Resumen

Nemiralisib está siendo desarrollado como fármaco antiinflamatorio para el tratamiento de enfermedades inflamatorias de las vías respiratorias. Este estudio está diseñado para evaluar la respuesta a la dosis, la eficacia, la seguridad y la farmacocinética de nemiralisib en un rango de dosis [hasta 750 microgramos (µg)] en comparación con placebo. El estudio consta de un período de selección, un período de tratamiento de 12 semanas y un período de seguimiento post-tratamiento de 12 semanas. Aproximadamente 1.250 sujetos con una exacerbación aguda moderada o grave de EPOC que requiera terapia de tratamiento estándar (TE) serán aleatorizados en este estudio doble ciego. Los sujetos recibirán diferentes dosis de nemiralisib o placebo mediante el inhalador ELLIPTA®. La duración total de la participación en el estudio es de aproximadamente 6 meses (170 días). ELLIPTA es la marca registrada del grupo de empresas GlaxoSmithKline (GSK).

Elegibilidad

Edad mínima: 40 YearsEdad máxima: 80 YearsSexo: ALL

Criterios de inclusión

to 80 years of age, inclusive, at Screening (Visit 1).
An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[ global initiative for chronic obstructive lung disease (GOLD), 2017\] as follows: "Chronic obstructive pulmonary disease is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases."
Current or former cigarette smoker with a history of cigarette smoking of \>=10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Screening (Visit 1). Number of pack years = (number of cigarettes per day / 20) x number of years smoked).
Acute exacerbation of COPD requiring an escalation in therapy to include oral/systemic corticosteroid(s) (prednisone 40 mg/day or equivalent) for 5 days and antibiotic(s) for 7 days; the dose and/or duration of prednisone (40 mg/day or equivalent) and/or the antibiotic can be modified according to the Investigator's/medically qualified designee's judgment or according to local country/institution practice. Acute exacerbation to be confirmed by an experienced physician and to represent a recent worsening of at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms. Major symptoms include subjective increase in dyspnea, increase in sputum volume or change in sputum color. Minor symptoms include increased cough, increased wheeze, sore throat, colds or fever (oral temperature \>37.5 degree Celsius) without other cause.
Body weight \>=45 kilogram (kg) and body mass index (BMI) within the range 16 - 35 kg per meter square (kg/m\^2) (inclusive)
Male and female subjects are eligible to participate in the study. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the 12-Week Double-Blind Treatment Period and for at least 5 half-lives (10 days) after the last of double-blind study treatment.
Capable of giving signed informed consent.

Criterios de exclusión

Current diagnosis of asthma, according to the Global Initiative for Asthma (GINA, 2017). Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD.
Potential of hydrogen (pH) \< 7.30 or the need for invasive mechanical ventilation.
Moderate/severe exacerbation of COPD for which SoC was started \>48 hours since diagnosis.
A chest X-ray \[or computed tomography (CT) scan\] that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray (or CT scan) must be taken at Screening (Visit 1). For sites in Germany: if a chest X-ray (or CT scan) within 1 year of Screening (Visit 1) is not available, approval to conduct a diagnostic chest X-ray (CT scan) will need to be obtained from the Federal Office for Radiation Protection (BfS).
Clinically significant pneumonia, identified by chest X-ray (CT scan) at Screening.
A diagnosis of alpha 1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, clinically overt bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary pulmonary hypertension, interstitial lung diseases,or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results.
A history or current evidence of clinically significant and unstable disease such as cardiovascular (e.g., subjects requiring implanted cardioverter defibrillator \[ICD\], pacemaker requiring a rate set \>60 beats per minute (bpm), uncontrolled hypertension, New Your Heart Association Class IV \[NYHA, 1994\], known left ventricular ejection fraction \<30 percent) neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or hematological abnormalities. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. (Note: subjects with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or noninsulin-dependent diabetes mellitus \[NIDDM\]) are permitted to be entered into the study).
Having undergone lung volume reduction surgery or lung resection for any other reason e.g. lung carcinoma
Liver diseases including ALT\>2x upper limit of normal (ULN); Total bilirubin \>1.5xULN (Isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent); current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study treatment; Positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment.
Positive hepatitis C ribonucleic acid (RNA) test result at Screening or within 3 months prior to first dose of study treatment.
Carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin are not excluded if the subject has been considered cured within 5 years since diagnosis.
History of allergy or hypersensitivity to any of the study medications \[e.g. beta-agonists, Phosphoinositide 3-Kinase Delta (PI3Kd) inhibitors\] or components of the inhalation powder (e.g., lactose). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the investigator, contraindicates the subject's participation are excluded.
Strong inhibitors of cytochrome P450 3A4 (CYP3A4) including antiretrovirals including protease inhibitors; Oral antifungal treatments such as ketoconazole and itraconazole. It is recommended that posaconazole is used as the oral antifungal treatment of choice. Short courses of up to 14 days are allowed for fluconazole and voriconazole, but chronic administrations are not permitted; Antibiotics such as telithromycin and troleandomycin (macrolide). It is recommended that azithromycin is used as the macrolide antibiotic of choice. Short courses up to 14 days are allowed for mibefradil (calcium channel blocker), erythromycin and clarithromycin (including intravenous clarithromycin) but chronic administrations are not permitted; Anti-epileptic treatments; and anti-tuberculosis therapy. These medications must all have been stopped at least 14 days prior to first dose of study treatment. Use of sensitive narrow therapeutic index CYP3A4 substrates including alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus; Intravenous theophylline will be allowed but only under strict therapeutic drug monitoring for signs of theophylline toxicity as a result of co-administration with nemiralisib; Subjects may be recruited into the study already under treatment with theophylline or started on theophylline following the start of treatment and before the end of 14 days post last dose.
Chronic treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for \>15 hours a day. Oxygen prn use (\<=15 hours per day) is not exclusionary. Oxygen use during an exacerbation is permitted.
Chronic treatment with anti-Tumor Necrosis Factor (anti-TNF), anti-Interleukin-1 (anti-IL1), or any other immunosuppressive therapy within 60 days prior to the first dose of double-blind study treatment.
Clinically significant sleep apnea that requires the use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) for \> 48 hours.
Any other investigational treatment within the following time periods prior to the first dose of double-blind study treatment in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product, whichever is longer. Note: subjects who participated in a previously completed study and/or were withdrawn from an ongoing study that included/includes nemiralisib are excluded from participating in this study.
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose of double-blind study treatment in the current study.
Abnormal, clinically significant ECG finding (e.g. myocardial Infarction or demonstrating a clinically significant arrhythmia requiring treatment) at Screening (Visit 1) or upon repeat prior to randomization.
QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>480 milliseconds (msec) for subjects with or without Bundle Branch Block, based on single QTcF value.
A positive test for human immunodeficiency virus (HIV) antibody at Screening.
Known or suspected history of alcohol or drug abuse within the last 2 years.
History of regular alcohol consumption defined as an average weekly intake of \>28 units for males or \>21 units for females within 6 months of Screening (Visit 1). One unit is equivalent to 8 grams of alcohol: a half-pint \[approximately 240 milliliter (mL)\] of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.

Intervenciones

drug

Placebo ELLIPTA

Placebo will be administered via oral inhalation route once daily in the morning.

drug

Nemiralisib ELLIPTA 50 µg

Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 50 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.

drug

Nemiralisib ELLIPTA 100 µg

Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 100 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.

drug

Nemiralisib ELLIPTA 250 µg

Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 250 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.

drug

Nemiralisib ELLIPTA 500 µg

Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 500 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.

drug

Nemiralisib ELLIPTA 750 µg

Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 750 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.

drug

Albuterol (Salbutamol) MDI or nebules

Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

drug

Standard of care therapy

SoC therapy for the index exacerbation is defined as treatment with oral/systemic corticosteroid (prednisone 40 mg/day or equivalent) for 5 days and antibiotic for 7 days. Subjects will receive SoC as prescribed by the Investigator or medically qualified designee. The dose and/or duration of prednisone and/or the antibiotic can be modified according to the Investigator's/medically qualified designee's judgment or according to local country/institution practice.

Ubicaciones

GSK Investigational Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

Florida, Buenos Aires, Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

San Rafael, Mendoza Province, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Santo Tomé, Santa Fe Province, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Mendoza, Argentina

GSK Investigational Site

Mendoza, Argentina

GSK Investigational Site

San Miguel de Tucumán, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Placebo ELLIPTA

Nemiralisib ELLIPTA 50 µg

Nemiralisib ELLIPTA 100 µg

Nemiralisib ELLIPTA 250 µg

Nemiralisib ELLIPTA 500 µg

Nemiralisib ELLIPTA 750 µg

Albuterol (Salbutamol) MDI or nebules

Standard of care therapy

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

GSK Investigational Site

GSK Investigational Site

Patrocinadores