Clinical trial NCT03069989: Single Doses of GSK3008348 in Idiopathic Pulmonary Fibrosis (IPF) Participants Using Positron Emission Tomography (PET) Imaging
Official title: A Study of Single Doses to Evaluate the Safety, Tolerability, Pharmacokinetics and Target Engagement of Nebulised GSK3008348 in Idiopathic Pulmonary Fibrosis Patients, Using Positron Emission Tomography (PET) Imaging
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Tolerability
IPF
PET imaging
Idiopathic Pulmonary Fibrosis
Safety
Pharmacokinetics
Double-blind
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-03-03
Enrollment: 8
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: GSK3008348 is being developed as a treatment for IPF. A first-time-in-human study showed that single nebulized doses of 1-3000 micrograms (mcg) GSK3008348 in healthy volunteers were well tolerated, with pharmacokinetic (PK) exposures within the defined limits set in the protocol. The proposed study is a 2-cohort study of single doses, intended to evaluate the safety, tolerability and PK of the drug in participants with IPF not currently treated with pirfenidone or nintedanib, and to obtain preliminary information on target engagement. Cohort 1 will be a 2-period, randomized, double-blind, placebo-controlled group with at least 7 days washout between doses, and follow-up period of up to 7-14 days. Cohort 2 is optional. It will be designed to further explore safety and to provide additional information on the target engagement profile of GSK3008348. The total duration of the study will be up to 62 days.


Eligibility criteria: Inclusion Criteria:

* Male participants aged \>= 50 years, and female participants aged \>=55 years, at the time of signing the informed consent.
* Diagnosis of definite or probable IPF as determined by a responsible and experienced chest physician and based on established criteria defined by the American Thoracic Society/European Respiratory Society Internationale Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.
* Ambulant and capable of attending outpatient visits.
* FVC \> 50 percent predicted and DLCO \> 40 percent predicted.
* Body weight \>= 45 kilograms (kg) and body mass index (BMI) within the range 18.0-35.0 kg/square meter (inclusive).
* Male and female
* Male participants: A male participant must agree to use contraception as detailed in this protocol during the study and for at least 90 days after the follow up visit, and refrain from donating sperm during this period.
* Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in the protocol.
* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions, listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

* ALT and bilirubin \> 1.5x upper limit of normal (ULN; 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).
* QT corrected (QTc) \> 450 milliseconds (msec), or QTc \> 480 msec in participants with Bundle Branch Block.
* Current IPF exacerbation, or upper or lower respiratory tract infection on admission to the clinical unit.
* History of or suffers from claustrophobia, or unable to lie flat and still on their back for up to 2 hrs in the PET scanner.
* Extent of emphysema greater than the extent of fibrotic change on High-Resolution Computed Tomography (HRCT) scan, based on investigator judgment.
* FEV1/FVC ratio \< 0.70 at screening (post-bronchodilator).
* History of sensitivity to the study treatment, or components thereof, or a history of drug or other allergy that, in the opinion of the investigators or Medical Monitor, contraindicates their participation.
* Any current oro-pharygneal disease or disorders as judged by the investigator.
* Currently taking pirfenidone or nintedanib, or received pirfenidone or nintedanib within 30 days of the first dose of study treatment.
* Taken, within 7 days or 5 half-lives (whichever is longer) before the first dose of study treatment, organic anion transporter (OAT) substrates with a narrow therapeutic index (example: methotrexate and tenofovir), vitamins, or dietary or herbal supplements, unless in the opinion of the investigator and sponsor the supplement will not interfere with the study medication.
* Long-term continuous home oxygen therapy (use of oxygen that is only intermittent and for symptom relief is acceptable).
* Participation in a clinical trial and receipt of an investigational medicinal product within the following time period before the first dose 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 new investigational medicinal products within 12 months before the first dose.
* Presence of Hepatitis B surface antigen (HBsAg) at screening, or positive Hepatitis C antibody test result at screening or within 3 months before the first dose of study treatment.

Note: participants with a positive Hepatitis C antibody test because of previous, resolved disease can be enrolled if a confirmatory negative Hepatitis C Ribonucleic Acid (RNA) test is obtained.

* Previous or current exposure to animals that may harbour Food and Mouth Disease Virus (FMDV2).
* Previous long term (\>= 3 months) residence in a country where FMDV2 is endemic (such as certain areas of Africa, Asia and South America.
* Where participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days.
* History of drug or alcohol abuse that in the opinion of the investigator affects their participation in the study.
* Exposure to ionizing radiation in excess of 10 Millisievert (mSv) above background over the previous 3 year period as a result of occupational exposure or previous participation in research studies. Clinically justified (therapeutic or diagnostic) exposures are not included in the exposure calculation.

Primary outcomes:
measure: Period 2: Volume of Distribution (VT) of [18F]-FBA-A20FMDV2 in the Whole Lung (Not Corrected for Air Volume) at 30 Minutes Post-dose Compared to Pre-dose
timeFrame: Baseline (pre-dose) and 30 minutes post-dose
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 62 days
measure: Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and WBC Count
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Hematology Parameter: Mean Corpuscle Volume
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameter: Mean Corpuscle Volume
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Hematology Parameter: Red Blood Cell Count
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Hematology Parameter: Red Blood Cell Count
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase and Gamma Glutamyl Transferase
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase and Gamma Glutamyl Transferase
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Chemistry Parameters: Albumin and Total Protein
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Chemistry Parameters: Albumin and Total Protein
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 1: Number of Participants With Abnormal Urinalysis Results by Dipstick
timeFrame: Baseline (Day -1) and 24 hours post-GSK3008348 dose
measure: Period 2: Number of Participants With Abnormal Urinalysis Results by Dipstick
timeFrame: Baseline (Day -1), 24 hours post-GSK3008348 dose and Day 15 (follow-up)
measure: Period 1: Change From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1), 0.5, 2, 4, 8 and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Vital Signs: DBP and SBP
timeFrame: Baseline (Day -1), 30 minutes (post-PET scan), Day 1 (prior to discharge) and Day 2 (pre-PET scan)
measure: Period 1: Change From Baseline in Vital Signs: Heart Rate
timeFrame: Baseline (Day -1), 0.5, 2, 4, 8 and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Vital Signs: Heart Rate
timeFrame: Baseline (Day -1), 30 minutes (post-PET scan), Day 1 (prior to discharge) and Day 2 (pre-PET scan)
measure: Period 1: Change From Baseline in Vital Sign: Respiration Rate
timeFrame: Baseline (Day -1), 0.5, 2, 4, 8 and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Vital Sign: Respiration Rate
timeFrame: Baseline (Day -1), 30 minutes (post-PET scan), Day 1 (prior to discharge) and Day 2 (pre-PET scan)
measure: Period 1: Change From Baseline in Vital Sign: Temperature
timeFrame: Baseline (Day -1), 0.5, 2, 4, 8 and 24 hours post-GSK3008348 dose
measure: Period 2: Change From Baseline in Vital Sign: Temperature
timeFrame: Baseline (Day -1), 30 minutes (post-PET scan), Day 1 (prior to discharge) and Day 2 (pre-PET scan)
measure: Period 1: Number of Participants With Abnormal Findings for 12-lead Electrocardiograms (ECG) Parameters
timeFrame: Pre-dose (Day -1), 0.5, 2, 4, 8 and 24 hours post-GSK3008348 dose
measure: Period 2: Number of Participants With Abnormal Findings for 12-lead ECG Parameters
timeFrame: Pre-dose (Day -1), 30 minutes (post-PET scan), Day 1 (prior to discharge), Day 2 (pre-PET scan) and Day 15 (follow-up)
measure: Period 1: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC)
timeFrame: Baseline (Day -1), 1 hour and 24 hours post-GSK3008348 dose
Secondary outcomes:
measure: Period 1: Area Under the Plasma Concentration-time Curve From Zero Hours to Time (AUC[0-t]) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18 and 24 hours post-GSK3008348 dose
measure: Period 2: AUC(0-t) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 2, 4, 22 and 30 hours post-GSK3008348 dose
measure: Period 1: Area Under the Plasma Concentration-time Curve From Zero Hours to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18 and 24 hours post-GSK3008348 dose
measure: Period 2: AUC(0-infinity) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 2, 4, 22 and 30 hours post-GSK3008348 dose
measure: Period 1: Maximum Observed Plasma Drug Concentration (Cmax) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18 and 24 hours post-GSK3008348 dose
measure: Period 2: Cmax After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 2, 4, 22 and 30 hours post-GSK3008348 dose
measure: Period 1: Time of Occurrence of Cmax (Tmax) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18 and 24 hours post-GSK3008348 dose
measure: Period 2: Tmax After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 2, 4, 22 and 30 hours post-GSK3008348 dose
measure: Period 1: Terminal Phase Half-life (t1/2) After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18 and 24 hours post-GSK3008348 dose
measure: Period 2: t1/2 After Single Dose Administration of GSK3008348
timeFrame: Pre-dose, and at 0.25, 0.5, 2, 4, 22 and 30 hours post-GSK3008348 dose
measure: Period 2: VT of [18F]-FBAA20FMDV2 in the Whole Lung (Not Corrected for Air Volume) Approximately 24 Hours Post-dose Compared to Pre-dose
timeFrame: Baseline (pre-dose) and 24 hours post-dose PET scan 2
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: