Last updated: 11/07/2018 08:00:49
The safety, tolerability, PK and PD of GSK2586881 in patients with acute lung injury
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: A two part study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2586881 in patients with acute lung injury
Trial description: This is an early phase (phase IIa), randomized, multi-center study in subjects with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The purpose of this study is to investigate the safety of GSK2586881 and to determine what effects it has on people with Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS). The study has two parts: Part A will be an open-label investigation in five subjects. Part B will be a double-blind, placebo controlled investigation and will involve approximately 60 subjects.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:
Heart rate assessments upto Day 7 (part B)
Timeframe: Up to Day 7
Diastolic and Systolic blood pressure assessments upto Day 7 (part B)
Timeframe: Up to Day 7
Electrocardiogram (ECG) parameters, including PR, QRS, QT, and QTCU and RR intervals upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameters basophils, eosinophil, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameters red blood cell count and reticulocyte count assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameter hemoglobin and mean corpuscle hemoglobin concentration (MCHC) assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameter mean corpuscle volume (MCV) assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameter mean corpuscle hemoglobin (MCH) assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Hematology parameter hematocrit assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Clinical chemistry parameters calcium, chloride, carbon dioxide, glucose, potassium, sodium, Urea/Blood urea nitrogen assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Clinical chemistry parameters direct bilirubin, total bilirubin, creatinine and uric acid assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Clinical chemistry parameters alkaline phosphatase, asparatate amino transferase, alanine amino transferase, gamma glutamyl transferase assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Clinical chemistry parameters albumin and total protein assessment upto Day 7 (part B)
Timeframe: Up to Day 7
Number of participant with adverse event (AE) and serious adverse event (SAE) assessment upto Day 7 (Part A)
Timeframe: Up to Day 7
Number of par with AE and serious adverse event (SAE) assessment upto Day 7 (Part B)
Timeframe: Up to Day 7
Secondary outcomes:
Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part A)
Timeframe: Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1), 0 hours, 1 hour, 12 hours, 24 hours (Day 2)
Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part B)
Timeframe: Pre-dose, 0.5 Hours, 2 hours, 6 hours, 12 hours (Day 1), 0 hours (Day 2), 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours (Day 3)
Analysis of pharmacokinetic parameter clearance (CL) for GSK2586881 (part A)
Timeframe: Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours
Analysis Pharmacokinetic parameter clearance (CL) for GSK2586881 (part B)
Timeframe: Pre-dose, 0 hour, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours, 24 hours, 25 hours, 36 hours, 48 hours
Pharmacodynamic/biomarker analysis (Renin-angiotensin system cascade biomarkers) to include Angiotensin (Ang) II and Ang (1-7) upto day 2 (part A)
Timeframe: Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1) and 0 hours, 1 hour, 12 hours and 24 hours (Day 2).
Pharmacodynamic/biomarker analysis (Renin-angiotensin system cascade biomarkers) to include Ang II/ Ang (1-7) upto day 2 (part A)
Timeframe: Pre-dose, 5 minutes, 10 minutes, 2 hours, 6 hours, 10 hours, 12 hours (Day 1) and 0 hours, 1 hour, 12 hours and 24 hours (Day 2).
Pharmacodynamic/biomarker analysis (Renin-angiotensin system cascade biomarkers) to include Ang II, Ang (1-7) and Ang (1-5) upto Day 5(part B)
Timeframe: 0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5.
Pharmacodynamic/biomarker analysis (Renin-angiotensin system cascade biomarkers) to include Ang II/Ang (1-5) and Ang II/Ang (1-7) upto Day 5(part B)
Timeframe: 0.5 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 48.5 hours, 50 hours, 54 hours, 60 hours, 66 hours, 72 hours, 96 hours and 120 hours upto Day 5.
Measures of oxygenation including level of positive end expiratory pressure (PEEP), peak ventilatory pressures and plateau ventilatory pressures upto Day 7 (part B)
Timeframe: 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Measure of oxygenation including fraction of inspired oxygen/ partial pressure of oxygen in arterial blood (PaO2/FiO2) ratio via pulse oximetry upto Day 7 (Part B)
Timeframe: 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Measure of oxygenation index upto Day 7 (Part B)
Timeframe: 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 24.5, 25, 26, 28, 30, 32, 36, 42, 48, 48.5, 49, 50, 52, 54, 56, 60, 66, 72 and 168 hours upto Day 7
Number of Participants with Acute Kidney Injury as Defined by Day 1 to Day 3 Change in Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease (RIFLE) Criteria Upto Day 3 (Part B)
Timeframe: Upto Day 3
Evaluation of Sequential Organ failure assessment (SOFA) score on Day 4 and Day 7 (part B)
Timeframe: Day 4 and Day 7
Biomarker analysis for serum inflammatory biomarkers, markers of neutrophil activation, markers of lung epithelial cell injury, Renin levels and Aldosterone levels upto Day 5 (Part B)
Timeframe: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Biomarker analysis for serum inflammatory biomarker C-reactive Protein (CRP) upto Day 5 (Part B)
Timeframe: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Biomarker analysis for markers of lung epithelial cell injury clara cell protein 16 [CCP16]) and surfactant protein D [SP-D] upto Day 5 (Part B)
Timeframe: 12 hours, 24 hours, 48 hours, 72 hours and 120 hours upto Day 5
Immunogenicity assessment with respect to Anti-Acetychollinesterase2 (ACE2) binding antibodies at follow-up Day 14 and follow-up Day 28 (part A)
Timeframe: Follow-up (Day 14) and follow-up (Day 28)
Immunogenicity assessment with respect to Anti-ACE2 binding antibodies at follow-up Day 14 and follow-up Day 28 (part B)
Timeframe: Follow-up (Day 14 )and follow-up (Day 28)
Interventions:
Drug: Dose 1 GSK2586881
Drug: Dose 2 GSK2586881
Drug: Dose 3 GSK2586881
Drug: Dose 4 GSK2586881
Drug: Placebo (saline)
Enrollment:
44
Observational study model:
Not applicable
Primary completion date:
2014-06-10
Time perspective:
Not applicable
Clinical publications:
Akram Khan; Cody Benthin; Brian Zeno; Timothy E. Albertson; John Boyd; Jason D. Christie; Richard Hall; Germain Poirier; Juan J. Ronco; Mark Tidswell; Kelly Hardes; William M. Powley; Tracey J. Wright; Sarah K. Siederer; David A. Fairman; David A. Lipson; Andrew I. Bayliffe; Aili L. Lazaar. A Pilot Clinical Trial of Recombinant Human Angiotensin Converting Enzyme 2 in Acute Respiratory Distress Syndrome. Crit Care. 2017;21:234
Medical condition
Lung Injury, Acute
Product
GSK2586881
Collaborators
Not applicable
Study date(s)
September 2012 to October 2014
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 80 years
Accepts healthy volunteers
No
- Male or female, 18 - 80 years of age (inclusive)
- Diagnosis of ALI with acute onset of PaO2/FiO2 ratio less than or equal to 300, and bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric, and requirement for positive pressure ventilation via an endotracheal tube, and no clinical evidence of left atrial hypertension
- Subjects whose clinical condition is deteriorating rapidly or any subject for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the study.
- Known positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody
Inclusion and exclusion criteria
Inclusion criteria:
- Male or female, 18
- 80 years of age (inclusive)
- Diagnosis of ALI with acute onset of PaO2/FiO2 ratio less than or equal to 300, and bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric, and requirement for positive pressure ventilation via an endotracheal tube, and no clinical evidence of left atrial hypertension
- Cause of ALI thought to be associated with infection, sepsis, pneumonia, aspiration, or similar as judged by the PI and/or medical monitor
- The subject must be randomized into the study within 48 hours from the time of diagnosis of ALI
- Period of hemodynamic stability (e.g. 4-6 hours) prior to the initiation of study treatment not requiring resuscitative measures with stable pressor requirements. In this study low-dose arginine vasopressin is not considered a pressor, and is permitted in Parts A and B.
- If mechanically ventilated, duration of mechanical ventilation must be less than 72 hours before dosing begins
- BMI within the range 19.0 – 38.0 kg/m2 inclusive
- The subject or legal decision maker is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- QTcB or QTcF less than 450 msec; or QTc less than 480 msec in subjects with Bundle Branch Block.
- Alanine aminotransferase (ALT) less than 5 x Upper Limit of Normal (ULN); bilirubin less than or equal to 1.5 x ULN.
Exclusion criteria:
- Subjects whose clinical condition is deteriorating rapidly or any subject for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the study.
- Known positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody
- Current or chronic history of liver disease (Child Pugh score of greater than or equal to 10), or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- Known history of substance abuse or alcohol abuse, within 6 months of the study causing chronic liver disease such as cirrhosis, chronic ascites or portal hypertension, or known evidence of withdrawal syndrome within the past 6 months.
- 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).
- Inability to discontinue use of Angiotensin converting enzyme type 1 inhibitors or Angiotensin receptor blockers.
- Patients requiring high doses of loop diuretics with significant intravascular volume depletion, as assessed clinically
- 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 GSK Medical Monitor, contraindicates their participation
- Pregnant females as determined by positive serum or urine hCG test prior to dosing
- Lactating females
- Unwillingness or inability to follow the procedures outlined in the protocol
- Subject is legally incapacitated (e.g. a prisoner)
- History of sensitivity to heparin or heparin-induced thrombocytopenia
- Unstable Hemoglobin (Hb less than 7) at time of drug infusion
- Malignancy or other irreversible condition for which 6 month mortality is estimated to be greater than 50%
- Arterial blood pH less than 7.1 or serum HCO3
- less than 15 (if ABG not available) before infusion is started
- Known severe chronic respiratory disease:
- known Forced Expiratory Volume in 1 second (FEV1)/ Forced Vital Capacity (FVC) less than 45% predicted, or
- known chronic hypercapnia (PaCO2 greater than 45 mmHg) or chronic hypoxemia (PaO2 less than 55 mmHg) on FiO2 =0.21, or
- known FEV1 less than 15 ml/kg (e.g. 1L for 70 kg person), or
- known radiographic evidence of chronic interstitial infiltration, or
- known hospitalization within the past six months for respiratory failure (PaCO2 greater than 50 mmHg or PaO2 less than 55 mmHg, or oxygen saturation less than 88% on FiO2 = 0.21), or
- known chronic restrictive, obstructive, neuromuscular, chest wall, or pulmonary vascular disease resulting in severe exercise restriction
- Known history of neuromuscular disease that would affect time on mechanical ventilation or impairs ability to ventilate spontaneously
- Vasculitis with diffuse alveolar hemorrhage
- Lung transplantation
- Pre-existing renal failure on hemodialysis or peritoneal dialysis requiring renal replacement therapy
- A patient will be excluded if in the judgement of the Principle Investigator or GSK medical monitor their participation could jeopardize the health of the subject or the integrity of the study.
Trial location(s)
Location
GSK Investigational Site
Ann Arbor, Michigan, United States, 48109
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Durham, North Carolina, United States, 27710
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Charleston, South Carolina, United States, 29425
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Springfield, Massachusetts, United States, 01199
Status
Study Complete
Location
GSK Investigational Site
Greensboro, North Carolina, United States, 27403
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Chicago, Illinois, United States, 60611
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Vancouver, British Columbia, Canada, V5Z 1M9
Status
Study Complete
Location
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
Status
Study Complete
Location
GSK Investigational Site
Sacramento, California, United States, 95817
Status
Study Complete
Location
GSK Investigational Site
Winston-Salem, North Carolina, United States, 27517
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Greenfield Park, Québec, Canada, J4V 2H1
Status
Study Complete
Location
GSK Investigational Site
Portland, Oregon, United States, 97239
Status
Study Complete
Location
GSK Investigational Site
Philadelphia, PA, Pennsylvania, United States, 19107
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Vancouver, British Columbia, Canada, V6Z 1Y6
Status
Study Complete
Location
GSK Investigational Site
New York, New York, United States, 10003
Status
Terminated/Withdrawn
Study documents
Scientific result summary
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
Completed
Actual primary completion date
2014-06-10
Actual study completion date
2014-06-10
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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