A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Dose-Response Relationship of Multiple Doses of GSK2269557 Administered as a Dry Powder to Chronic Obstructive Pulmonary Disease (COPD) Patients

NCT02130635 | Completed Phase 2 Results

• 1 other identifier: 115119
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief Summary

This is a randomised, double-blind, placebo controlled, parallel group study to evaluate the safety, tolerability, pharmacokinetics and dose response of multiple doses of GSK2269557 administered as a dry powder in COPD subjects. Pharmacodynamic effects on biomarkers will also be assessed. This study will have two parts. In Part A, subjects will be randomized to active or placebo treatment in a 3:1 ratio and in Part B, to placebo or one of the six doses of active treatment in an equal ratio. A sufficient number of COPD subjects (male and female of non-child bearing potential) will be screened to ensure that approximately 30 subjects are enrolled and at least 20 evaluable subjects are obtained for Part A and approximately 35 subjects will be enrolled for Part B. In both the parts, subjects will receive study treatment once daily for 14 consecutive days. Placebo control will be included for a valid evaluation of adverse events attributable to treatment versus those independent of treatment.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

PI3Kd; Pharmacodynamics; dry powder inhaler; GSK2269557; safety; COPD subjects

Outcome Measures

Primary Outcomes (15)

• Part A: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event

  An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.

  From the start of study treatment until follow-up (assessed for approximately 19 days)

• Part A: Change From Baseline in Counts of White Blood Cells (WBC), Total Neutrophils (Total Absolute Neutrophil Count [ANC]), Lymphocytes, Monocytes, Eosinophils, Basophils, and Platelets at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 h post-dose)

• Part A: Change From Baseline in Hematocrit at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Albumin and Total Protein at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points

  Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

• Part A: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline

  Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes \[min\] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). Potential clinical concern range for SBP was \<85 millimeters of mercury (mmHg) (low) and \>160 mmHg (high), for DBP \<45 mmHg (low) and \>100 mmHg (high) and for HR \<40 bpm and \>110 bpm. All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.

  Day 1, Day 7, and Day 14

• Part A: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline

  Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Clinical significance was judged by the investigator. Day 7 assessments could be conducted on Day 7 or Day 8.

  Day 1, Day 7, and Day 14

• Part A: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points

  Baseline is Day 1 pre-dose. FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded. Baseline was the maximum of the planned pre-dose measurements on Day 1. Change from Baseline at any post-dose time point was calculated as the post-dose value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.

  Baseline (Day 1 [pre-dose]), Day 1 (1 h post-dose), Day 7 (pre-dose and 1 h post-dose), and Day 14 (24 h post-dose)

• Part B: Adjusted Median Response of Cytokine (Interleukin 6 [IL6], Interleukin 8 [IL8], Tumor Necrosis Factor Alpha [TNFalpha]) Concentrations in Induced Sputum, on Day 7 and Day 14

  This outcome measure was used to estimate the inhibition levels of various doses of GSK2269557 by analyzing inflammatory cytokines IL6, IL8, and TNF alpha using Bayesian methods of statistical analysis, using non-informative prior distributions for all modeling parameters. Posterior medians (adjusted median response) and 95% credible intervals are reported here as medians and 95% confidence intervals respectively. 95% credible interval is reported as 2-sided 95% confidence in the statistical analyses. Day 7 assessments could be conducted on Day 7 or Day 8.

  Day 7 (pre-dose) and Day 14 (24 h post-dose)

Secondary Outcomes (21)

• Part A: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose

  Day 1 (Pre-dose, 5 min, 30 min, 1, 2, 4 & 6 hours post-dose)

• Part B: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose

  Pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, and 6 h post-dose on Day 1

• Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7

  Day 7 immediately after dosing

• Part B: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7

  Day 7 immediately after dosing

• Part A: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15

  Day 7 and Day 15

Study Arms (9)

Part A: GSK2269557 1000 MCG

EXPERIMENTAL

Subjects will receive 2 inhalations (2 x GSK2269557 500 mcg = total dose of 1000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 500 MCG

Part A: PLACEBO

PLACEBO COMPARATOR

Subjects will receive 2 inhalations of placebo once daily for 14 consecutive days

Drug: PLACEBO

Part B: GSK2269557 100 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (1 x GSK2269557 100 mcg and 3 x Placebo = total dose of 100 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 100 MCG; Drug: PLACEBO

Part B: GSK2269557 200 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 200 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 100 MCG; Drug: PLACEBO

Part B: GSK2269557 500 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (1 x GSK2269557 500 mcg and 3 x Placebo = total dose of 500 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days, once daily for 14 consecutive days

Drug: GSK2269557 500 MCG; Drug: PLACEBO

Part B: GSK2269557 700 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (1 x GSK2269557 500 mcg, 2 x GSK2269557 100 mcg and 1 x Placebo = total dose of 700 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 100 MCG; Drug: GSK2269557 500 MCG; Drug: PLACEBO

Part B: GSK2269557 1000 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 1000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 500 MCG; Drug: PLACEBO

Part B: GSK2269557 2000 MCG

EXPERIMENTAL

Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 2000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days

Drug: GSK2269557 500 MCG

Part B: PLACEBO

PLACEBO COMPARATOR

Subjects will receive 4 inhalations of placebo once daily for 14 consecutive days

Drug: PLACEBO

Interventions

GSK2269557 100 MCG DRUG

100 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device

Part B: GSK2269557 100 MCG; Part B: GSK2269557 200 MCG; Part B: GSK2269557 700 MCG

GSK2269557 500 MCG DRUG

500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device

Part A: GSK2269557 1000 MCG; Part B: GSK2269557 1000 MCG; Part B: GSK2269557 2000 MCG; Part B: GSK2269557 500 MCG; Part B: GSK2269557 700 MCG

PLACEBO DRUG

Lactose administered using a matching dry powder inhaler device

Part A: PLACEBO; Part B: GSK2269557 100 MCG; Part B: GSK2269557 1000 MCG; Part B: GSK2269557 200 MCG; Part B: GSK2269557 500 MCG; Part B: GSK2269557 700 MCG; Part B: PLACEBO

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The subject has a confirmed and established diagnosis of COPD, as defined by the Global Initiative for Chronic Obstructive lung Disease (GOLD) guidelines.
• Male or female of non-child bearing potential between 40 and 75 years of age inclusive, at the time of signing the informed consent.
• The subject has a post-bronchodilator \[400 microgram (mcg) salbutamol\] Maximal amount of air FEV1/FVC \<0.7 and FEV1 \>=40% to \<=80% of predicted (Predictions should be according to the European Community of Coal and Steel (ECCS) equations).
• 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)).
• The subject is able to produce \>100 milligram (mg) of sputum at screening.
• Body weight \>=45 kilogram (kg) and body mass index (BMI) within the range 17 - 32 kg/square meter (m\^2) (inclusive).
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, salpingo-oophrectomy or oophrectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-International units (MIU)/millilitre (mL) and estradiol \< 40 picogram (pg)/mL (\<147 picomole(pmol)/Liter \[L\]) is confirmatory\]. \[Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.\]; or has only same-sex partners, when this is her preferred and usual lifestyle.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.
• Based on averaged QTcF values of triplicate ECGs obtained over a brief recording period (e.g. 5 minutes): QTcF \<450 millisecond (msec); or QTcF\<480 msec in subjects with right bundle branch block.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

You may not qualify if:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones and cholecystectomy).
• Subjects who have a past or current medical condition 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) 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.
• 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 (approximately 240 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 (such as lactose) thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• A positive test for Human immunodeficiency virus (HIV) antibody - tested according to local policies.
• A positive pre-study Hepatitis B surface antigen (HBs-Ag) or positive total hepatitis B core antibody (anti-HBc IgM) or positive Hepatitis C antibody result within 3 months of screening.
• Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Lactating females.
• 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 four new chemical entities within 12 months prior to the first dosing day.
• Subject has poorly controlled or unstable COPD, defined as the occurrence of any of the following: Either: acute worsening of COPD (an exacerbation) that is managed by the subject at home requiring treatment with corticosteroids and/or antibiotics in the 4 weeks prior to the screening visit; or more than two exacerbations in the previous 2 months prior to the screening visit that required a course of oral corticosteroids and/or antibiotics, or for which the subject was hospitalised.
• Subject has had a respiratory tract infection treated with antibiotics in the 4 weeks prior to first dose.
• Subject requires regular treatment with oral corticosteroids or has received oral or parenteral corticosteroids within 4 weeks of screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Großhansdorf, Schleswig-Holstein, 22927, Germany

Location

GSK Investigational Site

Berlin, 14050, Germany

Location

Related Links

• IPD for this study will be made available via the Clinical Study Data Request site.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Nemiralisib

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2014
• First Posted: May 5, 2014
• Study Start: July 31, 2014
• Primary Completion: August 18, 2015
• Study Completion: August 18, 2015
• Last Updated: October 11, 2018
• Results First Posted: July 12, 2017

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

DE (2)