A Non-inferiority Study to Evaluate Efficacy, Safety and Tolerability of NEUMOTEROL® 400 and SYMBICORT® Forte in Adults With Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: NEUMOTEROL 400 (BFF 400/12 mcg) single capsule inhaler; SYMBICORT forte (BFF 320/9mcg) TURBUHALER inhaler; NEUMOTEX 400 (Budesonide 400 mcg); Salbutamol 100 mcg pMDI
Intervention description: Micronized 400 mcg budesonide+ 12 mcg formoterol fumarate along with micronized and crystalline lactose monohydrate (excipient), per capsule dispensed by single capsule inhaler, twice daily (administered once in the morning and once in the evening approximately 12 hours later).; Unit dose containing 320 mcg budesonide and 9 mcg formoterol fumarate (as dihidrate) along with lactose monohydrate as excipient. Administered as inhalation by TURBUHALER inhaler, twice daily (once in the morning and once in the evening approximately 12 hours later); Budesonide 400mcg will be administered to all the subjects twice daily, during the Run-in and Washout Periods; Salbutamol 100mcg will be administered as pMDI on demand, as rescue medication, throughout the entire study period until Visit 5
Intervention MeSH terms: Budesonide; Albuterol; Budesonide, Formoterol Fumarate Drug Combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 239.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: tolerability; NEUMOTEROL; efficacy; budesonide/formoterol fumarate 400/12 mcg; safety; Asthma; pharmacodynamics

Summary:

      This Phase IV study is an a multi-centre, randomised open label, two way cross-over design to
      evaluate the efficacy, safety, and tolerability of NEUMOTEROL 400 in subjects with asthma.
      The study will be used to demonstrate the non-inferiority of Budesonide/Formoterol Fumarate
      combination (BFF) 400/12 micrograms (mcg) single capsule inhaler (NEUMOTEROL 400) compared
      with BFF 320/9 mcg SYMBICORT Forte TURBUHALER® inhaler.

      The population for this study will be adult subjects (>=18 and <=80 years) with a diagnosis
      of asthma who have a pre-bronchodilator forced expiratory volume in one second (FEV1) of 40%
      to 85% of the predicted normal value, and are receiving a stable dose of inhaled
      corticosteroid inhaled corticosteroid (ICS) with or without long-acting beta-adrenergic
      agonist (LABA) prior to screening.

      The study will consist of six phases: Prescreening, Screening/Run-in (4 weeks), Treatment
      Period 1 (4 weeks), Washout (minimum 4 weeks), Treatment Period 2 (4 weeks) and Follow-up (1
      week). The total duration of the study for each subject will be at least 17 weeks. There will
      be up to 6 study visits and a follow-up telephone call.

      Pre-screening Visit will allow subjects who had recent asthma medication changes to be
      stabilized prior to Screening. During the run-in and wash-out periods, all the subjects will
      receive budesonide dry powder inhaler (DPI) 400 mcg twice daily (BID) (NEUMOTEX™ 400) and
      salbutamol 100mcg pressurized metered dose inhaler (pMDI) on demand, as rescue medication.
      The dose of NEUMOTEROL 400 (400/12 mcg) and SYMBICORT Forte (320/9 mcg) will be one
      inhalation BID, and each treatment will be given to all subjects for 4 weeks (with a 4-week
      Washout Period between treatments).

      The study will include 300 subjects for screening so that at least 210 will be randomised and
      a minimum of 168 subjects complete the study/are evaluable. Half the subjects will be on
      Regimen A in Treatment Period 1and will then be crossed over to Regimen B in Treatment Period
      2, and vice versa. Regimen A: BFF (400/12 mcg) by single capsule inhaler. Regimen B: BFF
      (320/9 mcg) TURBUHALER inhaler. The treatment periods will be separated by a washout Period
      of 4 weeks.

      NEUMOTEROL and NEUMOTEX are trademarks of the GSK group of companies SYMBICORT and TURBUHALER
      are trademarks of AstraZeneca
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female >=18 and <=80 years of age with a diagnosis of asthma at the time of
             signing the informed consent

          -  A female subject is eligible to participate if she is of: Non-child bearing potential
             defined as premenopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a
             blood sample with simultaneous follicle stimulating hormone >40 milli-international
             unit/milliliter (mIU/mL) and oestradiol <40 picogram/millilitre (pg/mL) [<147
             picomol/litre] is confirmatory) ; Females on hormone replacement therapy (HRT) and
             whose menopausal status is in doubt will be required to use one of the contraception
             methods (i.e., in accordance with the approved product label and the instructions of
             the physician for the duration of the study from Screening to follow-up contact) if
             they wish to continue their HRT during the study. Otherwise, they must discontinue HRT
             to allow confirmation of postmenopausal status before study enrolment. For most forms
             of HRT, at least 2 to 4 weeks should elapse between the cessation of therapy and the
             blood draw; this interval depends on the type and dosage of HRT. After confirmation of
             their postmenopausal status, they can resume use of HRT during the study without use
             of a contraceptive method; Child-bearing potential and is abstinent or agrees to use
             one of the contraception methods for an appropriate period of time (as determined by
             the product label or investigator) before the start of dosing to sufficiently minimise
             the risk of pregnancy at that point. Female subjects must agree to use contraception
             until at least 2 days post the last dose of study treatment ; Abstinence from
             penile-vaginal intercourse must be consistent with the preferred and usual lifestyle
             of the subject

          -  Severity of disease: A best pre-bronchodilator FEV1 of >=40% to <=85% of the predicted
             normal value at Visit 1 (Screening and Run-in Visit). . Percent predicted will be
             calculated using the European Respiratory Society Global Lung Function Initiative
             reference equations.

          -  Reversibility of disease: Demonstrated >=12% and >=200 mL reversibility of FEV1 within
             10 to 40 minutes after 2 to 4 inhalations of salbutamol inhalation aerosol (or
             equivalent nebulised treatment with salbutamol solution) at Visit 1 (Screening and
             Run-in Visit)

          -  Current anti-asthma therapy: All subjects must be using an ICS with or without LABA
             for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening
             and Run-in Visit). Two populations are eligible for enrolment: Subjects maintained on
             ICS monotherapy (Budesonide 400 mcg to 800 mcg BID or equivalent) for at least 8 weeks
             and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit) or
             Subjects maintained on an ICS/LABA combination product (e.g., NEUMOTEROL 200/6 BID or
             400/12 mcg BID or equivalent by other combination products or by separate inhalers)
             for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening
             and Run-in Visit). Subjects taking budesonide/formoterol as needed must switch to
             maintenance dosing (excluding the highest dose) with use of a SABA for symptom relief
             at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and
             Run-in Visit). NOTE: Subjects on low dose ICS monotherapy should only be enrolled, if,
             in the opinion of the investigator, after review of their medical history and clinical
             examination, they will be able to benefit from both an increase in ICS dose and the
             addition of LABA therapy arising from and ICS/LABA combination

          -  Ability to withhold LABA therapy : Other than what is provided during the study, LABA
             therapy is not permitted on the day of Visit 1(Screening and Run-in Visit) and
             throughout the entire study. The last dose of pre-study LABA and LABA/ICS combinations
             are to be taken on the day before Visit 1. According to investigators judgement,
             patients should be able to withhold LABA therapy during the run-in and wash-out
             period.

          -  SABA: All subjects must be able to replace their current SABA treatment with rescue
             salbutamol at Visit 1 (Screening and Run-in Visit) for use as needed for the duration
             of the study. Subjects must be able to withhold salbutamol for at least 6 hours before
             each study visit

          -  Liver safety criteria: Alanine aminotransferase (ALT) <=2×the upper limit of normal
             (ULN), Alkaline phosphatase and bilirubin <=1.5×ULN (isolated bilirubin >1.5×ULN is
             acceptable if bilirubin is fractionated and direct bilirubin is <35%) at Visit 1
             (Screening and Run-in Visit)

          -  Electrocardiography (ECG) safety criteria : The subject must have no ECG abnormalities
             that would, in the opinion of investigator, compromise subject safety, or
             significantly affect subject's ability to complete the trial. As such, the
             investigator will determine the clinical significance of any ECG abnormality and
             determine if a subject is precluded from entering the study. At Visit 1 (Screening and
             Run-in Visit), ECG safety criteria must be: QT interval corrected for heart rate (QTc)
             <450 microseconds (msec) or QTc <480 msec for patients with bundle branch block. The
             QTc is the QT interval corrected for heart rate according to either Bazett's formula
             (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread.
             The QTc should be based on single or averaged QTc values of triplicate ECGs obtained
             over a brief recording period. Investigators will be responsible for ensuring
             appropriate clinical interpretation of ECGs.

          -  The subject and/or the subject's legal guardian (if applicable) must be capable of
             giving informed consent/assent, which includes compliance with the study requirements
             and restrictions listed in the consent/assent form

        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 10 years

          -  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 (Screening and Run-in Visit) and led to a change in asthma
             management, or in the opinion of the investigator, is expected to affect the subject's
             asthma status or ability to participate in the study

          -  Asthma exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12
             weeks of Visit 1 (Screening and Run-in Visit)or that resulted in overnight
             hospitalisation requiring additional treatment for asthma within 6 months before Visit
             1 (Screening and Run-in Visit)

          -  Asthma severely uncontrolled: ACT bellow 15 at Visit 1

          -  Concurrent respiratory disease: A subject must not have current evidence of pneumonia,
             pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia,
             chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), or other
             respiratory abnormalities other than asthma

          -  Other concurrent diseases/abnormalities: A subject must not have any clinically
             significant, uncontrolled condition or disease state that, in the opinion of the
             investigator, would put the safety of the subject at risk through study participation
             or would confound the interpretation of the efficacy results if the condition/disease
             exacerbated during the study. Additional excluded conditions/diseases may include (but
             not limited to): congestive heart failure, known aortic aneurysm, clinically
             significant coronary heart disease, clinically significant cardiac arrhythmia, stroke
             within 3 months of Visit 1 (Screening and Run-in Visit), uncontrolled hypertension
             (two or more measurements with systolic blood pressure [BP] >160 millimeter mercury
             [mmHg], or diastolic BP >100 mmHg), Recent or poorly controlled peptic ulcer,
             Haematologic, hepatic, or renal disease, Immunologic compromise, Current
             malignancy(History of malignancy is acceptable only if subject has been in remission
             for one year before Visit 1 (Screening and Run-in Visit) (remission = no current
             evidence of malignancy and no treatment for the malignancy in the 12 months before
             Visit 1 [Screening and Run-in Visit]), Tuberculosis (current or untreated) (subjects
             with a history of tuberculosis infection who have completed an appropriate course of
             anti-tuberculous treatment may be suitable for study entry provided that there is no
             clinical suspicion of active or recurrent disease), Cushing's disease, Addison's
             disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder and recent
             history of drug or alcohol abuse.

          -  Evidence of a severe exacerbation, defined as deterioration of asthma requiring the
             use of systemic corticosteroids (tablets, suspension, or injection) for at least 3
             days or an in-patient hospitalisation or emergency department visit due to asthma that
             required systemic corticosteroids between Visit 1 (Screening and Run-in Visit) and
             Visit 2 (randomization and Treatment Period 1 Baseline Visit)

          -  Oropharyngeal examination: A subject will not be eligible for the Run-in if he/she has
             clinical visual evidence of candidiasis at Visit 1(Screening and Run-in Visit)

          -  Investigational medications: A subject must not have administered any investigational
             drug within 30 days before Visit 1(Screening and Run-in Visit) or within five
             half-lives of the prior investigational drug (whichever is the longer of the two). The
             prior investigational drug half-life may be confirmed with the prior investigational
             study sponsor or by consulting relevant study documentation

          -  Allergies: Drug allergy: Any adverse reaction including immediate or delayed
             hypersensitivity to any beta2 agonist, sympathomimetic drug, or any intranasal,
             inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the
             constituents of the BFF TURBUHALER inhaler and capsules (i.e., lactose) ; Milk protein
             allergy: history of severe milk protein allergy

          -  Concomitant medications: Administration of prescription or over the counter medication
             that would significantly affect the course of asthma, or interact with study
             treatment, such as: anticonvulsants (barbiturates, hydantoins, carbamazepine);
             polycyclic antidepressants; beta-adrenergic blocking agents; phenothiazines; and
             monoamine oxidase (MAO) inhibitors; Immunosuppressive medications: A subject must not
             be using or require use of immunosuppressive medications during the study; cytochrome
             P450 3A4 (CYP3A4) inhibitors: Subjects who have received a potent CYP3A4 inhibitor
             within 4 weeks of Visit 1(Screening and Run-in Visit) (e.g., ritonavir, ketoconazole,
             itraconazole) ; Unable to refrain from the use of prescription or nonprescription
             drugs, including vitamins, herbal and dietary supplements (including St John's wort)
             within 7 days (or 14 days if the drug is a potential enzyme inducer) or five
             half-lives (whichever is longer) before the first dose of study treatment, unless in
             the opinion of the investigator and medical monitor the medication will not interfere
             with the study procedures or compromise subject safety; Any subjects that have
             previously received or are currently receiving omalizumab .

          -  Medications prior to Screening : Use of the following medications within the defined
             times prior to Visit 1 (Screening and Run-in Visit): Corticosteroids (Systemic, oral,
             or depot corticosteroids) (12 Weeks); inhaled corticosteroids(Monotherapy or in
             combination with a LABA for a minimum of 8 weeks and maintained on a stable dose for 4
             weeks prior to Visit 1); SABA(6 hours prior to all spirometry assessments) (Study
             supplied SABA is permitted); LABA (Oral LABAs, inhaled LABAs or combination products
             containing inhaled LABAs) (1 day); Theophylline, ketotifen, sodium cromoglycate,
             nedocromil sodium (1 day); Short-acting anti-muscarinics (12 hours), Long-acting
             anti-muscarinics (7 days), Potent cytochrome P450 3A4 inhibitors (4 weeks),
             Leukotriene modifiers (48 hours), Immunosuppressive medication (6 months), Anti-
             immunoglobulin E (12 weeks); Prescription or over the counter medication that would
             significantly affect the course of asthma, or interact with sympathomimetic amines
             such as: anticonvulsants (1 day); Herbal medicines (Prescription or nonprescription
             drugs, including vitamins, herbal and dietary supplements [including St John's worth]
             unless in the opinion of the investigator and medical monitor the medication will not
             interfere with the study procedures or compromise subject safety) (7 days [or 14 days
             if the drug is a potential enzyme inducer] or five half-lives [whichever is longer]);
             Chinese traditional medicines (1 day) ; Any other investigational drug (30 days or
             within five half-lives, whichever is longer).

          -  Compliance: A subject 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 the daily diaries

          -  Tobacco use: Current smoker or a smoking history of >=10 pack-years (e.g., 20
             cigarettes/day for 10 years). A subject must not have used inhaled tobacco products
             within the past 3 months (e.g., cigarettes, cigars or pipe tobacco). One pack year is
             defined as 20 manufactured cigarettes (1 pack) smoked per day for 1 year.

          -  Pregnant females as determined by urine test at Visit 1 (Screening and Run-in Visit)
             or pre-dosing. A confirmatory serum pregnancy test is required if the urine test is
             questionable or positive

          -  Lactating females

          -  A positive hepatitis B surface antigen or positive hepatitis C test result

          -  Subject is mentally or legally incapacitated Unwillingness or inability to follow the
             procedures outlined in the protocol