Idiopathic Pulmonary Fibrosis
Conditions
Keywords
patients, FTIH, healthy volunteers, GSK3008348, [18F]-FBA-A20FMDV2, Idiopathic Pulmonary Fibrosis, PET
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.
Interventions
DRUGGSK3008348 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.
5% mannitol nebuliser solution. 4 ml of solution will be administered by nebulisation
RADIATIONGSK26346763: ([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.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part C: Changes in VT at various time points post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung | Baseline (from Day 1), Up to Day 29 | 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. |
| Part A: FEV1 and FVC as a measure of safety and tolerability | Up to Day 33 | 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 . |
| Part A: DLCO as a measure of safety and tolerability | Up to Day 20 | 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. |
| Part A: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability | Up to Day 19 | Subjects will be required to complete a taste questionnaire following dosing. |
| Part A: Composite of hematology laboratory tests as a measure of safety and tolerability | Up to Day 33 | 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. |
| Part A: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability | Up to Day 33 | 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. |
| Part A: Composite of urinalysis laboratory tests as a measure of safety and tolerability | Up to Day 33 | Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal). |
| Part B: AE as a measure of safety and tolerability | Up to Day 43 | 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. |
| 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 | Up to Day 43 | SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry. |
| Part B: ECG and Telemetry as a measure of safety and tolerability | Up to Day 31 | 12-lead ECG and cardiac telemetry will be performed. |
| Part B: FEV1 and FVC as a measure of safety and tolerability | Up to Day 43 | 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 . |
| Part B: DLCO as a measure of safety and tolerability | Up to Day 30 | 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. |
| Part B: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability | Up to Day 29 | Subjects will be required to complete a taste questionnaire following dosing. |
| 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 | Baseline (from Day 15), Up to Day 30 | 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. |
| Part B: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability | Up to Day 30 | 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. |
| Part B: Composite of urinalysis laboratory tests as a measure of safety and tolerability | Up to Day 30 | Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal) |
| 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 | Up to Day 33 | SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry. |
| Part A: ECG and Telemetry as a measure of safety and tolerability | Up to Day 21 | 12-lead ECG and cardiac telemetry will be performed. |
| Part B: Composite of hematology laboratory tests as a measure of safety and tolerability | Up to Day 30 | 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. |
| Part A: Number of participants with adverse events (AE) as a measure of safety and tolerability | Up to Day 33 | 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. |
| Part A: Temperature as a measure of safety and tolerability | Up to Day 33 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile. |
| 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 | 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. |
| 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 | 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. |
| 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 | Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile. |
| Part B: 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 | 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. |
| Part B: Changes in VT at 14-28 hours post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung | Baseline (from Day 15), Up to Day 30 | 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. |
| Part C: Area under the curve (AUC) following single doses of GSK3008348 | 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 | 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. |
| Part C: Cmax following single doses of GSK3008348 | 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 | Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile. |
| Part C: Tmax and t½ following single doses of GSK3008348 | 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 | 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. |
| Part C: AE as a measure of safety and tolerability | Up to Day 43 | 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. |
| Part C: Temperature as a measure of safety and tolerability | Up to Day 43 | — |
| Part C: Systolic and diastolic blood pressure as a measure of safety and tolerability | Up to Day 43 | — |
| Part C: Pulse rate and respiratory rate as a measure of safety and tolerability | Up to Day 43 | — |
| Part C: Peripheral capillary oxygen saturation (SpO2) levels as a measure of safety and tolerability | Up to Day 43 | SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry. |
| Part C: Composite of hematology laboratory tests as a measure of safety and tolerability | Up to Day 43 | 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. |
| Part C: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability | Up to Day 43 | 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. |
| Part C: Composite of urinalysis laboratory tests as a measure of safety and tolerability | Up to Day 43 | Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal) |
| 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 | 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. |
Countries
United Kingdom
Outcome results
None listed