The Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury

NCT01597635 | Completed Phase 2 Results

• 1 other identifier: 114622
• Study Type: interventional
• Target: 44
• Locations: 2 countries
• Sites: 19

Brief Summary

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.

Conditions

Lung Injury, Acute

Keywords

rhACE2; Acute Respiratory Distress Syndrome (ARDS); Acute Lung Injury; GSK2586881; critical care

Outcome Measures

Primary Outcomes (15)

• Heart Rate Assessments Upto Day 7 (Part B)

  Vital sign included heart rate. Assessments were performed at Pre-dose, 0.5 hours, 2 hours, 6 hours and 12 hours on Day 1, 0 hours on Day 2 at 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours on Day 3 and at follow-up on Day 7.

  Up to Day 7

• Diastolic and Systolic Blood Pressure Assessments Upto Day 7 (Part B)

  Vital sign included systolic blood pressure and diastolic blood pressure. Assessments were performed at Pre-dose, 0.5 hours, 2 hours, 6 hours and 12 hours on Day 1, 0 hours on Day 2 at 0 hours, 0.5 hours, 2 hours, 6 hours, 12 hours, 18 hours and 24 hours on Day 3 and at follow-up on Day 7.

  Up to Day 7

• Electrocardiogram (ECG) Parameters, Including PR, QRS, QT, and QTCU and RR Intervals Upto Day 7 (Part B)

  Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTCU and RR intervals. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameters Basophils, Eosinophil, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count Upto Day 7 (Part B)

  Hematology parameters included basophils, eosinophil, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameters Red Blood Cell Count and Reticulocyte Count Assessment Upto Day 7 (Part B)

  Hematology parameters included red blood cell count and reticulocyte count. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameter Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Assessment Upto Day 7 (Part B)

  Hematology parameters included hemoglobin and MCHC. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameter Mean Corpuscle Volume (MCV) Assessment Upto Day 7 (Part B)

  Hematology parameter included MCV. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameter Mean Corpuscle Hemoglobin (MCH) Assessment Upto Day 7 (Part B)

  Hematology parameter included MCH. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Hematology Parameter Hematocrit Assessment Upto Day 7 (Part B)

  Hematology parameter included hematocrit. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Clinical Chemistry Parameters Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen Assessment Upto Day 7 (Part B)

  Clinical chemistry parameters included calcium, chloride, carbon dioxide, glucose, potassium, sodium, Urea/Blood urea nitrogen. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Assessment Upto Day 7 (Part B)

  Clinical chemistry parameters included direct bilirubin, total bilirubin, creatinine and uric acid. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Clinical Chemistry Parameters Alkaline Phosphatase, Asparatate Amino Transferase, Alanine Amino Transferase, Gamma Glutamyl Transferase Assessment Upto Day 7 (Part B)

  Clinical chemistry parameters included alkaline phosphatase, asparatate amino transferase, alanine amino transferase, gamma glutamyl transferase. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Clinical Chemistry Parameters Albumin and Total Protein Assessment Upto Day 7 (Part B)

  Clinical chemistry parameters included albumin and total protein. Assessments were performed at Pre-dose on Day 1, at 12 hours on Day 3 and at follow-up Day 7.

  Up to Day 7

• Number of Participant With Adverse Event (AE) and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part A)

  An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.

  Up to Day 7

• Number of Par With AE and Serious Adverse Event (SAE) Assessment Upto Day 7 (Part B)

  An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.

  Up to Day 7

Secondary Outcomes (18)

• Analysis of GSK2586881 Plasma Pharmacokinetic Concentration (Part A)

  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)

  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)

  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)

  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)

  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).

Study Arms (2)

Part A

EXPERIMENTAL

4 increasing doses of GSK2586881 given over 2 days

Drug: Dose 1 GSK2586881; Drug: Dose 2 GSK2586881; Drug: Dose 3 GSK2586881; Drug: Dose 4 GSK2586881

Part B

EXPERIMENTAL

Repeat Medium-High dose of GSK2586881 (or placebo) over 3 days

Drug: Dose 3 GSK2586881; Drug: Placebo (saline)

Interventions

Dose 1 GSK2586881 DRUG

Low dose GSK2586881 administered intravenously

Part A

Dose 2 GSK2586881 DRUG

Medium dose GSK2586881 administered intravenously

Part A

Dose 3 GSK2586881 DRUG

Medium-High dose GSK2586881 administered intravenously

Part A; Part B

Dose 4 GSK2586881 DRUG

High dose GSK2586881 administered intravenously

Part A

Placebo (saline) DRUG

Administered intravenously to match intervention

Part B

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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%

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (19)

GSK Investigational Site

Sacramento, California, 95817, United States

Location

GSK Investigational Site

Chicago, Illinois, 60611, United States

Location

GSK Investigational Site

Springfield, Massachusetts, 01199, United States

Location

GSK Investigational Site

Ann Arbor, Michigan, 48109, United States

Location

GSK Investigational Site

New York, New York, 10003, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Greensboro, North Carolina, 27403, United States

Location

GSK Investigational Site

Winston-Salem, North Carolina, 27517, United States

Location

GSK Investigational Site

Columbus, Ohio, 43215, United States

Location

GSK Investigational Site

Portland, Oregon, 97239, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19107, United States

Location

GSK Investigational Site

Charleston, South Carolina, 29425, United States

Location

GSK Investigational Site

Vancouver, British Columbia, V5Z 1M9, Canada

Location

GSK Investigational Site

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

GSK Investigational Site

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

GSK Investigational Site

Kingston, Ontario, K7L 2V7, Canada

Location

GSK Investigational Site

Greenfield Park, Quebec, J4V 2H1, Canada

Location

GSK Investigational Site

Sainte-Foy, Quebec, G1V 4G5, Canada

Location

Related Publications (1)

• Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, Hardes K, Powley WM, Wright TJ, Siederer SK, Fairman DA, Lipson DA, Bayliffe AI, Lazaar AL. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017 Sep 7;21(1):234. doi: 10.1186/s13054-017-1823-x.

  PMID: 28877748 DERIVED

MeSH Terms

Conditions

Acute Lung Injury; Respiratory Distress Syndrome

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2012
• First Posted: May 14, 2012
• Study Start: September 1, 2012
• Primary Completion: October 1, 2014
• Study Completion: October 6, 2014
• Last Updated: September 28, 2017
• Results First Posted: September 28, 2017

Record last verified: 2017-08

Locations

US (13); CA (6)