Trial name or title

A randomised, double‐blind, placebo‐controlled, parallel group, multi‐centre study to evaluate the efficacy and safety of FF/VI inhalation powder delivered once‐daily for 12 weeks in the treatment of asthma in adolescent and adult participants of Asian ancestry currently treated with low to mid‐strength ICS or low‐strength combination therapy

Methods

Randomised double‐blind placebo‐controlled parallel‐group multi‐centre study

Participants

Participants of Asian ancestry with asthma. 12 years of age or older

Inclusion criteria

• Informed consent: All participants must be able and willing to give written informed consent to take part in the study

• Type of participants: outpatients, of Asian ancestry, 12 years of age or older at visit 1 (or ≥ 18 years of age or older if local regulations or the regulatory status of study medication permit enrolment of adults only), with a diagnosis of asthma as defined by the Global Initiative for Asthma (GINA 2009) ≥ 12 weeks before visit 1

• Gender: male or eligible female, defined as non‐childbearing potential or childbearing potential using a protocol‐defined acceptable method of birth control consistently and correctly. Female participants should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. A serum pregnancy test is required for females of childbearing potential at initial screening visit (visit 1) and at visit 5 or early withdrawal

• Severity of disease: best FEV₁ 40% to 90% of predicted normal value at visit 1, screening visit. Predicted values will be based upon NHANES III using adjustment for Asians (Hankinson 2010)

• Reversibility of disease: demonstrated ≥ 12% and ≥ 200 mL reversibility of FEV₁ within 10 to 40 minutes following 2 to 4 inhalations of albuterol/salbutamol inhalation aerosol (or 1 nebulised treatment with albuterol/salbutamol solution) at screening visit

• Current antiasthma therapy: All participants must be using an ICS, with or without LABA, for ≥ 12 weeks before visit 1, in accordance with protocol‐defined acceptable dose ranges

• SABA: All participants must be able to replace their current SABA with albuterol/salbutamol inhaler at visit 1 for use as needed for the duration of the study. Participants must be able to withhold albuterol/salbutamol for ≥ 4 hours before study visits

Exclusion criteria

• History of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 10 years

• Respiratory infection: culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that was not resolved within 4 weeks of visit 1 and led to a change in asthma management or, in the opinion of the investigator, was expected to affect participant asthma status or ability of participant to participate in the study

• Asthma exacerbation: any asthma exacerbation requiring OCS within 12 weeks of visit 1, or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months before visit 1

• Concurrent respiratory disease: Participant must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, COPD or respiratory abnormalities other than asthma

• Other concurrent diseases/abnormalities: Participant 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 interpretation of efficacy results if the condition/disease was exacerbated during the study

• Oropharyngeal examination: Participant will not be eligible for the run‐in if he/she has clinical visual evidence of candidiasis at visit 1

• Allergies: drug allergy: any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to constituents of the new powder inhaler (i.e. lactose or magnesium stearate). Milk protein allergy: history of severe milk protein allergy

• Concomitant medications: use of protocol‐defined prohibited medications before visit 1 or during the study, in accordance with the protocol

• Tobacco use: current smoker or participants with smoking history of 10 pack‐years ( i.e. 20 cigarettes/d for 10 years). Participant may not have used inhaled tobacco products within the past 3 months (i.e. cigarettes, cigars, smokeless or pipe tobacco)

• Affiliation with investigator site: Participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator or study co‐ordinator, or an employee of the participating investigator

• Previous participation: Participant may not have previously been randomised to treatment in another phase III FF/VI combination product study (i.e. HZA113714, HZA106827, HZA106829, HZA106837, HZA106839, HZA106851, HZA113091)

• Compliance: Participant will not be eligible if he/she or his/her parent or legal guardian has an infirmity, disability, disease or geographical location that seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of daily diaries

Interventions

FF/VI ICS/LABA combination vs placebo

Outcomes

Primary outcome measure

• Mean change from baseline in PM PEF averaged over 12‐week treatment period

Secondary outcome measures

• Mean change from baseline in daily AM PEF averaged over 12‐week treatment period

• Change from baseline in percentage of rescue‐free 24‐hour periods during 12‐week treatment period

• Change from baseline in percentage of symptom‐free 24‐hour periods during 12‐week treatment period

• Change from baseline in total AQLQ score at week 12

Starting date

January 2012

Contact information

GlaxoSmithKline Research and Development Limited

Notes

Trial name or title

A multi‐centee, randomised, double‐blind, dose‐ranging study to evaluate GSK573719 in combination with fluticasone furoate, fluticasone furoate alone and an active control of fluticasone furoate/vilanterol combination in participants with asthma

Methods

Randomised double‐blind cross‐over study

Participants

Participants with asthma. 18 years of age or older

Inclusion criteria

• Outpatient

• 18 years of age or older at visit 1

• Diagnosis of asthma

• Male or eligible female

• Pre‐bronchodilator FEV₁ 40% to 80% of predicted normal value at visit 1

• Demonstrated reversibility by ≥ 12% and ≥ 200 mL of FEV₁ within 40 minutes following albuterol at visit 1

• Need for regular controller therapy (i.e. ICSs alone or in combination with a LABA, or leukotriene modifier, etc.) for a minimum of 8 weeks before visit 1

Exclusion criteria

• History of life‐threatening asthma

• Respiratory infection not resolved

• Asthma exacerbation

• Concurrent respiratory disease

• Current smokers

• Other uncontrolled disease 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 interpretation of efficacy results if the condition/disease was exacerbated during the study

• Positive hepatitis B surface antigen or positive hepatitis C antibody and/or HIV

• Visual clinical evidence of oropharyngeal candidiasis

• Drug or milk protein allergies

• Concomitant medications affecting course of asthma

• Use of any other investigational medication within 30 days or 5 drug half‐lives (whichever is longer)

• Previous use of GSK573719

• Any disease preventing use of anticholinergics

• Any condition that impairs compliance with study protocol including visit schedule and completion of daily diaries

• Any participant with a history of alcohol or substance abuse

• Any affiliation with investigator's site

Interventions

FF 100 mcg vs FF/VI 100/25 mcg vs FF/GSK573719 100/15.6 to 250 mcg

Outcomes

Primary outcome measures

• Change from baseline in trough FEV₁

• FEV₁ value obtained 24 hours after morning dosing on day 14 of each treatment period

Secondary outcome measures

• Mean change from baseline in daily AM/PM PEF

• Mean change from baseline in rescue albuterol use

Starting date

April 2012

Contact information

GlaxoSmithKline Research and Development Limited; [email protected]

Notes

Trial name or title

A 12‐month, open label, randomised, effectiveness study to evaluate fluticasone furoate (GW685698)/vilanterol (GW642444) inhalation powder delivered once‐daily via a novel dry powder inhaler compared with usual maintenance therapy in participants with asthma

Methods

Randomised parallel‐group study

Participants

Participants with asthma. 18 years of age or older

Inclusion criteria

Participants eligible for enrolment in the study must meet all of the following criteria

• Informed consent: Participants must be able to provide informed consent and have their consent signed and dated

• Type of participants: participants with documented GP diagnosis of asthma as their primary respiratory disease

• Current antiasthma therapy: All participants must be prescribed maintenance therapy and must be receiving ICS with or without LABA (fixed combination or via separate inhalers) for ≥ 4 weeks before visit 2. Other background asthma medication such as antileukotrienes are permitted

• All participants receiving ICS monotherapy or ICS/LABA combination (this can be a fixed‐dose combination or an ICS alone or LABA alone in separate inhalers) must have had symptoms in the past week before visit 2. Symptoms are defined by daytime symptoms more than twice per week, use of SABA bronchodilator more than twice per week, any limitation of activities or any nocturnal symptoms/awakening (Symptoms are based on participant's recall and are consistent with GINA and agree in principle with BTS/SIGN guidelines)

• Participant questionnaires: Participants must be able to complete electronic participant questionnaires as well as questionnaires to be completed by phone or must provide a proxy (e.g. partner/relative/friend) who can do so on their behalf

• Gender and age: male or female participants ≥ 18 years of age at visit 1. A female is eligible to enter and participate in the study if she is of: non‐childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post‐menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post‐menopausal females are defined as amenorrhoeic for > 1 year with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However. in questionable cases, a blood sample with FSH > 40 MIU/mL and estradiol < 40 pg/mL (< 147 pmol/L) is confirmatory OR childbearing potential has a negative urine pregnancy test at visit 2, and participant agrees to one of the highly effective and acceptable contraceptive methods used consistently and correctly (i.e. in accordance with approved product label and instructions of the physician for the duration of the study ‐ visit 2 to end of study)

Exclusion criteria

Participants meeting any of the following criteria must not be enrolled in the study

• Recent history of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 6 months

• COPD: Participant must not have current evidence or GP diagnosis of COPD

• Other diseases/abnormalities: participants with historical or current evidence of uncontrolled or clinically significant disease. Significant is defined as any disease that, in the opinion of the GP/investigator, would put the safety of the patient at risk through study participation, or that would affect the efficacy or safety analysis if the disease/condition was exacerbated during the study

• Drug/food allergy: participants with a history of hypersensitivity to any of the study medications (e.g. beta₂‐agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, participants with a history of severe milk protein allergy that, in the opinion of the GP/investigator, contraindicates the participant's participation will also be excluded

• Investigational medications: Participant must not have used any investigational drug within 30 days before visit 2 or within 5 half‐lives (t½) of prior investigational study (whichever is the longer of the 2) (if unsure, discuss with medical monitor before screening)

• Long‐term user of systemic corticosteroids: participant who, in the opinion of the GP/investigator, is considered to be a long‐term user of systemic corticosteroids for respiratory or other indications (if unsure, discuss with the medical monitor before screening)

• Participants who are using LABA without an ICS as asthma maintenance therapy

• Participants who plan to move away from the geographical area where the study is being conducted during the study period and/or if participants have not consented to inclusion of their medical records in the electronic medical records database that is operational in the Salford area

Interventions

GW685698+GW642444 once‐daily via a novel dry powder inhaler vs existing maintenance therapy (ICS alone or in combination with a LABA)

Outcomes

Primary outcome measure

• Percentage of participants who have an ACT total score ≥ 20 at week 24 (6th month) assessment

Secondary outcome measures

• Percentage of participants with asthma control (ACT total score ≥ 20)

• Mean change from baseline in ACT total score

• Percentage of participants who have an increase from baseline of ≥ 3 in ACT total score

• Asthma‐related secondary care contacts

• Asthma‐related primary care contacts

• All secondary care contacts

• All primary care contacts

• Mean annual rate of severe asthma exacerbations

• Number of salbutamol inhalers (adjusted to equivalence of 200 actuations) collected by participants from study‐enrolled community pharmacies over the entire treatment period

• Time to discontinuation or modification of initial therapy

• Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) total score at week 52

• Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) environmental stimuli domain score at week 52

Starting date

November 2012

Contact information

GlaxoSmithKline Research and Development Limited; [email protected]

Notes

Trial name or title

A study to assess the bronchodilator effect of a single dose of fluticasone furoate (FF)/vilanterol (VI) 100/25 micrograms (mcg) combination when administered in adult participants with asthma

Methods

Randomised double‐blind placebo‐controlled cross‐over study

Participants

32 adult participants with moderately severe asthma

Inclusion criteria

• Asthma: a doctor diagnosis of asthma

• Age of participant: 18 to 65 years of age inclusive, at the time of signing the informed consent

• Severity of disease: screening pre‐bronchodilator FEV₁ ≥ 60% of predicted

• Reversibility of disease: demonstrated presence of reversible airway disease at screening

• Current therapy: on ICS with or without a SABA for ≥ 12 weeks before screening. Able to stop current short‐acting beta₂‐agonists (SABAs) and replace with albuterol/salbutamol inhaler

• Body weight and BMI: body weight ≥ 50 kg and BMI within the range 19.0 to 29.9 kg/m² (inclusive)

• Gender: male or female. A female participant is eligible to participate if she is of:

Non‐childbearing potential. Females on HRT and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post‐menopausal status before study enrolment.

Childbearing potential and agrees to use one of the contraception methods for an appropriate period of time (as determined by product label or investigator) before the start of dosing to sufficiently minimise risk of pregnancy at that point. Female participants must agree to use contraception until completion of the follow‐up visit.

• Liver criteria: AST and ALT < 2 × ULN; alkaline phosphatase and bilirubin ≤ 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)

• Consent: capable of giving written informed consent, which includes compliance with requirements and restrictions listed in the consent form

Exclusion criteria

• History of life‐threatening asthma

• Other significant pulmonary disease: pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, COPD, respiratory abnormalities other than asthma

• Respiratory infection: culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of screening that; led to a change in asthma management OR, in the opinion of the Investigator, is expected to affect the participant's asthma status, OR the participant's ability to participate in the study

• Asthma exacerbation: any asthma exacerbation requiring OCS within 12 weeks of screening or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months before screening

• Concomitant medications: use of medications, ICS prohibited for each study period from 24 hours before dosing to 72 hours after dosing; LABA, LTRA or LAMA prohibited for 12 weeks before screening; high doses of an ICS prohibited for 8 weeks before screening; OCS prohibited for 12 weeks before screening; potent CYP3A4 inhibitors prohibited within 4 weeks before dosing. The following medications may not be used during the study from first dosing to the end of period 2 inclusive: anticonvulsants, polycyclic antidepressants, beta‐adrenergic blocking agents, phenothiazines and MAO inhibitors

• Other concurrent diseases/abnormalities: Participant has 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 interpretation of study results if the condition/disease was exacerbated during the study

• Oropharyngeal examination: Participant will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening

• Pregnant and lactating females: pregnant females as determined by positive serum human chorionic gonadotropin (hCG) test at screening or by positive urine hCG test before dosing. Lactating females

• Allergies: milk protein allergy: history of severe milk protein allergy. Drug allergy: any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to constituents of the DPI (i.e. lactose or magnesium stearate). Historical allergy: history of drug or other allergy that, in the opinion of the investigator or the GSK medical monitor, contraindicates participation

• 12‐Lead ECG abnormality: significant abnormality in the 12‐lead ECG performed at screening

• Tobacco use: current smokers or smoking history ≥ 10 pack‐years. Participant may not have used any inhaled tobacco products in the 12‐month period preceding the screening visit

• Previous participation: exposure to more than 4 new chemical entities within 12 months before first dosing day

Interventions

After screening, participant will be randomised and will be assigned to 1 of 2 treatment sequences (AB or BA, where A is placebo and B is FF/VI 100/25 mcg). Between the 2 treatment periods, a washout period of 7 to 14 days will occur

Outcomes

Serial FEV₁ measurements will be taken at 15 and 30 minutes, and at 1, 2, 4, 12, 24, 36, 48, 60 and 72 hours post dose. Safety assessments will include vital signs, ECGs, AE monitoring and laboratory safety tests; however, these will not constitute study endpoints. Results of the study will provide supporting information to prescribers on the bronchodilator effect of FF/VI over 72 hours

Starting date

Information on http://clinicaltrials.gov/ in October 2013 indicated that study was not yet recruiting. Estimated primary completion date: December 2013

Contact information

GlaxoSmithKline Research and Development Limited; [email protected]

Notes

Trial name or title

A study to compare the efficacy and safety of fluticasone furoate (FF) 100 mcg once‐daily with fluticasone propionate (FP) 250 mcg twice‐daily and FP 100 mcg twice‐daily in well‐controlled asthmatic Japanese participants

Methods

Randomised double‐blind multi‐centre parallel‐group study

Participants

Exclusion criteria

• History of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within past 10 years

• Respiratory infection: culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that was not resolved within 8 weeks of visit 1 and led to a change in asthma management or, in the opinion of the investigator, is expected to affect the participant's asthma status or ability to participate in the study

• Asthma exacerbation: any asthma exacerbation requiring systemic corticosteroids or injection within 12 weeks of visit 1, or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months before visit 1

• Concurrent respiratory disease: Participant must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, COPD or any respiratory abnormalities other than asthma

• Other concurrent diseases/abnormalities: Participant must not have a 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 interpretation of efficacy results if the condition/disease was exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to, the following: congestive heart failure, known aortic aneurysm, clinically significant coronary heart disease, clinically significant cardiac arrhythmia, stroke within 3 months of visit 1, uncontrolled hypertension (≥ 2 measurements with systolic BP > 160 mmHg, or DBP > 100 mmHg), recent or poorly controlled peptic ulcer, haematologic, hepatic or renal disease, immunologic compromise, current malignancy (history of malignancy is acceptable only if participant has been in remission for 1 year before visit 1 (remission = no current evidence of malignancy and no treatment for malignancy in the 12 months before visit 1), tuberculosis (current or untreated) (participants with a history of tuberculosis infection who have completed an appropriate course of antituberculous treatment may be suitable for study entry provided there is no clinical suspicion of active or recurrent disease), Cushing's disease, Addison's disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, recent history of drug or alcohol abuse

• Oropharyngeal examination: Participant will not be eligible for the run‐in if he/she has clinical visual evidence of candidiasis at visit 1

• Investigational medications: Participant must not have used any investigational drug within 30 days before visit 1 or within 5 half‐lives (t1/2) of the prior investigational study (whichever is longer of the 2)

• Allergies: drug allergy: any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to constituents of the investigational product (i.e. lactose or magnesium stearate); milk protein allergy: history of severe milk protein allergy

• Concomitant medication: administration of prescription or over‐the‐counter medication that would significantly affect the course of asthma, or interact with study drug, such as anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants; beta‐adrenergic blocking agents; phenothiazines and MAO inhibitors. Immunosuppressive medications: Participant must not be using or require use of immunosuppressive medications during the study.

Note: Immunotherapy is permitted for treatment of allergies during the study, provided it was initiated ≥ 4 weeks before visit 1 and participants remain in the maintenance phase for the duration of the study; cytochrome P450 3A4 (CYP3A4) inhibitors: participants who have received a potent CYP3A4 inhibitor within 4 weeks of visit 1 (e.g. clarithromycin, atazanavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir; ritonavir; saquinavir; telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine)

• Compliance: Participant will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, disease or geographical location that seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of eDiaries and a paper medical conditions diary

• Tobacco use: current smoker or smoking history of 10 pack‐years (e.g. 20 cigarettes/d for 10 years). Participant may not have used inhaled tobacco products within the past 3 months (i.e. cigarettes, cigars or pipe tobacco)

• Affiliation with investigator's site: Participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator or study co‐ordinator, or an employee of the participating investigator

Other exclusion criteria at visit 2 and visit 5

• Evidence of clinically significant abnormal laboratory tests during visit 1 that are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each investigator will use his/her own discretion in determining the clinical significance of the abnormality

• Changes in asthma medication (excluding salbutamol inhalation aerosol provided at visit 1)

• Occurrence of a culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during run‐in and open‐label treatment periods that led to a change in asthma management or, in the opinion of the investigator, is expected to affect participant's asthma status or ability of the participant to participate in the study

• Any asthma exacerbation requiring systemic corticosteroids or injection or that resulted in overnight hospitalisation requiring additional treatment for asthma. Clinical visual evidence of oral candidiasis at visit 2 and visit 5

• Positive urine pregnancy test for all females of childbearing potential at visit 2 and visit 5

• Participants for whom the investigator decides that it is impossible for participant to do "switch (visit 2)" and "step‐down (visit 5)"

Interventions

• Arm 1: FF/VI 100/25 mcg participants will receive FF/VI 100/25 mcg once‐daily via DPI for 8 weeks in the open‐label treatment period

• Arm 2: FF 100 mcg participants will receive FP matching placebo twice‐daily (morning and evening) and FF 100 mcg once‐daily in the evening, via DPI for 12 weeks in the double‐blind treatment period

• Arm 3: FP 250 mcg participants will receive FP 250 mcg twice‐daily (morning and evening) and FF matching placebo once‐daily in the evening, via DPI for 12 weeks in the double‐blind treatment period

• Arm 4: FP 100 mcg participants will receive FP 100 mcg twice‐daily (morning and evening) and FF matching placebo once‐daily in the evening, via DPI for 12 weeks in the double‐blind treatment period

Outcomes

Primary outcome measures

• Time to withdrawal due to poorly controlled (requires step‐up) asthma during period 2

• Proportion of participants with well‐controlled asthma at the end of period 2

Secondary outcome measures

• Mean change from baseline in clinic visit trough FEV₁ at the end of period 2

• Mean change from baseline in daily AM and PM PEF averaged during period 2

• Mean change from baseline in percentage of symptom‐free 24‐hour periods during period 2

• Mean change from baseline in percentage of rescue‐free 24‐hour periods during period 2

• Mean change from baseline in ACT score during period 2

• Proportion of participants with ACT score ≥ 20 at the end of period 2

Starting date

March 2014

Contact information

GlaxoSmithKline Research and Development Limited; [email protected]

Notes

Trial name or title

An efficacy and safety study of fluticasone furoate/vilanterol 100/25 microgram (mcg) inhalation powder, fluticasone propionate/salmeterol 250/50 mcg inhalation powder and fluticasone propionate 250 mcg inhalation powder in adults and adolescents with persistent asthma

Methods

Randomised double‐blind double‐dummy parallel‐group multi‐centre non‐inferiority study

Participants

Inclusion criteria

• Participants must give their signed and dated written informed consent to participate before commencing any study‐related activities

• Participants must be outpatients ≥ 12 years of age at visit 1 who have had a diagnosis of asthma, as defined by the National Institutes of Health, for ≥ 12 weeks before visit 1 (Note: Countries with local restrictions prohibiting enrolment of adolescents will enrol only participants ≥ 18 years of age)

• Participants may be male or an eligible female. An eligible female is defined as having non‐childbearing potential or having childbearing potential and a negative urine pregnancy test at screening and agrees to use an acceptable method of birth control consistently and correctly

• Participants must have a best pre‐bronchodilator FEV₁ ≥ 80% of predicted normal value

• Participants are eligible if they have received mid‐dose ICS plus LABA (equivalent to FP/SAL 250/50 twice‐daily or an equivalent combination via separate inhalers) for at least the 12 weeks immediately preceding visit 1

• All participants must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at visit 1 for use, as needed, for the duration of the study. Participants must be able to withhold albuterol/salbutamol for ≥ 6 hours before study visits

• If in the opinion of the investigator the participant's asthma is well controlled

Exclusion criteria

• History of life‐threatening asthma, defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 5 years

• Culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of visit 1 and led to a change in asthma management or, in the opinion of the investigator, was expected to affect the participant's asthma status or the ability of the participant to participate in the study

• Any asthma exacerbation requiring OCS within 12 weeks of visit 1 or resulting in an overnight hospitalisation requiring additional treatment for asthma within 6 months before visit 1

• Participant must not have current evidence of atelectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic obstructive pulmonary disease, pneumonia, pneumothorax, interstitial lung disease or any evidence of concurrent respiratory disease other than asthma

• Participant 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 interpretation of results if the condition/disease was exacerbated during the study

• Participant must not have used any investigational drug within 30 days before visit 1 or within 5 half‐lives (t½) of the prior investigational study, whichever is longer of the 2

• Any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of RELVAR ELLIPTA inhaler, SERETIDE ACCUHALER/DISKUS inhaler or FP 250

• History of severe milk protein allergy

• Administration of prescription or non‐prescription medication that would significantly affect the course of asthma, or interact with study drug

• Participant must not be using or require the use of immunosuppressive medications during the study

• Participant will not be eligible if he/she or his/her parent or legal guardian has an infirmity, disability, disease or geographical location that seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of daily diaries

• Current tobacco smoker or smoking history of 10 pack‐years (20 cigarettes/d for 10 years). Participant may not have used inhaled tobacco products or inhaled marijuana within the past 3 months (e.g. cigarettes, cigars, electronic cigarettes, pipe tobacco)

• Participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator or study co‐ordinator, or is an employee of the participating investigator

Interventions

• Experimental 1: FF/VI 100/25 mcg by inhalation once‐daily (PM) via ELLIPTA plus placebo by inhalation twice‐daily (AM and PM) via ACCUHALER/DISKUS for 24 weeks. Interventions: drug: FF/VI 100/25 mcg via ELLIPTA inhaler; drug: placebo inhalation powder via ACCUHALER/DISKUS inhaler

• Experimental 2: FP/SAL 250/50 mcg by inhalation twice‐daily (AM and PM) via ACCUHALER/DISKUS plus placebo by inhalation once‐daily (PM) via ELLIPTA for 24 weeks. Interventions: drug: placebo inhalation powders via ELLIPTA inhaler; drug: FP/SAL 250/50 mcg via ACCUHALER/DISKUS inhaler

• Experimental 3: FP 250 mcg by inhalation twice‐daily (AM and PM) via ACCUHALER/DISKUS plus placebo by inhalation once‐daily (PM) via ELLIPTA for 24 weeks

Outcomes

Primary outcome measures

• Change from baseline in clinic visit PM FEV₁ (pre‐bronchodilator and pre‐dose) at the end of the 24‐week treatment period

Secondary outcome measures

• Change from baseline in percentage of rescue‐free 24‐hour periods during 24‐week treatment period

• Change from baseline in percentage of symptom‐free 24‐hour periods during 24‐week treatment period

• Change from baseline in AM PEF averaged over 24‐week treatment period

• Percentage of participants controlled at the end of the 24‐week treatment period

• Change from baseline in PM PEF averaged over 24‐week treatment period

Starting date

February 2015

Contact information

GlaxoSmithKline Research and Development Limited; [email protected]

Notes

Trial name or title

An efficacy and safety study of fluticasone furoate/vilanterol 100/25 microgram (mcg) inhalation powder, FP/SAL 250/50 mcg inhalation powder and fluticasone propionate 250 mcg inhalation powder in adults and adolescents with persistent asthma

Methods

This study is a randomised double‐blind double‐dummy parallel‐group multi‐centre non‐inferiority study

Participants

Inclusion criteria

• Participants must give their signed and dated written informed consent to participate before commencing any study‐related activities

• Participants must be outpatients ≥ 12 years of age at visit 1 who have had a diagnosis of asthma, as defined by the National Institutes of Health, for ≥ 12 weeks before visit 1 (Note: Countries with local restrictions prohibiting enrolment of adolescents will enrol only participants ≥ 18 years of age)

• Participants may be male or an eligible female. An eligible female is defined as having non‐childbearing potential or having childbearing potential and a negative urine pregnancy test at screening and agrees to use an acceptable method of birth control consistently and correctly

• Participants must have FEV₁ ≥ 80% of predicted normal value

• Participants are eligible if they have received mid‐dose ICS plus LABA (equivalent to FP/SAL 250/50 twice‐daily or an equivalent combination via separate inhalers) for at least the 12 weeks immediately preceding visit 1

• All participants must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at visit 1 for use, as needed, for the duration of the study. Participants must be able to withhold albuterol/salbutamol for ≥ 6 hours before study visits

• If in the opinion of the investigator, the participant's asthma is well controlled

Exclusion criteria

• History of life‐threatening asthma, defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 5 years

• Culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of visit 1 and led to a change in asthma management or, in the opinion of the investigator, was expected to affect the participant's asthma status or the participant's ability to participate in the study

• Any asthma exacerbation requiring oral corticosteroids within 12 weeks of visit 1 or resulting in an overnight hospitalisation requiring additional treatment for asthma within 6 months before visit 1

• Participant must not have current evidence of atelectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic obstructive pulmonary disease, pneumonia, pneumothorax, interstitial lung disease, or any evidence of concurrent respiratory disease other than asthma

• Participant 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 interpretation of results if the condition/disease was exacerbated during the study

• Participant must not have used any investigational drug within 30 days before visit 1 or within 5 half‐lives (t½) of the prior investigational study, whichever is longer of the 2

• Any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of RELVAR ELLIPTA inhaler, SERETIDE ACCUHALER/DISKUS inhaler or FP 250

• History of severe milk protein allergy

• Administration of prescription or non‐prescription medication that would significantly affect the course of asthma, or interact with study drug

• Participant must not be using or require the use of immunosuppressive medications during the study

• Participant will not be eligible if he/she or his/her parent or legal guardian has an infirmity, disability, disease or geographical location that seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of daily diaries

• Current tobacco smoker or has a smoking history of 10 pack‐years (20 cigarettes/d for 10 years). Participant may not have used inhaled tobacco products or inhaled marijuana within the past 3 months (e.g. cigarettes, cigars, electronic cigarettes, pipe tobacco)

• Participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator or study co‐ordinator, or an employee of the participating investigator

Interventions

The study will enrol adult and adolescent asthmatic participants who are currently receiving mid‐dose inhaled corticosteroids (ICSs) plus a long‐acting beta₂‐agonist (LABA) (equivalent to FP/SAL 250/50 microgram (mcg) twice‐daily (BD)), via a fixed‐dose combination product or through separate inhalers. The study consists of a LABA washout period of 5 days and a run‐in period of 4 weeks, followed by a treatment period of 24 weeks and a follow‐up contact period of 1 week. The total duration of the study is 30 weeks. Approximately 1461 participants will be randomised to 1 of the following 3 treatments (487 per treatment): FF/VI 100/25 mcg once‐daily (OD) in the evening (PM) via ELLIPTA inhaler plus placebo BD via ACCUHALER/DISKUS; FP/SAL 250/50 mcg BD via ACCUHALER/DISKUS inhaler plus placebo OD (PM) via ELLIPTA inhaler; FP 250 mcg BD via ACCUHALER/DISKUS inhaler plus placebo OD (PM) via ELLIPTA inhaler. In addition, all participants will be supplied with albuterol/salbutamol inhalation aerosol for use as needed to treat acute asthma symptoms

Outcomes

Primary outcome measures

• Change from baseline in clinic visit evening (PM) forced expiratory volume in 1 second (FEV₁) (pre‐bronchodilator and pre‐dose) at the end of the 24‐week treatment period (time frame: baseline and week 24) (designated as safety issue: no) FEV₁ is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. Baseline will be the pre‐dose value obtained at the visit 3 clinic visit. Change from baseline will be calculated as the week 24 value minus the baseline value

Secondary outcome measures

• Change from baseline in percentage of rescue‐free 24‐hour periods during 24‐week treatment period (time frame: baseline and weeks 1 to 24) (designated as safety issue: no). Participants will record the number of inhalations of rescue medication used during the day and night in a daily electronic diary (eDiary). A 24‐hour period in which a participant's responses to both morning and evening assessments indicated no rescue medication use will be considered to be a rescue‐free 24‐hour period. Baseline value will be derived from the last 7 days of the daily eDiary before randomisation of participant. Change from baseline will be calculated as the value during the 24‐week treatment period minus the baseline value

• Change from baseline in percentage of symptom‐free 24‐hour periods during 24‐week treatment period (time frame: baseline and weeks 1 to 24) (designated as safety issue: no). Asthma symptoms will be recorded in a daily eDairy by participants every day morning and evening. A 24‐hour period in which a participant's responses to both morning and evening assessments indicated no symptoms will be considered to be a symptom‐free 24‐hour period. Baseline value will be derived from the last 7 days before randomisation of the participant. Change from baseline will be calculated as the value during the 24‐week treatment period minus the baseline value

• Change from baseline in morning (AM) peak expiratory flow (PEF) averaged over 24‐week treatment period (time frame: baseline and weeks 1 to 24) (designated as safety issue: no). PEF is defined as maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF will be measured by participants using a hand‐held electronic peak flow meter each morning before the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of 3 measurements will be recorded. Change from baseline (defined from the last 7 days before randomisation of the participant) will be calculated as the value of the averaged daily AM PEF over the 24‐week treatment period minus the baseline value

• Percentage of participants controlled at the end of the 24‐week treatment period (time frame: week 24) (designated as safety issue: no). Percentage of participants controlled will be defined using an Asthma Control Test (ACT) score ≥ 20 at the end of the 24‐week treatment period. The ACT is a 5‐item questionnaire developed as a measure of a participant's asthma control that can be quickly and easily completed in clinical practice. The questionnaire will be self completed by participants

• Change from baseline in PM PEF averaged over 24‐week treatment period (time frame: baseline and weeks 1 to 24) (designated as safety issue: no). PEF is defined as maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF will be measured by participants using a hand‐held electronic peak flow meter each evening before the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from baseline (defined as the last 7 days before randomisation of participants) will be calculated as the value of the averaged daily PM PEF over the 24‐week treatment period minus the baseline value

Starting date

March 2015

Contact information

US GSK Clinical Trials Call Center

Notes

Trial name or title

A study to compare the efficacy of fluticasone furoate/vilanterol inhalation powder with usual inhaled corticosteroids (ICS)/long‐acting beta‐agonists (LABA) in persistent asthma

Methods

Multi‐centre open‐label randomised parallel‐group study

Participants

Inclusion criteria

• Informed consent: capable of giving signed informed consent, which includes compliance with requirements and restrictions listed in the consent form and in this protocol

• Gender and age: male or female participants ≥ 18 and ≤ 75 years of age at screening visit

Female participant is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), is not lactating and at least one of the following conditions applies:

• Non‐reproductive potential defined as pre‐menopausal females with 1 of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow‐up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhoea (in questionable cases, a blood sample with simultaneous follicle‐stimulating hormone (FSH) and oestradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)); females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post‐menopausal status before study enrolment

• Reproductive potential and agrees to follow 1 of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days before the first dose of study medication and until week 24

GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP

This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle, or for participants who are and will continue to be abstinent from penile‐vaginal intercourse on a long‐term and persistent basis: contraceptive subdermal implant that meets standard operating procedure (SOP) effectiveness criteria, including a < 1% rate of failure per year, as stated in the product label; intrauterine device or intrauterine system that meets SOP effectiveness criteria, including a < 1% rate of failure per year, as stated in the product label; oral contraceptive, either combined or progestogen alone; injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches; male partner sterilisation with documentation of azoospermia before entry of female participant into the study, and this male is the sole partner for that participant; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository). These allowed methods of contraception are effective only when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.

• Types of participants: participants with documented physician's diagnosis of asthma ≥ 1 year, unsatisfactorily controlled asthma (ACT < 20 at screening and randomisation visit) treated by ICS alone and intended to be treated by ICS/LABA maintenance therapy; participant will be eligible for inclusion in this study only if affiliated with or a beneficiary of a Social Security category

• Current asthma therapy: All participants must be prescribed maintenance therapy and receiving ICS alone without LABA for ≥ 4 weeks before randomisation visit; other background asthma medication such as anti‐leukotrienes or theophylline is permitted as an alternative to ICS alone, if initiated ≥ 4 weeks before screening visit

• Participant questionnaires: Participants must be able to complete the questionnaires themselves

Exclusion criteria:

• History of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 6 months before screening and randomisation visit

• Participants having a severe and unstable asthma, with ACT score < 15 at screening and randomisation visit, history of repeated severe exacerbations (3/y) and/or a severe exacerbation in the previous 6 weeks before screening and randomisation visit

• Chronic obstructive pulmonary disease (COPD): respiratory disease: A participant must not have current evidence or diagnosis of chronic obstructive pulmonary disease at screening visit

• Current or former cigarette smokers with a history of cigarette smoking ≥ 10 pack‐years at screening (number of pack‐years = (number of cigarettes per day/20) × number of years smoked (e.g. 20 cigarettes per day for 10 years, 10 cigarettes per day for 20 years))

• Other diseases/abnormalities: participants with historical or current evidence of uncontrolled or clinically significant disease at screening and randomisation visit. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would affect the efficacy or safety analysis if the disease/condition was exacerbated during the study

• Participants with a history of adverse reaction, including immediate or delayed hypersensitivity to any intranasal, inhaled or systemic corticosteroid and LABA therapy and to components of the inhalation powder (e.g. lactose, magnesium stearate) at screening and randomisation visit. In addition, participants with a history of severe milk protein allergy that, in the opinion of the Investigator, contraindicates the participant's participation

• Investigational medications: A participant must not have used any investigational drug within 30 days before randomisation visit or within 5 half‐lives (t½) of the prior investigational study (whichever is longer of the 2) (if unsure, discuss with the medical monitor before screening)

• Long‐term user of systemic corticosteroids: participant who, in the opinion of the Investigator, is considered to be a long‐term user of systemic corticosteroids for respiratory or other indications (if unsure, discuss with the medical monitor before screening) at screening visit

• Participants treated by the monoclonal antibody omalizumab at screening visit. Treatment with omalizumab is not allowed during the study

• Participants involved in other clinical trials at screening visit

• Affiliation with investigator site: is an investigator, sub‐investigator, study co‐ordinator or employee of a participating investigator or study site, or immediate family member of the aforementioned who is involved in this study

• Participants who plan to move away during the study from the geographical area where the study is being conducted

Interventions

To evaluate the efficacy and safety of FF/VI compared with 2 usual ICS/LABA fixed combinations (FP/SAL or budesonide/formoterol (BUD/F)) in participants with persistent asthma, in "close to real life" settings. FF/VI will be administered once‐daily (QD) via ELLIPTA dry powder inhaler (DPI), and FP/SAL or BUD/F will be administered twice‐daily (BID) via DISKUS and TURBUHALER DPI, respectively. ELLIPTA is a new powder inhaler designed to be easy to use. The total duration of individual participation will be approximately 6 months (24 weeks)

Outcomes

Primary outcome measures

• Change from baseline in Asthma Control Test (ACT) total score at week 12 (time frame: baseline and week 12) (designated as safety issue: no). ACT is a validated self administered questionnaire utilising 5 questions to assess asthma control during the past 4 weeks on a 5‐point categorical scale (1 to 5). The total score is calculated as the sum of the scores from all 5 questions. By answering all 5 questions, a participant with asthma can obtain a score that may range between 5 and 25, with higher scores indicating better control. Change from baseline was calculated as total ACT score at week 12 minus total ACT score at baseline

Secondary outcome measures

• Change from baseline in ACT score at week 24 (time frame: baseline and week 24) (designated as safety issue: no). ACT is a validated self administered questionnaire utilising 5 questions to assess asthma control during the past 4 weeks on a 5‐point categorical scale (1 to 5). The total score is calculated as the sum of the scores from all 5 questions. By answering all 5 questions, a participant with asthma can obtain a score that may range between 5 and 25, with higher scores indicating better control. Change from baseline was calculated as total ACT score at week 24 minus total ACT score at baseline

• Percentage of participants making at least 1 Type A error (likely to be critical) and overall errors at week 12 and at week 24 independent of use at week 12 (time frame: week 12 and week 24) (designated as safety issue: no). Participants will be asked to read the instruction leaflet of the assigned device and will be instructed by the investigator on the proper use of inhalers. Then, participant will be asked to self administer dose of assigned study drug. Any errors (critical or non‐critical) made by the participant will be recorded by the healthcare professional (HCP). A critical error is defined as an error that may impact the ability of the drug to reach the lung and hence impact efficacy. Overall errors includes non‐critical errors

Starting date

July 2015

Contact information

US GSK Clinical Trials Call Center

Notes

Trial name or title

Crossover study comparing fluticasone furoate (FF)/vilanterol (VI) once‐daily versus fluticasone propionate (FP) twice‐daily in participants with asthma and exercise‐induced bronchoconstriction (EIB)

Methods

Multi‐centre randomised double‐blind double‐dummy cross‐over study with two 2‐week treatment periods separated by a 2‐week washout period

Participants

Participants with asthma and exercise‐induced bronchoconstriction (EIB) between 12 and 50 years of age

Inclusion criteria

Participants eligible for enrolment in the study must meet the following criteria

• Informed consent: Participants must give their signed and dated written informed consent to participate before commencing any study‐related activities

• Age range: 12 to 50 years of age, inclusive, at visit 1 (screening)

• Diagnosis: diagnosis of asthma, as defined by the National Institutes of Health for ≥ 12 weeks before visit 1

• Asthma severity: Participants must have a pre‐bronchodilator FEV₁ ≥ 70% of predicted normal value. Predicted values will be based upon Global Lung Function Initiative equations for spirometry reference values

• Evidence of EIB: Participants must answer "Yes" to at least 2 of the following 3 questions reflecting on the previous 12 months: Are you short of breath during exercise or other physical exertion? Do you wheeze after exercise or other physical exertion? Do you cough after exercise or other physical exertion?

• Concurrent antiasthma therapy: Participants must be taking low‐ to moderate‐dose inhaled steroids for 12 weeks before visit 1 to participate, with no change in dose for the 4 weeks before visit 1

• Gender: Participants may be male or an eligible female. A female is eligible to enter and participate in the study if she is of non‐childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post‐menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post‐menopausal females are defined as amenorrhoeic for longer than 1 year, with an appropriate clinical profile (e.g. age appropriate, > 45 years), in the absence of hormone replacement therapy

OR

• Childbearing potential: has a negative pregnancy test at screening, and agrees to acceptable contraceptive methods approved in local country, when used consistently and correctly (i.e. in accordance with the approved product label and instructions of the physician for the duration of the study ‐ screening to follow‐up contact)

• Albuterol/salbutamol use: All participants must be able to replace their current short‐acting beta₂‐agonist with albuterol/salbutamol, to be used only on an as‐needed basis for the duration of the study. Each participant must be judged capable of withholding albuterol/salbutamol for ≥ 6 hours before performing spirometric evaluations

• Physical capacity: Each participant must be physically able to perform exercise challenges on a treadmill when bronchodilators have been withheld

Exclusion criteria

Participants are not eligible for enrolment in the study if they meet the following criteria

• Intermittent asthma, seasonal asthma or exercise‐induced bronchoconstriction only: Participants with only intermittent or seasonal asthma or only exercise‐induced asthma are excluded from participation in this study

• History of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 10 years

• Asthma exacerbation: any asthma exacerbation requiring oral corticosteroids within 12 weeks of visit 1, or that resulted in an overnight hospitalisation requiring additional treatment for asthma within 6 months before visit 1

• Symptomatic allergic rhinitis: Participants with symptomatic allergic rhinitis at visit 1 may be treated for up to 4 weeks with intranasal corticosteroids, followed by a repeat screening visit to determine eligibility before entry into the study. Participants who continue to be symptomatic after up to 4 weeks of treatment will be excluded

• 12‐Lead electrocardiogram (ECG): A participant is not eligible if he/she has an abnormal, clinically significant ECG as determined by investigator at the screening visit.

• Pregnancy: women who are pregnant or lactating or are planning on becoming pregnant during the study

• Respiratory infection: culture‐documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of visit 1 and led to a change in asthma management or, in the opinion of the investigator, is expected to affect participant's asthma status or ability of participant to participate in the study

• Concurrent respiratory disease: A participant must not have current evidence of atelectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic obstructive pulmonary disease (COPD) (current or past diagnosis including asthma/COPD overlap), pneumonia, pneumothorax, interstitial lung disease or any evidence of concurrent respiratory disease other than asthma

• Other concurrent diseases/abnormalities: A participant 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 interpretation of efficacy results if the condition/disease was exacerbated during the study

• Investigational medications: A participant must not have used any investigational drug within 30 days before visit 1 or within 5 half‐lives (t1/2) of the prior investigational study, whichever is longer of the 2 periods

• Allergies: drug allergy: any adverse reaction including immediate or delayed hypersensitivity to any beta₂‐agonist or sympathomimetic drug, or to any intranasal, inhaled or systemic corticosteroid therapy, or excipients used with FF/VI 100/25 or FP 250 (i.e. drug, lactose or magnesium stearate); milk protein allergy: history of severe milk protein allergyl latex allergy: history of allergy or sensitivity to latex that, in the opinion of the investigator, contraindicates participation of the patient in the study

• Concomitant medication: administration of prescription or non‐prescription medication that would significantly affect the course of asthma, or interact with study drug

• Immunosuppressive medication: A participant must not be using or require the use of immunosuppressive medications during the study

• Compliance: A participant will not be eligible if he/she or his/her parent or legal guardian has an infirmity, disability, disease or geographical location that seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol

• Tobacco/Marijuana use: current tobacco smoker or has a smoking history of ≥ 10 pack‐years (20 cigarettes/d for 10 years). Participant may not have used inhaled tobacco products or inhaled marijuana within the past 3 months (e.g. cigarettes, cigars, electronic cigarettes, pipe tobacco)

• Affiliation with investigator's site: Participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator or study co‐ordinator, or an employee of the participating investigator

Interventions

This study is designed to compare fluticasone furoate (FF)/vilanterol (VI) once‐daily vs fluticasone propionate (FP) twice‐daily in participants with asthma and exercise‐induced bronchoconstriction (EIB)

Outcomes

Primary outcome measures

• Maximal percent decrease from pre‐exercise forced expiratory volume in 1 second (FEV₁) following exercise challenge at 12 hours post evening dose at the end of 2‐week treatment period

• Maximal percent decrease will be defined as percent change from pre‐exercise FEV₁ to minimum FEV₁ collected within 1 hour following exercise challenge at 12 hours post dose

Secondary outcome measures

• Maximal percent decrease from pre‐ exercise FEV₁ following exercise challenge at 23 hours post evening dose at the end of 2‐week treatment period

• Maximal percent decrease will be defined as percent change from pre‐exercise FEV₁ to minimum FEV₁ collected within 1 hour following exercise challenge at 23 hours post dose. Pre‐exercise FEV₁ will be defined as FEV₁ value collected before the exercise challenge test at 23 hours post dose. Serial spirometry will be performed at time points 5, 10, 15, 30, 45 and 60 minutes post exercise challenges

• Proportion of participants with a 30‐minute post‐challenge FEV₁ that was no more than 5% lower than their pre‐exercise FEV₁ following the exercise challenge at 12 hours and 23 hours post evening dose at the end of 2‐week treatment period

• Serial spirometry will be performed at time points 5, 10, 15, 30, 45 and 60 minutes post exercise challenges

• Weighted mean for percent decrease from pre‐exercise FEV₁ following exercise challenge at 12 hours and 23 hours post evening dose at the end of 2‐week treatment period

• Serial spirometry will be performed at time points 5, 10, 15, 30, 45 and 60 minutes post exercise challenges

Starting date

March 2016

Contact information

GlaxoSmithKline

Notes

Trial name or title

A study to evaluate the effect of fluticasone/formoterol breath actuated inhaler (BAI) or Relvar Ellipta DPI on ventilation heterogeneity in asthma

Methods

A randomised assessor‐blinded parallel‐group trial

Participants

Inclusion criteria for participants on Seretide Accuhaler 250/50 µg at screening

• Male and female participants ≥ 18 years old

• Adequate contraception

• Documented clinical history of asthma for ≥ 6 months before screening visit

• Using Seretide Accuhaler at a stable dose of 250/50 μg twice‐daily at screening for ≥ 8 weeks

• Uncontrolled asthma as defined by Asthma Control Questionnaire (ACQ‐6) score ≥ 1.0

• R5‐R20 ≥ 0.10 kPa/L/s as measured on impulse oscillometry during screening visit

• Historical evidence (within 24 months) of eosinophilic airways disease evidenced by sputum eosinophil count ≥ 3% and/or FeNO 35 ppb

Inclusion criteria for participants on equivalent /higher dose or other ICS‐LABAs or higher dose of Seretide at screening

• Male and female participants ≥ 18 years old

• Adequate contraception

• Documented clinical history of asthma for ≥ 6 months before screening visit

• R5‐R20 ≥ 0.07 kPa/L/s as measured on impulse oscillometry during screening visit 5. Historical evidence (within past 24 months) of eosinophilic airways disease, evidenced by sputum eosinophil count ≥ 3% and/or FeNo ≥ 35 ppb

Exclusion criteria for all participants

• Any severe chronic respiratory disease other than asthma

• Participant has a smoking history ≥ 10 "pack‐years" (i.e. ≥ 1 pack of 20 cigarettes/d for 10 years or 10 packs/d for 1 year, etc)

• Current smoking history within 12 months before screening visit

• Near fatal or life‐threatening (including intubation) asthma within the past year

• Known history of systemic (injectable or oral) corticosteroid medication within 1 month of visit 1

• Evidence of clinically unstable disease as determined by medical history or physical examination that, in the investigator's opinion, precludes entry into the study. 'Clinically unstable' is defined as any disease that, in the opinion of the Investigator, would put the patient at risk through study participation, or would affect the outcome of the study

• In the investigator's opinion, a clinically significant upper or lower respiratory infection within 4 weeks before visit 1

• Current evidence or known history of alcohol and/or substance abuse within 12 months before screening visit

• Participant has taken β‐blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, astemizole, quinidine type antiarrhythmics or potent CYP 3A4 inhibitors such as ketoconazole within 1 week before screening visit

• Current use of bronchodilators/anti‐inflammatory agents other than those specified in the protocol

• Known or suspected sensitivity to study drug or excipients

• Participation in a clinical drug study within 30 days of screening visit

• Current participation in a clinical study

Exclusion criteria for participant or participants undergoing OR‐MRI and HD‐CT

• Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to presence of non‐MRI compatible artificial heart valves, hydrocephalus shunts, intracranial aneurysm clips, joint replacements or metal implants, pacemakers or other cardiac rhythm management devices, claustrophobia, history of metal in the eye, presence of shrapnel from a war injury, callipers or braces, dentures, dental plates or hearing aids that include metal and cannot be removed, history of epilepsy or blackouts, ear implants, piercings that cannot be removed, intrauterine contraceptive device or coil

• Inability to stay in the supine position for the duration of the scanning procedure

• Obesity (body weight > 140 kg)

Interventions

Comparison between fluticasone/formoterol BAI vs fluticasone/vilanterol DPI (Relvar Ellipta DPI)

Outcomes

Primary outcome measures

• Measurement of peripheral airway resistance (R5‐R20)

• Measurement of peripheral airway resistance (R5‐R20)

Secondary outcome measures

• Ventilation heterogeneity (using functional respiratory imaging)

• Distal airway volume and resistance (using impulse oscillometry)

• Evaluation of asthma control (using ACQ‐6)

• Evaluation of health status (using AQLQ

Starting date

April 2016

Contact information

Mundipharma Research Limited

Notes

Trial name or title

A randomised effectiveness study comparing fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) with standard treatment in chronic obstructive pulmonary disease (COPD)

Methods

This is a phase III multi‐centre randomised open‐label study

Participants

Inclusion criteria

Participants eligible for enrolment in the study must meet all of the following criteria

• Types of participants: participants with documented GP diagnosis of COPD, and currently receiving maintenance therapy

• Informed consent: Participants must be able to provide informed consent, have their consent signed and dated. Participants must be able to complete the electronic participant questionnaires or allow a proxy to do so on their behalf

• Gender and age: male or female participants ≥ 40 years of age at visit 1. A female is eligible to enter and participate in the study if she is of non‐childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post‐menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post‐menopausal females are defined as amenorrhoeic for longer than 1 year with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However, in questionable cases, a blood sample with FSH > 40 MIU/mL and oestradiol < 40 pg/mL (< 140 pmol/L) is confirmatory. Or with childbearing potential has a negative urine pregnancy test at visit 2, and agrees to 1 of the highly effective and acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and instructions of the physician for the duration of the study ‐ visit 2 to the end of the study)

• Participants with exacerbation history

• Current COPD maintenance therapy

Exclusion criteria

Participants meeting any of the following criteria must not be enrolled in the study

• Participants with any life‐threatening condition (e.g. low probability (in the opinion of the GP/Investigator) of 12‐month survival due to severity of COPD or co‐morbid condition) at point of entry into the study

• Other diseases/abnormalities: participants with historical or current evidence of uncontrolled or clinically significant disease. Significant is defined as any disease that, in the opinion of the GP/ Investigator, would put the safety of the patient at risk through participation or would affect the efficacy or safety analysis if the disease/condition was exacerbated during the study

• Participants with unstable COPD, defined as the occurrence of the following in the 2 weeks before visit 2: acute worsening of COPD that is managed by the participant with corticosteroids or antibiotics or that requires treatment prescribed by a physician

• Long‐term user of oral corticosteroids: participants who, in the opinion of the GP/Investigator, are considered to be long‐term users of oral corticosteroids for respiratory or other indications (if unsure, discuss with the medical monitor before screening)

• Drug/food allergy: participants with a history of hypersensitivity to any of the study medications (e.g. beta‐agonists, corticosteroids) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, participants with a history of severe milk protein allergy that, in the opinion of the GP/investigator, contraindicates the patient's participation

• Investigational medications: A participant must not have used any investigational drug treatment within 30 days before visit 2 or within 5 half‐lives (t½) of the prior investigational study (whichever is the longer of the 2)

• Participants who plan to move away during the study period from the geographical area where the study is being conducted and/or participants who have not consented to inclusio of their medical records in the electronic medical records database that is operational in the Salford area

Interventions

This study is designed to compare the effectiveness and safety of FF/VI. Inhalation powder (100 mcg FF, GW685698)/25 mcg VI, GW642444)) delivered once‐daily via a novel dry powder inhaler (NDPI) compared with existing COPD maintenance therapy over 12 months in participants diagnosed with COPD. Participants who meet eligibility criteria are randomised and will enter a 12‐month treatment period

Outcomes

Primary outcome measures

• Mean annual rate of moderate and severe exacerbations (time frame: 12 months) (designated as safety issue: no). A moderate exacerbation is defined by the participant receiving an exacerbation‐related prescription of oral corticosteroids and/or antibiotic (with NHS contact) not requiring hospitalisation. A severe exacerbation is defined as an exacerbation‐related hospitalisation

Secondary outcome measures

• Variety of healthcare utilisation endpoints (time frame: 12 months). (designated as safety issue: no). Healthcare utilisation

• Serious adverse events and non‐serious adverse drug reactions (time frame: 12 months). (designated as safety issue: no). Frequency and types of serious adverse events and non‐serious adverse drug reactions

• Patient‐reported outcomes (time frame: 12 months). (designated as safety issue: no). Patient‐reported outcomes

Starting date

January 2012

Contact information

GlaxoSmithKline

Notes

Trial name or title

An effectiveness study comparing fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) with standard treatment in asthma

Methods

Multi‐centre randomised open‐label study

Participants

Inclusion criteria

Participants eligible for enrolment in the study must meet all of the following criteria

• Informed consent: Participants must be able to provide informed consent, have their consent signed and dated

• Types of participants: participants with documented GP diagnosis of asthma as their primary respiratory disease

• Current antiasthma therapy: All participants must be prescribed maintenance therapy and must be receiving ICS with or without LABA (fixed combination or via separate inhalers) and for at least 4 weeks before visit 2. Other background asthma medications such as anti‐leukotrienes are permitted

• All participants receiving ICS monotherapy or ICS/LABA combination (this can be a fixed‐dose combination or an ICS alone or LABA alone in separate inhalers) must have had symptoms in the past week before visit 2. Symptoms are defined by daytime symptoms more than twice per week, use of a short‐acting beta₂‐agonist bronchodilator more than twice per week, any limitation of activities or any nocturnal symptoms/awakening (Symptoms are based on participant's recall and are consistent with the GINA and in principle with BTS/SIGN guidelines)

• Participant questionnaires: Participants must be able to complete the electronic participant questionnaires as well as those questionnaires completed by phone or provide a proxy (e.g. partner/relative/friend who can do so on their behalf)

• Gender and age: male or female participants ≥ 18 years of age at visit 1. A female is eligible to enter and participate in the study if she is of:non‐childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post‐menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post‐menopausal females are defined as amenorrhoeic for longer than 1 year with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However, in questionable cases, a blood sample with FSH > 40 MIU/mL and oestradiol < 40 pg/mL (< 147 pmol/L) is confirmatory

OR

Childbearing potential with a negative urine pregnancy test at visit 2, and agrees to one of the highly effective and acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and instructions of the physician for the duration of the study ‐ visit 2 to the end of the study)

Exclusion criteria

Participants meeting any of the following criteria must not be enrolled in the study

• Recent history of life‐threatening asthma: defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the past 6 months

• COPD: respiratory disease: Participant must not have current evidence or GP diagnosis of chronic obstructive pulmonary disease

• Other diseases/abnormalities: participants with historical or current evidence of uncontrolled or clinically significant disease. Significant is defined as any disease that, in the opinion of the GP/investigator, would put the safety of the patient at risk through study participation or would affect the efficacy or safety analysis if the disease/condition was exacerbated during the study

• Drug/food allergy: participants with a history of hypersensitivity to any of the study medications (e.g. beta₂‐agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, participants with a history of severe milk protein allergy that, in the opinion of the GP/ Investigator, contraindicates the patient's participation

• Investigational medications: Participant must not have used any investigational drug within 30 days before visit 2 or within 5 half‐lives (t½) of the prior investigational study (whichever is longer of the 2) (if unsure, discuss with the medical monitor before screening)

• Long‐term user of systemic corticosteroids: participant who, in the opinion of the GP/investigator, is considered to be a long‐term user of systemic corticosteroids for respiratory or other indications (if unsure, discuss with the medical monitor before screening)

• Participants who are using LABA without an ICS as asthma maintenance therapy

• Participants who plan to move away during the study period from the geographical area where the study is being conducted and/or participants who have not consented to inclusion of their medical records in the electronic medical records database that is operational in the Salford area

Interventions

This study is designed to compare the effectiveness and safety of FF/VI inhalation powder ((100 mcg FF), GW685698)/25 mcg VI, GW642444) or 200 mcg FF, GW685698)/25 mcg VI, GW642444)) delivered once‐daily via a novel dry powder inhaler (NDPI) compared with the existing asthma maintenance therapy over 12 months in participants diagnosed with asthma. Participants who meet the eligibility criteria are randomised and will enter a 12‐month treatment period

Outcomes

Primary outcome measures

• Percentage of participants who have an ACT total score ≥ 20 at week 24 (6th month) assessment (time frame: week 24) (designated as safety issue: no]

• Percentage of participants who have an ACT total score ≥ 20 at week 24 (6th month) assessment

Secondary outcome measures

• Percentage of participants with asthma control (ACT total score ≥ 20) (time frame: weeks 12, 40 and 52) (designated as safety issue: no). Percentage of participants with asthma control (ACT total score ≥ 20)

• Mean change from baseline in ACT total score (time frame: weeks 12, 24, 40 and 52) (designated as safety issue: no). Mean change from baseline in ACT total score

• Percentage of participants who have an increase from baseline ≥ 3 in ACT total score (time frame: weeks 12, 24, 40 and 52) (designated as safety issue: no). Percentage of participants who have an increase from baseline ≥ 3 in ACT total score

• Asthma‐related secondary care contacts (time frame: 12 months) (designated as safety issue: no). Asthma‐related secondary care contacts

• Asthma‐related primary care contacts (time frame: 12 months) (designated as safety issue: no). Asthma‐related primary care contacts

• All secondary care contacts (time frame: 12 months) (designated as safety issue: no). All secondary care contacts

• All primary care contacts (time frame: 12 months) (designated as safety issue: no). All primary care contacts

• Mean annual rate of severe asthma exacerbations (time frame: 12 months) (designated as safety issue: no). Mean annual rate of severe asthma exacerbations

• Number of salbutamol inhalers (adjusted to equivalence of 200 actuations) collected by participants from study‐enrolled community pharmacies over the entire treatment period (time frame: 12 months) (designated as safety issue: no). Number of salbutamol inhalers (adjusted to equivalence of 200 actuations) collected by participants from study‐enrolled community pharmacies over the entire treatment period

• Time to discontinuation or modification of initial therapy (time frame: 12 months) (designated as safety issue: no). Time to discontinuation or modification of initial therapy

• Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) total score at week 52 (time frame: week 52) (designated as safety issue: no). Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) total score at week 52

• Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) environmental stimuli domain score at week 52 (time frame: week 52) (designated as safety issue: no). Percentage of participants who have an increase from baseline ≥ 0.5 in AQLQ(S) environmental stimuli domain score at week 52

Starting date

November 2012

Contact information

US GSK Clinical Trials Call Center

Notes