Resumen

Este estudio de Fase IV es un diseño multicéntrico, aleatorizado, abierto, cruzado de dos vías para evaluar la eficacia, seguridad y tolerabilidad de NEUMOTEROL 400 en sujetos con asma. El estudio se utilizará para demostrar la no inferioridad de la combinación budesonida/fumarato de formoterol (BFF) 400/12 microgramos (mcg) en inhalador monodosis (NEUMOTEROL 400) en comparación con BFF 320/9 mcg inhalador SYMBICORT Forte TURBUHALER®. La población de este estudio serán sujetos adultos (≥ 18 y ≤ 80 años) con diagnóstico de asma que tengan un volumen espiratorio forzado en el primer segundo (VEF1) prebroncodilatador del 40% al 85% del valor normal predicho, y que estén recibiendo una dosis estable de corticosteroide inhalado (CSI) con o sin agonista beta-adrenérgico de acción prolongada (LABA) antes del tamizaje. El estudio constará de seis fases: pretamizaje, tamizaje/período de rodaje (4 semanas), Período de tratamiento 1 (4 semanas), período de lavado (mínimo 4 semanas), Período de tratamiento 2 (4 semanas) y seguimiento (1 semana). La duración total del estudio para cada sujeto será de al menos 17 semanas. Se realizarán hasta 6 visitas al estudio y una llamada telefónica de seguimiento. La visita de pretamizaje permitirá que los sujetos con cambios recientes en la medicación para el asma se estabilicen antes del tamizaje. Durante los períodos de rodaje y lavado, todos los sujetos recibirán budesonida inhalador de polvo seco (DPI) 400 mcg dos veces al día (BID) (NEUMOTEX™ 400) y salbutamol 100 mcg inhalador presurizado de dosis medida (pMDI) a demanda como medicación de rescate. La dosis de NEUMOTEROL 400 (400/12 mcg) y SYMBICORT Forte (320/9 mcg) será una inhalación BID, y cada tratamiento se administrará a todos los sujetos durante 4 semanas (con un período de lavado de 4 semanas entre tratamientos). El estudio incluirá 300 sujetos para tamizaje, de modo que al menos 210 sean aleatorizados y un mínimo de 168 completen el estudio o sean evaluables. La mitad de los sujetos seguirá el Régimen A en el Período de tratamiento 1 y luego cambiará al Régimen B en el Período de tratamiento 2, y viceversa. Régimen A: BFF (400/12 mcg) en inhalador monodosis. Régimen B: BFF (320/9 mcg) inhalador TURBUHALER. Los períodos de tratamiento estarán separados por un período de lavado de 4 semanas. NEUMOTEROL y NEUMOTEX son marcas registradas del grupo de empresas GSK. SYMBICORT y TURBUHALER son marcas registradas de AstraZeneca.

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 80 YearsSexo: ALL

Criterios de inclusión

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

Criterios de exclusión

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

Intervenciones

drug

NEUMOTEROL 400 (BFF 400/12 mcg) single capsule inhaler

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).

drug

SYMBICORT forte (BFF 320/9mcg) TURBUHALER inhaler

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)

drug

NEUMOTEX 400 (Budesonide 400 mcg)

Budesonide 400mcg will be administered to all the subjects twice daily, during the Run-in and Washout Periods

drug

Salbutamol 100 mcg pMDI

Salbutamol 100mcg will be administered as pMDI on demand, as rescue medication, throughout the entire study period until Visit 5

Ubicaciones

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

La Plata, Buenos Aires, Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Vicente López, Buenos Aires, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Berazategui, Argentina

GSK Investigational Site

Berazategui, Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Monte Grande, Argentina

GSK Investigational Site

Rosario, Argentina

Estudio aleatorizado, multicéntrico, abierto, cruzado, de no inferioridad para evaluar la eficacia, seguridad y tolerabilidad de Neumoterol 400 y Symbicort Forte en adultos con asma

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

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

Ubicaciones

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

Patrocinadores