Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, Heparin, ODSH, Exacerbations of COPD
Brief summary
The purpose of this study is to determine whether ODSH, when added to conventional treatment, is more effective in treating COPD exacerbations than conventional therapy alone.
Detailed description
The management of acute exacerbations of COPD today is qualitatively the same as it was 40 years ago: bronchodilators, corticosteroids, and antibiotics. Because of the prominent pathophysiological role of neutrophils in exacerbations of COPD, neutrophils and their toxic oxidants and proteases represent therapeutic targets which are currently unchallenged in the treatment of this aspect of the disease. Ideally, to disrupt neutrophilic airway inflammation, one would both block neutrophilic influx from the vascular space into the airway, as well as neutralize or inactivate prominent neutrophilic toxins such as the proteases HLE and cathepsin G. Heparin is a sulfated mucopolysaccharide that slows blood clot formation by inhibiting the reactions that lead to formation of fibrin clots. Physicians use heparin to prevent blood clot formation during open-heart surgery, bypass surgery and dialysis. Heparin also prevents previously formed clots from becoming larger and causing more serious problems. Heparin has other biological properties, most notably anti-inflammatory activity. At doses required to be therapeutically beneficial as an anti-inflammatory, heparin can cause severe, potentially life-threatening hemorrhage. ParinGenix has chemically modified heparin to retain the anti-inflammatory activity while reducing anti-coagulant properties. Heparin has long been known to be a potent inhibitor, both in vitro and in vivo, of the cationic neutrophil proteases HLE and cathepsin G. However, heparin also has numerous other important anti-inflammatory effects. P-selectin is the primary endothelial attachment molecule mediating neutrophil rolling along the vessel wall. At concentrations close to those achieved in plasma near the high range of therapeutic anticoagulation, heparin inhibits P-selectin and P-selectin mediated interaction of leukocytes with endothelium. Heparin also blocks the leukocyte integrin Mac-1 (CD11b/CD18) and Mac-1-dependent leukocyte adherence to endothelial ICAM. These combined effects on rolling, integrin-dependent attachment and perhaps other aspects of cellular passage through the basement membrane prevent neutrophil accumulation in areas of inflammation. As an example, when given in much higher concentrations than those appropriate for therapeutic anticoagulation, heparin efficiently blocks neutrophilic influx into ischemic reperfused myocardium and brain reducing the size of both myocardial infarction and ischemic stroke. Thus, heparin and heparin analogues may have the potential to also reduce inflammatory influx of neutrophils into the airway during exacerbations of COPD. All subjects will receive standard of care treatment, including corticosteroids, beta-2 agonists, and antibiotics as well as ODSH or placebo.
Interventions
DRUGOpen-Label
ODSH administered open-label
Placebo-Control Arm: Bolus infusion followed by a 96 hour continuous infusion of 0.9%Sodium Chloride
DRUGODSH
Randomized, Blinded, ODSH Arm
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients (40 years of age or older) with an established diagnosis of COPD based upon medical history who are being admitted to the hospital to treat an exacerbation of COPD; 2. Normal prothrombin time and activated partial thromboplastin time; Platelet count; hemoglobin and hematocrit
Exclusion criteria
1. Certain diseases such as: * asthma; * left heart failure or pulmonary embolism; * lung cancer; * pneumonia * liver or kidney disease * blood clotting disorder * Positive HIV or hepatitis tests * GI bleeding, physical trauma with bleeding, any disease with bleeding within 60 days of study entry 2. Certain medications such as: * Plavix® * Warfarin * Heparin therapy * Certain antibiotics 3. Exacerbations that are too severe (requiring intubation and mechanical ventilation) 4. Women of child-bearing potential, pregnancy or breast-feeding 5. Unable or unwilling to provide informed consent and follow study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Failure | Time to hospital discharge and 21 days post-treatment, up to 31 days | The primary outcome of the study is Treatment Failure as defined by Failure to discharge from hospital based on GOLD (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease) criteria or relapse after DC from hospital. |
Countries
Belgium, Canada, Germany, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-Label Open-Label ODSH | 13 |
| Placebo Comparator: Placebo-Control: 0.9% Sodium Chloride Placebo Comparator: Placebo-Control: 0.9% Sodium Chloride Administered as bolus; then continuous administration over 96 hours in hospitalized subjects with exacerbations of COPD | 66 |
| ODSH Treatment Group ODSH Treatment Group Administered as bolus; then continuous administration over 96 hours in hospitalized subjects with exacerbations of COPD | 72 |
| Total | 151 |
Baseline characteristics
| Characteristic | Open-Label | Placebo Comparator: Placebo-Control: 0.9% Sodium Chloride | ODSH Treatment Group | Total |
|---|---|---|---|---|
| Age, Customized | 63.8 years STANDARD_DEVIATION 15 | 68.5 years STANDARD_DEVIATION 10.24 | 67.2 years STANDARD_DEVIATION 9.53 | 66.5 years STANDARD_DEVIATION 10.43 |
| Region of Enrollment United States | 13 participants | 66 participants | 72 participants | 151 participants |
| Sex/Gender, Customized Female | 9 Participants | 25 Participants | 23 Participants | 57 Participants |
| Sex/Gender, Customized Male | 4 Participants | 41 Participants | 49 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 13 / 65 | 48 / 69 |
| serious Total, serious adverse events | 1 / 13 | 4 / 65 | 2 / 69 |
Outcome results
Primary
Incidence of Treatment Failure
The primary outcome of the study is Treatment Failure as defined by Failure to discharge from hospital based on GOLD (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease) criteria or relapse after DC from hospital.
Time frame: Time to hospital discharge and 21 days post-treatment, up to 31 days
Population: Of the 138 subjects randomized, 132 were analyzed in the intent-to-treat population. Of the 6 excluded from the intent-to-treat population, 4 did not receive study drug and 2 lacked information for assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.9% Sodium Chloride | Incidence of Treatment Failure | 24.6 percentage of failures |
| Randomized, Blinded, ODSH Arm | Incidence of Treatment Failure | 32.4 percentage of failures |