Clinical trial NCT00457951: A Study Designed to Evaluate ODSH in Subjects With Exacerbations of COPD
Official title: An Open-Label Phase Followed by a Randomized, Double-Blind, Placebo-Controlled Phase in a Study Designed to Evaluate Intravenous 2-O, 3-O Desulfated Heparin (ODSH) in Subjects With Exacerbations of Chronic Obstructive Pulmonary Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: Chronic Obstructive Pulmonary Disease
COPD
Heparin
ODSH
Exacerbations of COPD
Lead sponsor: Chimerix
Sponsor class: INDUSTRY
First posted: 2007-04-09
Enrollment: 158
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of Treatment Failure
timeFrame: Time to hospital discharge and 21 days post-treatment, up to 31 days
Secondary outcomes:
Other outcomes:
Locations:
city: Orange
country: United States
facility: Pulmonary Consultants & Primary Care
state: California
city: Marietta
country: United States
facility: Wellstar Kennestone Hospital
state: Georgia
city: Shreveport
country: United States
facility: Louisiana State University Health Sciences Center in Shreveport
state: Louisiana
city: Saint Louis
country: United States
facility: Washington Universtiy School of Medicine
state: Missouri
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Philadelphia
country: United States
facility: Temple University of the Commonwealth of Higher Education
state: Pennsylvania
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center
state: Texas
city: Tyler
country: United States
facility: University of Texas Health Care Center at Tyler
state: Texas
city: Everett
country: United States
facility: Western Washington Medical Group
state: Washington
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
city: Liege
country: Belgium
facility: CHU Liege Domain Universitaire du Sart Tilman
city: Yvior
country: Belgium
facility: Cliniques Universiaries U.C.L. de Mont-Gondinne
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Kelowna
country: Canada
facility: Kelowna General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Coastal Health
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Halifax
country: Canada
facility: QE II Health Sciences Centre
state: Nova Scotia
city: Mississauga
country: Canada
facility: Credit Valley Hospital,
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital, Civic Campus
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Quebec City
country: Canada
facility: Laval Hospital
state: Quebec
city: Gerlingen
country: Germany
facility: Klinik Schillerhohe
city: Grosshansdorf
country: Germany
facility: Pneumologisches Forschungsinstitut GmbH
city: Hannover
country: Germany
facility: Medizinsche Hochschule
city: Mainz
country: Germany
facility: Uniklinikum Mainz
city: Munchen
country: Germany
facility: Klinikum der LMU Innenstadt
city: Czestochowa
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Najswietszej Marii Panny
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny SUM w Katowicach
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla II
city: Lodz
country: Poland
facility: Samodzielny Publiczny ZOZ, Uniwersytecki Szpital Liniczny nr 1 im Norberta Barlickiego
city: Lublin
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego, Samodzielny Publiczny Zespol Opieki Zdrowotnej
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Klinczny nr 4 W Lublinie
city: Olawa
country: Poland
facility: Zespol Opieki Zdrowotnej w Olawie
city: Poznan
country: Poland
facility: Wieklopolskie Centrum Chorob Pluc i Gruzlicy
city: Warszawa
country: Poland
facility: I Klinika Chorob Plus, Instyut Gruzlicy i Chorob Pluc
city: Warszawa
country: Poland
facility: Miedzyleski Szpital Specjalistyczny w Warszawie
city: Wroclaw
country: Poland
facility: Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego
Study officials:
affiliation: Hannover Medical School
name: Tobias Welte, MD
role: PRINCIPAL_INVESTIGATOR
References: