Clinical trial NCT02294734: An Efficacy Study of GSK2269557 Added to Standard Care in Subjects With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Official title: A Randomised, Double-blind (Sponsor Unblinded), Placebo-controlled, Parallel-group, Multicentre Study to Evaluate the Efficacy and Safety of GSK2269557 Administered in Addition to Standard of Care in Adult Subjects Diagnosed With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: functional respiratory capacity
High-resolution computed tomography
GSK2269557
acute exacerbation of COPD
lung capacity
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-11-19
Enrollment: 126
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy of GSK2269557 administered in addition to standard of care in adult subjects diagnosed with an acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD). Additionally study will also assess safety, tolerability and pharmacokinetic data. The total duration of the study will be 13-14 weeks including screening, treatment period and a follow up visit. Subjects will receive once daily study treatment administration starting on Day 1. Study is planned to recruit approximately 120 subjects such that approximately 100 subjects complete the study.


Eligibility criteria: Inclusion Criteria:

* Between 40 and 80 years of age inclusive, at the time of signing the informed consent
* The subject has a confirmed and established diagnosis of COPD, as defined by the global initiative for chronic Obstructive Lung Disease (GOLD) guidelines for at least 6 months prior to entry.
* The subject has a post-bronchodilator FEV1/Forced Vital Capacity (FVC) \< 0.7 and FEV1 \<= 80 % of predicted (Predictions should be according to the European Community of Coal and Steel \[ECCS\] equations), documented in the last 5 years.
* Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to include corticosteroid and antibiotics. Acute exacerbation to be confirmed by an experienced physician and represent a recent change in at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms. Major symptoms: subjective increase in dyspnea, increase in sputum volume, and change in sputum colour. Minor symptoms: cough, wheeze and sore throat.
* The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = \[cigarettes per day smoked/20 x number of years smoked\])
* Body weight \>= 45 kilogram (kg) and body mass index (BMI) within the range 18 - 32 kg/metered squared (m\^2) (inclusive).
* Male
* Female subject : is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as: Pre-menopausal females with one of the following: documented tubal ligation, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy and documented bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol 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 prior to study enrolment.

Reproductive potential and agrees to follow one 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 prior to the first dose of study medication and until completion of the follow-up visit.

GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP):

Contraceptive subdermal implant that meets the 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 the 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 sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject.

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository).

* Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until after the completion of the follow up visit.

Vasectomy with documentation of azoospermia. Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label. Oral Contraceptive, either combined or progestogen alone or injectable progestogen. Contraceptive vaginal ring. Percutaneous contraceptive patches.

These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the study protocol.

Exclusion Criteria:

* To avoid recruitment of subjects with a severe COPD exacerbation, the presence of any one of the following severity criteria will render the subject ineligible for inclusion in the study:

Need for invasive mechanical ventilation (short term (\< 48hour) Non-invasive Ventilation (NIV) or Continuous Positive Airway Pressure \[CPAP\] is acceptable).

Haemodynamic instability or clinically significant heart failure. Confusion.

* Subjects who have a history or current medical conditions or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions \[e.g. hypertension or non-insulin dependent diabetes mellitus\] are permitted to be entered into the study).
* Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma 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.
* Alanine aminotransferase \>2x upper limit of normal (ULN) and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* A subject with 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 \[in consultation with the GSK Medical Monitor if required\] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or demonstrating a clinically significant arrhythmia requiring treatment.
* QTcF \> 450 millisecond (msec) or QTcF \> 480 msec in subjects with Bundle Branch Block, based on single QTcF value.
* Subjects who have undergone lung volume reduction surgery.
* Subject is currently on chronic treatment with macrolides; long term oxygen therapy (\> 15 hours/day).
* The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-TNF), anti-Interleukin-1 (anti-IL1), or any other immunosuppressive therapy within 60 days prior to dosing.
* History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>28 units for males or \>21 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint ( equivalent to 240 milliliter \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* History of sensitivity to any of the study medications, or components thereof (such as lactose) or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
* A known (historical) positive test for human immune virus (HIV) antibody.
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. NOTE: Because of the short window for screening, treatment with GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal Investigator in consultation with the Medical Monitor.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day.

Primary outcomes:
measure: Change From Baseline in Specific Imaging Airway Volume (siVaw), Measured at FRC and TLC Scan Conditions, Presented in Longitudinal and Scan Trimmed Scan Types, Measured in 5 Lobes and 5 Regions at Screening, Day 12 and Day 28
timeFrame: Baseline, Day 12 and Day 28
Secondary outcomes:
measure: Change From Baseline in Imaging Airways Volume: iVaw, Measured at FRC and TLC Scan Conditions, Presented in Longitudinal and Scan Trimmed Scan Types, Measured in 5 Lobes and 5 Regions at Screening, Day 12 and Day 28
timeFrame: Baseline, Day 12 and Day 28
measure: Change From Baseline in Imaging Airways Resistance ( iRaw) Measured at FRC and TLC Scan Conditions, Presented in Scan Trimmed Scan Types, Measured in 5 Lobes and 5 Regions at Screening, Day 12 and Day 28
timeFrame: Baseline, Day 12 and Day 28
measure: Change From Baseline in Imaging Specific Airways Resistance: siRaw Measured at FRC and TLC Scan Conditions, Presented in Scan Trimmed Scan Types, Measured in 5 Lobes and 5 Regions at Screening, Day 12 and Day 28
timeFrame: Baseline, Day 12 and Day 28
measure: Change From Baseline in Lung Lobar Volumes Measured at FRC and TLC Scan Conditions, Presented in Longitudinal Scan Types, Measured in 5 Lobes and 5 Regions at Day 12 and Day 28
timeFrame: Baseline, Day 12 and Day 28
measure: Change From Baseline in Imaging Trachea Length and Diameter After 12 Days of Treatment and After 28 Days of Treatment
timeFrame: Baseline, Day 12 and Day 28
measure: Change From Baseline in Imaging Trachea Length/Diameter After 12 Days of Treatment and After 28 Days of Treatment
timeFrame: Baseline, Day 12 and Day 28
measure: Number of Participants With Adverse Events (AE)
timeFrame: From start of IP through the Study Phase (84 days post-dose) (assessed up to follow-up duration of approximately 100 days)
measure: Number of Participants With Abnormal Hematology Parameters
timeFrame: Day 1, Day 12, Day 28, Day 56, Day 84 and at follow-up (approximately 100 Days)
measure: Number of Participants With Abnormal Clinical Chemistry Parameters
timeFrame: Day 1, Day 12, Day 28, Day 56, Day 84 and at follow-up (approximately 100 days)
measure: Number of Participants With Abnormal Vital Signs
timeFrame: Day 1, Day 12, Day 28, Day 56, Day 84 and at follow-up (approximately 100 days)
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG)
timeFrame: Day 1, Day 12, Day 28, Day 56, Day 84 and at follow-up (approximately 100 days)
measure: Day 1 Plasma Concentration up to 24 Hours (Hrs) Post-dose
timeFrame: Pre-dose, 5 min, 3 hrs and 24 hrs
measure: Trough Concentration After 12 Days, 28 Days, 56 Days and 84 Days of Treatment
timeFrame: Pre-dose Day 12, Day 28, Day 56, and Day 84
measure: Changes From Baseline in Forced Expiratory Volume in One Second (FEV1) Measured Daily
timeFrame: Baseline, Day 28, and Day 84
measure: Changes From Baseline in Peak Expiratory Flow (PEF) Measured Daily
timeFrame: Baseline, Day 28, and Day 84
measure: Percent Change From Baseline in Diffusion Capacity (DLco, Kco) After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Change From Baseline in Total Lung Capacity (TLC) After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Change From Baseline in Residual Volume After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Change From Baseline in Functional Residual Capacity After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Change From Baseline in Specific Resistance (sRaw) After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Change From Baseline in Specific Conductance (sGaw) After 28 Days and After 84 Days of Treatment
timeFrame: Baseline, Day 28 and Day 84
measure: Questionnaires CAT and MMRC Scale at Baseline, Day 28 and Day 84
timeFrame: Baseline, Day 28 and Day 84
measure: Number of Participants With Treatment Failures
timeFrame: 13 weeks
Other outcomes:
Locations:
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Erpent
country: Belgium
facility: GSK Investigational Site
city: Aalborg
country: Denmark
facility: GSK Investigational Site
city: Hvidovre
country: Denmark
facility: GSK Investigational Site
city: Kobenhavn
country: Denmark
facility: GSK Investigational Site
city: Odense
country: Denmark
facility: GSK Investigational Site
city: Almelo
country: Netherlands
facility: GSK Investigational Site
city: Eindhoven
country: Netherlands
facility: GSK Investigational Site
city: Zutphen
country: Netherlands
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Vladimir
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cahn A, Hamblin JN, Robertson J, Begg M, Jarvis E, Wilson R, Dear G, Leemereise C, Cui Y, Mizuma M, Montembault M, Van Holsbeke C, Vos W, De Backer W, De Backer J, Hessel EM. An Inhaled PI3Kdelta Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial. Int J Chron Obstruct Pulmon Dis. 2021 Jun 3;16:1607-1619. doi: 10.2147/COPD.S309129. eCollection 2021.