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

Idiopathic Pulmonary Fibrosis Clinical Trial

Official title:

A FTIH Study With GSK3008348 in Healthy Volunteers and Patients With Idiopathic Pulmonary Fibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02612051
• Other study ID #: 200262
• Status: Completed
• Phase: Phase 1
• First received: November 19, 2015
• Last updated: April 28, 2017
• Start date: December 4, 2015
• Est. completion date: June 2, 2016

Study information

• Verified date: April 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: June 2, 2016
• Est. primary completion date: June 2, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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.

• A subject with a potentially clinically significant abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects with FEV1, FVC and DLCO values outside the normal range may be included only if the investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

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)

• Female subjects are eligible to participate if they are of non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 month of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-international unit (MIU)/millilitre (ml) and estradiol > 141 picomole (pmol)/litre (l) is confirmatory (as a precaution a pregnancy test is conducted prior to dosing, a positive test leads to exclusion).

• 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

Exclusion Criteria:

• 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.

Parts B and C:

• History or suffers from claustrophobia or subject feels unable to lie flat and still on their back for a period of up to 2 hours in the PET/ CT scanner (note, one rest period will be allowed during the scan if required).

• Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations or occupational exposure resulting in radiation exposure greater than 10 millisievert (mSv) over the past 3 years or greater than 10 mSv in a single year including the proposed study. Clinical exposure from which the subject receives a direct benefit is not included in these calculations.

• Subjects with current IPF exacerbation, upper or lower respiratory tract infection.

• Subjects with severe co-existent chronic obstructive pulmonary disease (COPD), for example FEV1 < 60% predicted.

All Parts:

• Use of prohibited medication

• Subjects who are currently taking Pirfenidone or Nintedanib or who have received Pirfenidone or Nintedanib within the 30 days prior to the first dosing day will be excluded from the study.

• Subjects prescribed long-term continuous home oxygen therapy (those whose use of oxygen is intermittent and for symptom relief only are not excluded)

• History of alcohol consumption regularly in excess of: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.

• History of sensitivity to heparin or heparin-induced thrombocytopenia.

• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

• 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. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase chain reaction (PCR) test is obtained.

• A positive pre-study drug/alcohol screen.

• A positive test for human immunodeficiency virus (HIV) antibody.

• 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 four new chemical entities within 12 months prior to the first dosing day.

Parts B and C:

• Previous or current exposure to animals that may harbour foot 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)

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• GSK3008348 Nebuliser solution
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.
• Placebo Nebuliser solution
5% mannitol nebuliser solution. 4 ml of solution will be administered by nebulisation

Radiation:
• GSK26346763: ([18F]-FBA-A20FMDV2) IV infusion
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.

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	London

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Part A: Temperature as a measure of safety and tolerability		Up to Day 33
Primary	Part A: Systolic and diastolic blood pressure as a measure of safety and tolerability		Up to Day 33
Primary	Part A: Pulse rate and respiratory rate as a measure of safety and tolerability		Up to Day 33
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Part B: Temperature as a measure of safety and tolerability		Up to Day 43
Primary	Part B: Systolic and diastolic blood pressure as a measure of safety and tolerability		Up to Day 43
Primary	Part B: Pulse rate and respiratory rate as a measure of safety and tolerability		Up to Day 43
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Part A: Area under the curve (AUC) following single doses of GSK3008348	AUC from time zero to infinity (AUC[0-inf]), AUC from time zero to the time of last quantifiable concentration (AUC[0-t]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.	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
Secondary	Part A: Cmax following single doses of GSK3008348	Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.	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
Secondary	Part A: Tmax and t½ following single doses of GSK3008348	Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.	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
Secondary	Part B: Area under the curve (AUC) following single doses of GSK3008348	AUC from time zero to infinity (AUC[0-inf]), AUC from time zero to the time of last quantifiable concentration (AUC[0-t]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.	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
Secondary	Part B: Cmax following single doses of GSK3008348	Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.	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
Secondary	Part B: Tmax and t½ following single doses of GSK3008348	Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.	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
Secondary	Part B: Changes in VT at 14-28 hours 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 15), Up to Day 30
Secondary	Part C: Area under the curve (AUC) following single doses of GSK3008348	AUC from time zero to infinity (AUC[0-inf]), AUC from time zero to the time of last quantifiable concentration (AUC[0-t]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.	Blood samples will be collected at pre-dose and post-nebulisation 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
Secondary	Part C: Cmax following single doses of GSK3008348	Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.	Blood samples will be collected at pre-dose and post-nebulisation 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
Secondary	Part C: Tmax and t½ following single doses of GSK3008348	Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.	Blood samples will be collected at pre-dose and post-nebulisation 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
Secondary	Part C: 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
Secondary	Part C: Temperature as a measure of safety and tolerability		Up to Day 43
Secondary	Part C: Systolic and diastolic blood pressure as a measure of safety and tolerability		Up to Day 43
Secondary	Part C: Pulse rate and respiratory rate as a measure of safety and tolerability		Up to Day 43
Secondary	Part C: 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 43
Secondary	Part C: 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 43
Secondary	Part C: 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 43
Secondary	Part C: 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 43

External Links

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