throughout the study.
6. Tobacco Use: >10 pack year history or use of any tobacco products within 1 year
of screening (Visit 1). This includes cigarettes, cigars, pipe, chewing
tobacco, and snuff.
7. Questionable Validity of Consent: A subject must not have any infirmity or
disability that would limit the subject's consent.
8. Positive Pregnancy Test (for all females who have had menarche): A current
positive pregnancy test.
9. Investigational Medications: A subject must not have had use of any
investigational drug within 30 days of screening (Visit 1).
10. Site Affiliation: A subject may not participate if he/she is a participating
investigator, sub-investigator, study coordinator, employee of a participating
investigator or is in any way associated with the administration of the study.
Immediate family members of these individuals are also excluded.
11. Compliance with Study Requirements: A subject may not participate if, in the
opinion of the investigator, there are present or anticipated circumstances that
will prohibit the subject from being compliant with study visits and procedures
(e. g. geographic location that will prohibit subject from required clinic visit
schedule).
GSK Investigational Site, Buenos Aires 1221, Argentina
GSK Investigational Site, Buenos Aires 1437, Argentina
GSK Investigational Site, Ciudad Autónoma de Buenos Aires C1121ABE, Argentina
GSK Investigational Site, Mendoza M5500CCG, Argentina
GSK Investigational Site, Santa Fe 3000, Argentina
GSK Investigational Site, Tucuman 4000, Argentina
GSK Investigational Site, Rio de Janeiro 20221-903, Brazil
GSK Investigational Site, São Paulo 04079002, Brazil
GSK Investigational Site, Quezon City 1101, Philippines
GSK Investigational Site, Quezon City 1109, Philippines
GSK Investigational Site, Birmingham, Alabama 35209, United States
GSK Investigational Site, Birmingham, Alabama 35294, United States
GSK Investigational Site, Mobile, Alabama 36608, United States
GSK Investigational Site, Vancouver, British Columbia V5Z 1K3, Canada
GSK Investigational Site, Fresno, California 93720, United States
GSK Investigational Site, Fullerton, California 92835, United States
GSK Investigational Site, Huntington Beach, California 92647, United States
GSK Investigational Site, Long Beach, California 90808, United States
GSK Investigational Site, Los Angeles, California 90048, United States
GSK Investigational Site, San Diego, California 92120, United States
GSK Investigational Site, Stockton, California 95207, United States
GSK Investigational Site, Vista, California 92083, United States
GSK Investigational Site, Pueblo, Colorado 81008, United States
GSK Investigational Site, Hudson, Florida 34667, United States
GSK Investigational Site, South Miami, Florida 33143, United States
GSK Investigational Site, Tampa, Florida 33613, United States
GSK Investigational Site, Albany, Georgia 31707, United States
GSK Investigational Site, Gainesville, Georgia 30501, United States
GSK Investigational Site, Lawrenceville, Georgia 30045, United States
GSK Investigational Site, Savannah, Georgia 31406, United States
GSK Investigational Site, Coeur D'Alene, Idaho 83814, United States
GSK Investigational Site, Evansville, Indiana 47710, United States
GSK Investigational Site, Owensboro, Kentucky 42301, United States
GSK Investigational Site, Sunset, Louisiana 70584, United States
GSK Investigational Site, Rochester, Minnesota 55905, United States
GSK Investigational Site, Chesterfield, Missouri 63017, United States
GSK Investigational Site, Jefferson City, Missouri 65101, United States
GSK Investigational Site, Missoula, Montana 59808, United States
GSK Investigational Site, Lincoln, Nebraska 68505, United States
GSK Investigational Site, Papillion, Nebraska 68046, United States
GSK Investigational Site, Moncton, New Brunswick E1C 2Z3, Canada
GSK Investigational Site, Ocean, New Jersey 07712, United States
GSK Investigational Site, New York, New York 10016, United States
GSK Investigational Site, Charlotte, North Carolina 28207, United States
GSK Investigational Site, Winston-Salem, North Carolina 27103, United States
GSK Investigational Site, Fargo, North Dakota 58104, United States
GSK Investigational Site, Canton, Ohio 44718, United States
GSK Investigational Site, Oklahoma City, Oklahoma 73120, United States
GSK Investigational Site, Kitchener, Ontario N2C 2N9, Canada
GSK Investigational Site, Newmarket, Ontario L3Y 5G8, Canada
GSK Investigational Site, Oshawa, Ontario L1H 7K4, Canada
GSK Investigational Site, Toronto, Ontario M9V 4B4, Canada
GSK Investigational Site, Lake Oswego, Oregon 97035, United States
GSK Investigational Site, Medford, Oregon 97504, United States
GSK Investigational Site, Collegeville, Pennsylvania 19426, United States
GSK Investigational Site, Erie, Pennsylvania 16508, United States
GSK Investigational Site, Philadelphia, Pennsylvania 19102, United States
GSK Investigational Site, Saint Leonard, Quebec H1S 3A9, Canada
GSK Investigational Site, Sainte-Foy, Quebec G1W 4R4, Canada
GSK Investigational Site, St-Romuald, Quebec G6W 5M6, Canada
GSK Investigational Site, Cumberland, Rhode Island 02864, United States
GSK Investigational Site, Porto Alegre, Rio Grande Do Sul 90610-000, Brazil
GSK Investigational Site, Florianopolis, Santa Catarina, Brazil
GSK Investigational Site, Rosario, Santa Fe 2000, Argentina
GSK Investigational Site, Charleston, South Carolina 29406-7108, United States
GSK Investigational Site, Greenville, South Carolina 29615, United States
GSK Investigational Site, Greer, South Carolina 29651, United States
GSK Investigational Site, Santo Andre, São Paulo 09060-670, Brazil
GSK Investigational Site, El Paso, Texas 79903, United States
GSK Investigational Site, Houston, Texas 77070, United States
GSK Investigational Site, Killeen, Texas 76542, United States
GSK Investigational Site, San Antonio, Texas 78229, United States
GSK Investigational Site, Waco, Texas 76712, United States
GSK Investigational Site, Murray, Utah 84107, United States
GSK Investigational Site, Norfolk, Virginia 23507, United States
GSK Investigational Site, Gig Harbor, Washington 98335, United States
GSK Investigational Site, Tacoma, Washington 98405, United States
GSK Investigational Site, Morgantown, West Virginia 26505, United States
GSK Investigational Site, Greenfield, Wisconsin 53228, United States
GSK Investigational Site, Madison, Wisconsin 53972, United States
GSK Investigational Site, Milwaukee, Wisconsin 53209, United States
Anderson WH, Koshy BT, Huang L, Mosteller M, Stinnett SW, Condreay LD, Ortega H. Genetic analysis of asthma exacerbations. Ann Allergy Asthma Immunol. 2013 Jun;110(6):416-422.e2. doi: 10.1016/j.anai.2013.04.002.
Kerwin E, Prazma CM, Sutton L, Stempel DA. Safety and efficacy of long-term treatment with fluticasone propionate and salmeterol via DISKUS versus fluticasone propionate alone. Clin Res Reg Aff 2011;28(1):14-21.
