First Time in Human (FTIH) Study of GSK3008348 in Healthy Volunteers and Idiopathic Pulmonary Fibrosis Patients

NCT02612051 | Completed Phase 1

• 1 other identifier: 200262
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

GSK3008348 is an investigational drug, being developed by GlaxoSmithKline Research and Development Limited (the Sponsor, a pharmaceutical company based in the UK) for the treatment of Idiopathic Pulmonary Fibrosis (IPF). IPF is a rare and poorly understood disease that causes scarring of the lungs. The main symptoms are shortness of breath and a dry cough. Symptoms generally worsen over time and in some subjects may prove fatal. The cause of IPF is unknown. This is a First Time in Human, Phase 1, 3-part study which is being carried out on behalf of the Sponsor by Quintiles. The primary purpose of Part A is to examine the safety and tolerability of single nebulised (a medicated spray) doses of GSK3008348 following inhalation in healthy volunteers. The secondary objective is to determine how and at what rate the body absorbs, distributes, breaksdown and eliminates the drug. Parts B and C of this study will be in-patients with Idiopathic Pulmonary Fibrosis (IPF). The purpose of Part B and C is to examine the safety and tolerability, and how much of the drug binds to its target, following single nebulised (a medicated spray) doses of GSK3008348 following inhalation in patients with Idiopathic Pulmonary Fibrosis (IPF). The secondary objective is to determine how and at what rate the bodies of these patients absorbs, distributes, breaksdown and eliminates the drug. The total duration of Part A will be 65 - 87 days, Part B 62 days and Part C 43 days.

Conditions

Idiopathic Pulmonary Fibrosis

Keywords

patients; FTIH; healthy volunteers; GSK3008348; [18F]-FBA-A20FMDV2; Idiopathic Pulmonary Fibrosis; PET

Outcome Measures

Primary Outcomes (26)

• Part A: Number of participants with adverse events (AE) as a measure of safety and tolerability

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.

  Up to Day 33

• Part A: Temperature as a measure of safety and tolerability

  Up to Day 33

• Part A: Systolic and diastolic blood pressure as a measure of safety and tolerability

  Up to Day 33

• Part A: Pulse rate and respiratory rate as a measure of safety and tolerability

  Up to Day 33

• Part A: Peripheral capillary oxygen saturation (SpO2) levels as a measure of safety and tolerability

  SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry.

  Up to Day 33

• Part A: ECG and Telemetry as a measure of safety and tolerability

  12-lead ECG and cardiac telemetry will be performed.

  Up to Day 21

• Part A: FEV1 and FVC as a measure of safety and tolerability

  Forced expiratory volume in 1 second (FEV1) is the volume of air that can forcibly be blown out in one second, after full inspiration. Forced vital capacity (FVC) is the volume of air that can forcibly be blown out after full inspiration. Lung function test will be performed to obtain FEV1 and FVC .

  Up to Day 33

• Part A: DLCO as a measure of safety and tolerability

  Diffusing capacity (DLCO) is the carbon monoxide uptake from a single inspiration in a standard time (usually 10 seconds). Lung function test will be performed to obtain DLCO.

  Up to Day 20

• Part A: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability

  Subjects will be required to complete a taste questionnaire following dosing.

  Up to Day 19

• Part A: Composite of hematology laboratory tests as a measure of safety and tolerability

  Hematology laboratory tests will include platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

  Up to Day 33

• Part A: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability

  Clinical chemistry laboratory tests will include urea, creatinine, glucose non-fasted, creatinine phosphokinase, potassium, sodium, calcium, aspartate aminotransferase alanine transaminase,total and direct bilirubin, total protein, alkaline phosphatise and albumin.

  Up to Day 33

• Part A: Composite of urinalysis laboratory tests as a measure of safety and tolerability

  Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal).

  Up to Day 33

• Part B: AE as a measure of safety and tolerability

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.

  Up to Day 43

• Part B: Temperature as a measure of safety and tolerability

  Up to Day 43

• Part B: Systolic and diastolic blood pressure as a measure of safety and tolerability

  Up to Day 43

• Part B: Pulse rate and respiratory rate as a measure of safety and tolerability

  Up to Day 43

• Part B: SpO2 levels as a measure of safety and tolerability

  SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry.

  Up to Day 43

• Part B: ECG and Telemetry as a measure of safety and tolerability

  12-lead ECG and cardiac telemetry will be performed.

  Up to Day 31

• Part B: FEV1 and FVC as a measure of safety and tolerability

  FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FVC is the volume of air that can forcibly be blown out after full inspiration. Lung function test will be performed to obtain FEV1 and FVC .

  Up to Day 43

• Part B: DLCO as a measure of safety and tolerability

  DLCO is the carbon monoxide uptake from a single inspiration in a standard time (usually 10 seconds). Lung function test will be performed to obtain DLCO.

  Up to Day 30

• Part B: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability

  Subjects will be required to complete a taste questionnaire following dosing.

  Up to Day 29

• Part B: Changes in volume of distribution [VT]) at approximately 1 hour post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung

  Positron Emission Tomography (PET) scan and a sample of blood will be taken simultaneously for measurement of \[18F\]-FBA-A20FMDV2 concentration. The blood volume in tissue will be determined by dividing the tissue tracer concentration by the blood value. Changes in the uptake of \[18F\]-FBA-A20FMDV2 in the lung will be calculated.

  Baseline (from Day 15), Up to Day 30

• Part B: Composite of hematology laboratory tests as a measure of safety and tolerability

  Hematology laboratory tests will include platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

  Up to Day 30

• Part B: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability

  Clinical chemistry laboratory tests will include urea, creatinine, glucose fasted, creatinine phosphokinase, potassium, sodium, calcium, aspartate aminotransferase alanine transaminase, total and direct bilirubin, total protein, alkaline phosphatise and albumin.

  Up to Day 30

• Part B: Composite of urinalysis laboratory tests as a measure of safety and tolerability

  Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)

  Up to Day 30

• Part C: Changes in VT at various time points post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung

  PET scan and a sample of blood will be taken simultaneously for measurement of \[18F\]-FBA-A20FMDV2 concentration. The blood volume in tissue will be determined by dividing the tissue tracer concentration by the blood value. Changes in the uptake of \[18F\]-FBA-A20FMDV2 in the lung will be calculated.

  Baseline (from Day 1), Up to Day 29

Secondary Outcomes (18)

• Part A: Area under the curve (AUC) following single doses of GSK3008348

  Blood samples will be collected at pre-dose and at 5, 10, 15, 30 minutes (mins), 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period

• Part A: Cmax following single doses of GSK3008348

  Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period

• Part A: Tmax and t½ following single doses of GSK3008348

  Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period

• Part B: Area under the curve (AUC) following single doses of GSK3008348

  Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period

• Part B: Cmax following single doses of GSK3008348

  Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period

Study Arms (8)

Part A, Cohort 1: GSK3008348 1-3000 mcg/Placebo

EXPERIMENTAL

Healthy subjects will receive single 3 ascending doses of GSK3008348 (ranging from 1 to 3000 microgram \[mcg\]) and matching placebo by nebulisation in one of the four treatment period according to randomization. There will be washout period of at least 6 days between the doses. Actual doses may involve either an increase or a decrease in the planned dose as well as a repeat of the previous.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution

Part A, Cohort 2: GSK3008348 1-3000 mcg/Placebo

EXPERIMENTAL

Healthy subjects will receive single 3 ascending doses of GSK3008348 (ranging from 1 to 3000 microgram \[mcg\]) and matching placebo by nebulisation in one of the four treatment period according to randomization. There will be washout period of at least 6 days between the doses. Actual doses may involve either an increase or a decrease in the planned dose as well as a repeat of the previous.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution

Part A, Cohort 3: GSK3008348 1-3000 mcg/Placebo

EXPERIMENTAL

Healthy subjects will receive single 3 ascending doses of GSK3008348 (ranging from 1 to 3000 microgram \[mcg\]) and matching placebo by nebulisation in one of the four treatment period according to randomization. There will be washout period of at least 6 days between the doses. Actual doses may involve either an increase or a decrease in the planned dose as well as a repeat of the previous.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution

Part B, Cohort 4: GSK3008348/Placebo, IPF, Period 2 PET Scan

EXPERIMENTAL

IPF subject will receive single dose of GSK3008348 (safe and tolerated dose as per cohort 1 to 3) or Placebo in two treatment periods according to randomization. There will be washout period of 6 to 28 days between the doses. Subjects will receive up to three microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution; Radiation: GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion

Part B, Cohort 5: GSK3008348/Placebo, IPF, Period 2 PET Scan

EXPERIMENTAL

IPF subject will receive single dose of GSK3008348 (safe and tolerated dose as per cohort 1 to 3) or Placebo in two treatment periods according to randomization. There will be washout period of 6 to 28 days between the doses. Subjects will receive up to three microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution; Radiation: GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion

Part B, Cohort 6: GSK3008348/Placebo, IPF, Period 2 PET Scan

EXPERIMENTAL

IPF subject will receive single dose of GSK3008348 (safe and tolerated dose as per cohort 1 to 3) or Placebo in two treatment periods according to randomization. There will be washout period of 6 to 28 days between the doses. Subjects will receive up to three microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution; Radiation: GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion

Part B, Cohort 7: GSK3008348/Placebo, IPF, Period 2 PET Scan

EXPERIMENTAL

IPF subject will receive single dose of GSK3008348 (safe and tolerated dose as per cohort 1 to 3) or Placebo in two treatment periods according to randomization. There will be washout period of 6 to 28 days between the doses. Subjects will receive up to three microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2.

Drug: GSK3008348 Nebuliser solution; Drug: Placebo Nebuliser solution; Radiation: GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion

Part C, Cohort 8: GSK3008348, IPF, PET Scan

EXPERIMENTAL

IPF subject will receive single dose of GSK3008348 (safe and tolerated dose as per Part B) in two treatment periods. There will be washout period of 6 to 14 days between the doses. Subjects will receive up to three microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in both periods.

Drug: GSK3008348 Nebuliser solution; Radiation: GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion

Interventions

GSK3008348 Nebuliser solution DRUG

Nebuliser solution formulated at 5000 mcg/mL with 5% mannitol, citric acid, sodium citrate and water for injection, pH adjusted using Hydrochloric acid or Sodium hydroxide to the target pH 5.4 +/- 0.4. 4 ml of diluted dose of appropriate concentration will be administered by nebulisation.

Part A, Cohort 1: GSK3008348 1-3000 mcg/Placebo; Part A, Cohort 2: GSK3008348 1-3000 mcg/Placebo; Part A, Cohort 3: GSK3008348 1-3000 mcg/Placebo; Part B, Cohort 4: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 5: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 6: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 7: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part C, Cohort 8: GSK3008348, IPF, PET Scan

Placebo Nebuliser solution DRUG

5% mannitol nebuliser solution. 4 ml of solution will be administered by nebulisation

Part A, Cohort 1: GSK3008348 1-3000 mcg/Placebo; Part A, Cohort 2: GSK3008348 1-3000 mcg/Placebo; Part A, Cohort 3: GSK3008348 1-3000 mcg/Placebo; Part B, Cohort 4: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 5: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 6: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 7: GSK3008348/Placebo, IPF, Period 2 PET Scan

GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion RADIATION

Formulated in 0.9% saline. The maximum amount of radioactivity injected during each PET scan will be 150 Megabecquerel (MBq) and maximum mass of \[18F\]-FBA-A20FMDV2 administered across all three administrations will be 100 mcg. Intravenous bolus infusion of 20 ml will be administered over about 30 seconds.

Part B, Cohort 4: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 5: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 6: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part B, Cohort 7: GSK3008348/Placebo, IPF, Period 2 PET Scan; Part C, Cohort 8: GSK3008348, IPF, PET Scan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A:
• \- Male and female subjects \>= 18 years at the time of signing the consent form.
• Parts B and C :
• \- Male subjects \>= 45 years and female subjects \>= 55 years at the time of signing the consent form.
• Part A:
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, 12-lead ECG and pulmonary function tests.

You may not qualify if:

• Parts B and C:
• Subject is ambulant and capable of attending a PET scan visit as an outpatient.
• Subjects will have a diagnosis of 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 Pnuemonias.
• FVC \> 50 % predicted and DLCO \> 50% predicted. Following a review of the safety data at the interim, these criteria may be altered to FVC \> 50% predicted and DLCO \> 40% predicted.
• Part A:
• \- Body weight \>=50 Kilogram (kg) and BMI within the range 19.0 - 35.0 kg/meter square (m\^2) (inclusive).
• Parts B and C:
• Body weight \>=45 kg and BMI within the range 18.0 - 35.0 kg/m\^2 (inclusive)
• 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 90 days after the last dose of study medication. a. Vasectomy with documentation of azoospermia b. Male condom plus partner use of one of the contraceptive options below: i. 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 ii. 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 iii. Oral Contraceptive, either combined or progestogen alone iv. Injectable progestogen v. Contraceptive vaginal ring vi. Percutaneous contraceptive patches This is an all-inclusive list of those methods that meet the following GlaxoSmithKline (GSK) definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. 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 protocol
• Alanine transaminase and bilirubin \>1.5x5xupper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or history of photosensitivity.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• QT interval corrected for heart rate (QTc )\> 450 millisecond (msec) or QTc \> 480 msec in subjects with Bundle Branch Block
• Current upper or lower respiratory tract infection on admission to the clinical unit.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, SE1 1YR, United Kingdom

Location

Related Links

• Results for study 200262 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Idiopathic Pulmonary Fibrosis

Interventions

Infusions, Intravenous

Condition Hierarchy (Ancestors)

Pulmonary Fibrosis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Infusions, Parenteral

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2015
• First Posted: November 23, 2015
• Study Start: December 4, 2015
• Primary Completion: June 2, 2016
• Study Completion: June 2, 2016
• Last Updated: May 1, 2017

Record last verified: 2017-04

Locations

GB (1)