Hypertension, Pulmonary
Conditions
Keywords
Idiopathic Pulmonary Arterial Hypertension, Biodistribution, Positron Emission Tomography, [11C]-GSK2256098, Healthy subjects
Brief summary
Pulmonary arterial hypertension (PAH) involves the narrowing of blood vessels connected to and within the lungs. Focal adhesion kinase (FAK) is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes which leads to stiffening and thickening of blood vessels in lungs. This further increases the blood pressure within the lungs and impairs their blood flow. This study aims to demonstrate biodistribution of FAK inhibitor, GSK2256098, in cardiopulmonary sites i.e. heart and lung tissues. The uptake of 11C-radiolabelled GSK2256098 within the lung and / or heart of healthy subjects and idiopathic pulmonary arterial hypertension (iPAH) patients will be assessed using Positron Emission Tomography (PET). Based on study results the decision as to whether a follow-on phase 2 trial should be initiated to investigate the therapeutic utility of GSK2256098 in iPAH will be decided. Sufficient number of subjects will be screened (up to 30 days prior to scan) to enrol 12 healthy subjects and 12 PAH patients in the study. Enrolled subjects will receive a microdose of \[11C\]-GSK2256098 on a scanning day which will be followed by the follow-up visit (2-4 weeks post-last dose).
Interventions
DRUG[11C]-GSK2256098 500 MBq
\[11C\]-GSK2256098 injection will be provided as IV infusion, 20 mL, containing up to 5% ethanol in saline.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion criteria for healthy volunteers \- Healthy subjects enrolled between 40 to 70 years inclusive at the time of signing the informed consent. Healthy subjects will be recruited to be age (+/-5 years) and gender matched to idiopathic PAH patients. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. * Normal spirometry at Screening (forced expiratory volume in 1 second \[FEV1\] and forced vital capacity \[FVC\] \>= 80% of predicted - measurements to be taken in triplicate and the highest value must be \>= 80% of predicted). * A subject with a clinical abnormality or laboratory parameter(s) outside the reference range for the population being studied may be included only if the investigator, in consultation with the medical monitor if deemed necessary, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Subject is ambulant and capable of attending for PET- computed tomography (CT) imaging. * A negative Allen's test in at least one arm for arterial blood sampling (indicating adequate collateral circulation to the hand from both the radial and ulnar arteries). * Body weight \>=50 kg and body mass index (BMI) within the range 18.5 - 35 kilogram/meter\^2 (kg/m\^2) (inclusive). * Male or Female A. Males: 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 3 months after the scan. In addition, they must not plan to father a child, or donate sperm, for 3 months after the scan. 1. Vasectomy with documentation of azoospermia. 2. Male condom plus partner use of one of the contraceptive options below: • Contraceptive subdermal implant * Intrauterine device or intrauterine system * Oral Contraceptive, either combined or progestogen alone Injectable progestogen * Contraceptive vaginal ring * Percutaneous contraceptive patches B. Females: a. Non-reproductive potential defined as: Pre-menopausal females with one of the following; i) Documented tubal ligation ii) Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion iii) Hysterectomy iv) Documented Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective 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. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Inclusion criteria for PAH Patients: * PAH patients enrolled between 40 to 70 years inclusive at the time of signing the informed consent. * Subjects medically diagnosed with idiopathic and inherited PAH, and clinically Functional Class II-IV. * Subject is ambulant and capable of attending for PET-CT imaging. * A negative Allen's test in at least one arm for arterial blood sampling (indicating adequate collateral circulation to the hand from both the radial and ulnar arteries). * Body weight \>=50 kg and BMI within the range 18.5 - 35 kg/m\^2 (inclusive). * Male or Female A. Males: 1. Male subjects with female partners of child bearing potential must comply with the following contraception requirements from scan until 3 months after the last dose of study medication. In addition, they must not plan to father a child, or donate sperm, for 3 months after the scan. 2. Vasectomy with documentation of azoospermia. 3. Male condom plus partner use of one of the contraceptive options below: * Contraceptive subdermal implant * Intrauterine device or intrauterine system * Oral Contraceptive, either combined or progestogen alone Injectable progestogen * Contraceptive vaginal ring * Percutaneous contraceptive patches B. Females: A female subject of non-child bearing potential is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies: a. Non-reproductive potential defined as: Pre-menopausal females with one of the following: i) Documented tubal ligation ii) Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion iii) Hysterectomy iv) Documented Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous FSH and estradiol levels consistent with menopause. Females on HRT and whose menopausal status is in doubt will be required to use one of the highly effective 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. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Day 1 | The PET scan was acquired to measure the uptake of radiolabeled GSK2256098 in the heart and lungs, assessed as the volume of distribution (VT). The analysis was performed on Safety Population which comprised of all participants who received a microdose of study treatment. |
| Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Day 1 | The PET scan was acquired to measure the uptake of radiolabeled GSK2256098 in the heart and lungs, assessed as the mean standardized uptake value (SUV) averaged over the 60 minute period between 30 and 90 minutes. The analysis was performed on Safety Population which comprised of all participants who received a microdose of study treatment. |
Countries
United Kingdom
Participant flow
Recruitment details
Healthy volunteers and participants with Pulmonary Arterial Hypertension (PAH) were included in this study to evaluate the bio-distribution of \[11C\]- GSK2256098 in the lungs and heart using Positron Emission Tomography (PET).
Pre-assignment details
A total of 14 participants were screened, of which 4 participants were screen failures. Remaining 10 participants were included in the study.
Participants by arm
| Arm | Count |
|---|---|
| PAH Participants Participants received one microdose that is (i.e.) less than 10 micrograms of radiolabeled GSK2256098 in a 20 milliliter (mL) volume, via intravenous (IV) route. A PET scan was performed immediately after the IV administration. | 5 |
| Healthy Volunteers Participants received one microdose i.e. less than 10 micrograms of radiolabeled GSK2256098 in a 20 mL volume, via IV route. A PET scan was performed immediately after the IV administration. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | PAH Participants | Healthy Volunteers | Total |
|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 5.81 | 64.0 Years STANDARD_DEVIATION 7 | 63.6 Years STANDARD_DEVIATION 6.08 |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White Heritage | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 3 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan
The PET scan was acquired to measure the uptake of radiolabeled GSK2256098 in the heart and lungs, assessed as the mean standardized uptake value (SUV) averaged over the 60 minute period between 30 and 90 minutes. The analysis was performed on Safety Population which comprised of all participants who received a microdose of study treatment.
Time frame: Day 1
Population: Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PAH Participants | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Heart, left ventricular wall | 1.0738 Grams per milliliter (g/mL) | Standard Deviation 0.04931 |
| PAH Participants | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Heart, right ventricular wall | 1.0143 Grams per milliliter (g/mL) | Standard Deviation 0.10994 |
| PAH Participants | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Lung | 0.2988 Grams per milliliter (g/mL) | Standard Deviation 0.0515 |
| Healthy Volunteers | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Heart, left ventricular wall | 1.0697 Grams per milliliter (g/mL) | Standard Deviation 0.2007 |
| Healthy Volunteers | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Heart, right ventricular wall | 0.9689 Grams per milliliter (g/mL) | Standard Deviation 0.19018 |
| Healthy Volunteers | Standardized Uptake Values (SUV) of Radiolabeled GSK2256098 Measured by PET Scan | Lung | 0.2891 Grams per milliliter (g/mL) | Standard Deviation 0.06851 |
95% CI: [0.846, 1.189]
95% CI: [0.853, 1.269]
95% CI: [0.786, 1.34]
Primary
Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan
The PET scan was acquired to measure the uptake of radiolabeled GSK2256098 in the heart and lungs, assessed as the volume of distribution (VT). The analysis was performed on Safety Population which comprised of all participants who received a microdose of study treatment.
Time frame: Day 1
Population: Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PAH Participants | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Heart, left ventricular wall | 1.0811 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.14769 |
| PAH Participants | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Heart, right ventricular wall | 0.8117 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.15253 |
| PAH Participants | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Lung | 0.0858 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.02364 |
| Healthy Volunteers | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Heart, left ventricular wall | 1.3027 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.18754 |
| Healthy Volunteers | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Heart, right ventricular wall | 0.5571 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.12824 |
| Healthy Volunteers | Volume of Distribution of Radiolabeled GSK2256098 Measured by PET Scan | Lung | 0.0904 Milliliter per cubic centimeter(mL/cm^3) | Standard Deviation 0.01592 |
95% CI: [0.682, 0.979]
95% CI: [1.113, 1.891]
95% CI: [0.692, 1.241]