Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

GlaxoSmithKline (GSK)

Status and phase: Terminated; Phase 2

Conditions: Pulmonary Disease, Chronic Obstructive

Treatments: Drug: Nemiralisib ELLIPTA 750 µg; Drug: Albuterol (Salbutamol) MDI or nebules; Drug: Nemiralisib ELLIPTA 500 µg; Drug: Standard of care therapy; Drug: Nemiralisib ELLIPTA 250 µg; Drug: Nemiralisib ELLIPTA 50 µg; Drug: Nemiralisib ELLIPTA 100 µg; Drug: Placebo ELLIPTA

Study type: Interventional

Funder types: Industry

Identifiers

NCT03345407

2017-001074-42 (EudraCT Number)

200879

Details and patient eligibility

About

Nemiralisib is being developed as an anti-inflammatory drug for the treatment of inflammatory airways disease. This study is designed to assess the dose response, efficacy, safety, and pharmacokinetics of nemiralisib across a range of doses [up to 750 micrograms (µg)] compared with placebo. The study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week Post-Treatment Follow-Up Period. Approximately 1,250 subjects with an acute moderate or severe exacerbation of COPD requiring standard of care (SoC) therapy will be randomized in this double-blind study. Subjects will be randomized to receive different doses of nemiralisib or placebo via ELLIPTA® inhaler. The total duration of study participation is approximately 6 months (170 days). ELLIPTA is the registered trademark of GlaxoSmithKline (GSK) group of companies.

Enrollment: 943 patients

Sex: All

Ages: 40 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 40 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.

Exclusion criteria

• 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.
• A clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the exclusion criteria, outside of the reference range for the population being studied may be included if the Investigator [in consultation with the GlaxoSmithKline (GSK) Medical Monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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943 participants in 6 patient groups, including a placebo group

placebo once daily

Placebo Comparator group

Description:

Eligible subjects will receive placebo ELLIPTA dry powder (blended with lactose) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Standard of care therapy

Drug: Placebo ELLIPTA

Drug: Albuterol (Salbutamol) MDI or nebules

Nemiralisib 50 µg once daily

Experimental group

Description:

Eligible subjects will receive nemiralisib ELLIPTA 50 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Standard of care therapy

Drug: Nemiralisib ELLIPTA 50 µg

Drug: Albuterol (Salbutamol) MDI or nebules

Nemiralisib 100 µg once daily

Experimental group

Description:

Eligible subjects will receive nemiralisib ELLIPTA 100 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Standard of care therapy

Drug: Albuterol (Salbutamol) MDI or nebules

Drug: Nemiralisib ELLIPTA 100 µg

Nemiralisib 250 µg once daily

Experimental group

Description:

Eligible subjects will receive nemiralisib ELLIPTA 250 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Standard of care therapy

Drug: Albuterol (Salbutamol) MDI or nebules

Drug: Nemiralisib ELLIPTA 250 µg

Nemiralisib 500 µg once daily

Experimental group

Description:

Eligible subjects will receive nemiralisib ELLIPTA 500 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Standard of care therapy

Drug: Nemiralisib ELLIPTA 500 µg

Drug: Albuterol (Salbutamol) MDI or nebules

Nemiralisib 750 µg once daily

Experimental group

Description:

Eligible subjects will receive nemiralisib ELLIPTA 750 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.

Treatment:

Drug: Nemiralisib ELLIPTA 750 µg

Drug: Standard of care therapy

Drug: Albuterol (Salbutamol) MDI or nebules