Last updated: 07/17/2024 17:23:57
Study of GSK2586881 on acute hypoxia and exercise
EudraCT ID
EU CT Number
Not applicable
Trial status
Other
Other
Trial overview
Official title: The effects of GSK2586881 on the responses to acute hypoxia and exercise
Trial description: This study is conducted to examine how GSK2586881, a recombinant human ACE2 peptide, modulates the acute hypoxic pulmonary vasoconstriction (HPV) response in healthy volunteers. The study will be single-center, randomized, placebo-controlled and double blind (sponsor open). Subjects will be randomized to receive a single intravenous (IV) dose of GSK2586881 or placebo (saline) in a crossover design. The primary objective of the study is to evaluate the effect of a single IV dose of GSK2586881 on the HPV response in healthy volunteers during exercise under hypoxic conditions. Approximately 35 subjects will be enrolled for a maximum of 56 days.
Primary purpose:
Treatment
Trial design:
Crossover Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:
Change from baseline in Pulmonary Artery Systolic Pressure (PASP)
Timeframe: Baseline and up to 16 days
Secondary outcomes:
Change from baseline in Renin-Angiotensin System (RAS) peptides in response to hypoxia and exercise
Timeframe: Baseline and up to 16 days
Safety as assessed by Heart rate
Timeframe: Up to 26 days
Safety as assessed by Blood pressure
Timeframe: Up to 26 days
Oxygen saturation by continuous pulse oximetry
Timeframe: Up to 16 days
Electrocardiogram (ECG) assessment as a measure of safety
Timeframe: Up to 26 days
Number of subjects with any adverse event(s) (AE)
Timeframe: Up to 26 days
Number of subjects with positive anti- Angiotensin converting enzyme type 2 (ACE2) binding and neutralizing antibodies
Timeframe: Day 1 predose (treatment period 2)
Number of subjects with abnormal hematology laboratory parameters, as a measure of safety
Timeframe: Up to 26 days
Number of subjects with abnormal clinical chemistry parameters, as a measure of safety
Timeframe: Up to 26 days
Number of subjects having abnormal urinalysis as a measure of safety
Timeframe: Up to 26 days
Measurement of plasma concentrations of a single IV dose of GSK2586881
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of time to Cmax (tmax) of a single IV dose of GSK2586881
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of area under the plasma concentration-time curve (AUC) (0 to 2.5 hours) post dose
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of AUC (0.5 to 2.0 hours) post dose
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of plasma clearance
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of volume of distribution
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Measurement of apparent terminal phase half-life (t1/2)
Timeframe: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods
Interventions:
Enrollment:
17
Primary completion date:
2019-04-01
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
David A. Hall, Kate Hanrott, Philipp Badorrek, Dominik Berliner, David C. Budd, Rhena Eames, Will M. Powley, Debbie Hewens, Sarah Siederer, Aili L. Lazaar, Tony Cahn, Jens M. Hohlfeld. Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study. Pulm Ther. 2021;:1-15
DOI: 10.1007/s41030-021-00164-7
PMID: 34189703
Medical condition
healthy volunteers
Product
GSK2586881
Collaborators
Not applicable
Study date(s)
May 2017 to January 2019
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18 - 40 years
Accepts healthy volunteers
Yes
- Between 18 and 40 years of age inclusive, at the time of signing the informed consent.
- 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. A subject with a clinical 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. Note: Screened subjects with laboratory values outside of the normal range may be repeated once for inclusion into the study at the discretion of the Investigator.
- ALT >1.5x Upper limit of normal (ULN).
- Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Inclusion and exclusion criteria
Inclusion criteria:
- Between 18 and 40 years of age inclusive, at the time of signing the informed consent.
- 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. A subject with a clinical 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. Note: Screened subjects with laboratory values outside of the normal range may be repeated once for inclusion into the study at the discretion of the Investigator.
- Screening echocardiogram of good quality, without clinically significant abnormalities, and with mild-moderate tricuspid regurgitation sufficient for the reliable estimation of PASP, as determined by the echocardiography core laboratory or responsible cardiologist. Screening PASP within the normal range according to site standards.
- Subjects have not resided at an altitude >1500 meter (m) for more than 7 days in the last 4 month
- Able to complete all study procedures.
- Any contraindication (orthopedic, cardiac etc.) to perform exercise on a bicycle ergometer.
- Body weight 50 to 100 kilogram (kg) (inclusive).
- Male or female (non Child Bearing Potential): 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 at least five half-lives of study medication OR for a cycle of spermatogenesis following five terminal half-lives 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 (Contraceptive subdermal implant, Intrauterine device or intrauterine system, Oral Contraceptive- either combined or progestogen alone, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches). This is an all-inclusive list of those methods that meet the following 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 GSK definition is based on the definition provided by the International Conference on Harmonization (ICH).The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not lactating, and the following condition applies: Non-reproductive potential defined as, 1. Pre-menopausal females with one of the following (Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy). 2. 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 (refer to laboratory reference ranges for confirmatory levels)]. 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. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
- Capable of giving signed informed consent as described in study protocol which includes compliance with the requirements and restrictions listed in the consent form and in the study protocol.
Exclusion criteria:
- ALT >1.5x Upper limit of normal (ULN).
- Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- QTc > 450 millisecond (msec.)
- Unable to refrain from prescription or non-prescription drugs, including agents active in the central nervous system, vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study, unless in the opinion of the Investigator and/or GSK Medical Monitor (if needed) the medication will not interfere with the study procedures or compromise subject safety.
- History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 milliliter [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 6 months prior to screening
- 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. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
- 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.
Trial location(s)
Location
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
Status
Study Complete
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Other
Actual primary completion date
2019-04-01
Actual study completion date
2019-04-01
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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