A Study Designed to Evaluate ODSH in Subjects With Exacerbations of COPD

• Sponsor: Chimerix (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00457951
• Collaborator: (none)
• Enrollment: 158
• Locations: 38
• Arms: 3
• Duration (Months): 30
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Open-Label; Drug: Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride; Drug: ODSH	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 158 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2007
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open Label Initial six subjects treated with ODSH open-label to confirm safety in subjects with an acute exacerbation of COPD; six additional patients will be enrolled following safety review.	Drug: Open-Label; ODSH administered open-label; Other Names: PGX-100
Placebo Comparator: 0.9% Sodium Chloride Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride Solution bolus; dose of 0.375mg/kg/hr over 96 hours.	Drug: Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride; Placebo-Control Arm: Bolus infusion followed by a 96 hour continuous infusion of 0.9%Sodium Chloride; Other Names: 0.9% Sodium Chloride Solution Placebo-Control Arm
Active Comparator: Randomized, Blinded, ODSH Arm Subjects will receive standard of care treatment. ODSH is administered in bolus doses estimated to inhibit inflammatory mediators randomized 1:1 to ODSH 8mg/kg or placebo. The continuous infusion dose will be 0.375 mg/kg/hr over 96 hours.	Drug: ODSH; Randomized, Blinded, ODSH Arm; Other Names: PGX-100

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

1. Certain medications such as:

• Plavix®

• Warfarin

• Heparin therapy

• Certain antibiotics

1. Exacerbations that are too severe (requiring intubation and mechanical ventilation)

2. Women of child-bearing potential, pregnancy or breast-feeding

3. Unable or unwilling to provide informed consent and follow study procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Consultants & Primary Care	Orange	California	United States	92868
2	Wellstar Kennestone Hospital	Marietta	Georgia	United States	30060
3	Louisiana State University Health Sciences Center in Shreveport	Shreveport	Louisiana	United States	71130
4	Washington Universtiy School of Medicine	Saint Louis	Missouri	United States	63110
5	The Oregon Clinic	Portland	Oregon	United States	97220
6	Temple University of the Commonwealth of Higher Education	Philadelphia	Pennsylvania	United States	19140
7	Methodist Hospital	Houston	Texas	United States	77030
8	Michael E. DeBakey VA Medical Center	Houston	Texas	United States	77030
9	University of Texas Health Care Center at Tyler	Tyler	Texas	United States	75708
10	Western Washington Medical Group	Everett	Washington	United States	98201
11	University Hospital Gasthuisberg	Leuven		Belgium	3000
12	CHU Liege Domain Universitaire du Sart Tilman	Liege		Belgium	4000
13	Cliniques Universiaries U.C.L. de Mont-Gondinne	Yvior		Belgium	5530
14	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
15	Kelowna General Hospital	Kelowna	British Columbia	Canada	V1Y 1T2
16	Vancouver Coastal Health	Vancouver	British Columbia	Canada	V5Z 1M9
17	St. Boniface General Hospital	Winnipeg	Manitoba	Canada	R2H 2A6
18	QE II Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 1V7
19	Credit Valley Hospital,	Mississauga	Ontario	Canada
20	The Ottawa Hospital, Civic Campus	Ottawa	Ontario	Canada	K1Y 4E9
21	University of Toronto	Toronto	Ontario	Canada	H2X-2P4
22	Laval Hospital	Quebec City	Quebec	Canada	G1V 4G5
23	Klinik Schillerhohe	Gerlingen		Germany	70839
24	Pneumologisches Forschungsinstitut GmbH	Grosshansdorf		Germany	22927
25	Medizinsche Hochschule	Hannover		Germany	30625
26	Uniklinikum Mainz	Mainz		Germany	55101
27	Klinikum der LMU Innenstadt	Munchen		Germany	80336
28	Wojewodzki Szpital Specjalistyczny im. Najswietszej Marii Panny	Czestochowa		Poland	42-200
29	Samodzielny Publiczny Szpital Kliniczny SUM w Katowicach	Katowice		Poland	40-752
30	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Krakow		Poland	31-202
31	Samodzielny Publiczny ZOZ, Uniwersytecki Szpital Liniczny nr 1 im Norberta Barlickiego	Lodz		Poland	90-153
32	Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego, Samodzielny Publiczny Zespol Opieki Zdrowotnej	Lublin		Poland	20-718
33	Samodzielny Publiczny Szpital Klinczny nr 4 W Lublinie	Lublin		Poland	20-954
34	Zespol Opieki Zdrowotnej w Olawie	Olawa		Poland	55-200
35	Wieklopolskie Centrum Chorob Pluc i Gruzlicy	Poznan		Poland	60-569
36	I Klinika Chorob Plus, Instyut Gruzlicy i Chorob Pluc	Warszawa		Poland	01-138
37	Miedzyleski Szpital Specjalistyczny w Warszawie	Warszawa		Poland	04-749
38	Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego	Wroclaw		Poland	50-417

Sponsors and Collaborators

• Chimerix

Investigators

• Principal Investigator: Tobias Welte, MD, Hannover Medical School

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Chimerix
• ClinicalTrials.gov Identifier: NCT00457951
• Other Study ID Numbers: PGX-ODSH-2006
• First Posted: Apr 9, 2007
• Last Update Posted: Dec 2, 2021
• Last Verified: Oct 1, 2016

• Keywords provided by Chimerix: Chronic Obstructive Pulmonary Disease; COPD; Heparin; ODSH; Exacerbations of COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Arm/Group Title	Open Label	Placebo Comparator: 0.9% Sodium Chloride	ODSH Treatment Group
Arm/Group Description	Open Label The original protocol called for 304 subjects with exacerbation of COPD to be enrolled into the study. Thirteen patients with exacerbation of COPD were enrolled in the initial open label portion of the study. Of these thirteen subjects, the initial seven subjects were treated with an IV bolus of ODSH at 8 mg/kg followed by a continuous infusion of ODSH at 0.5 mg/kg/hr for 72 hours. After an ad hoc safety committee assessed the safety of the data from the first seven subjects, six more subjects were treated concomitantly treated with ODSH and enoxaparin, a low molecular weight heparin commonly used for seriously ill hospitalized patients as DVT prophylaxis.	Double-blind randomized phase: Normal Saline infusion: Bolus infusion followed by a 4 day continuous infusion of placebo.	Double-blind randomized phase: The subjects receiving ODSH in the randomized portion of the study received 0.375 mg/kg/hr continuous IV infusion of ODSH for 96 hours.
Period Title: Overall Study
STARTED	13	66	72
COMPLETED	13	50	60
NOT COMPLETED	0	16	12

Baseline Characteristics

Arm/Group Title	Open-Label	Placebo Comparator: Placebo-Control: 0.9% Sodium Chloride	ODSH Treatment Group	Total
Arm/Group Description	Open-Label ODSH	Placebo Comparator: Placebo-Control: 0.9% Sodium Chloride Administered as bolus; then continuous administration over 96 hours in hospitalized subjects with exacerbations of COPD	ODSH Treatment Group Administered as bolus; then continuous administration over 96 hours in hospitalized subjects with exacerbations of COPD	Total of all reporting groups
Overall Participants	13	66	72	151
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.8 (15)	68.5 (10.24)	67.2 (9.53)	66.5 (10.43)
Sex/Gender, Customized (Count of Participants)
Female	9 69.2%	25 37.9%	23 31.9%	57 37.7%
Male	4 30.8%	41 62.1%	49 68.1%	94 62.3%
Region of Enrollment (participants) [Number]
United States	13 100%	66 100%	72 100%	151 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Treatment Failure
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	0.9% Sodium Chloride	Randomized, Blinded, ODSH Arm
Arm/Group Description	Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride Solution bolus; dose of 0.375mg/kg/hr over 96 hours. Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride: Placebo-Control Arm: Bolus infusion followed by a 96 hour continuous infusion of 0.9%Sodium Chloride	Subjects will receive standard of care treatment. ODSH is administered in bolus doses estimated to inhibit inflammatory mediators randomized 1:1 to ODSH 8mg/kg or placebo. The continuous infusion dose will be 0.375 mg/kg/hr over 96 hours. ODSH: Randomized, Blinded, ODSH Arm
Measure Participants	64	68
Number (95% Confidence Interval) [percentage of failures]	24.6	32.4

Adverse Events

Time Frame	D1 to D90
Adverse Event Reporting Description	Of the 145 subjects consented in the randomized phase, 138 were randomized. Of the 138 randomized subjects, 134 were included in the safety population; 4 of the 138 randomized subjects did not receive study medication.
Arm/Group Title	Open Label		Placebo Comparator: 0.9% Sodium Chloride		ODSH Treatment Group
Arm/Group Description	Initial six subjects treated with ODSH open-label to confirm safety in subjects with an acute exacerbation of COPD; six additional patients will be enrolled following safety review. Open-Label: ODSH administered open-label		Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride Solution bolus; dose of 0.375mg/kg/hr over 96 hours. Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride: Placebo-Control Arm: Bolus infusion followed by a 96 hour continuous infusion of 0.9%Sodium Chloride		Subjects will receive standard of care treatment. ODSH is administered in bolus doses estimated to inhibit inflammatory mediators randomized 1:1 to ODSH 8mg/kg or placebo. The continuous infusion dose will be 0.375 mg/kg/hr over 96 hours. ODSH: Randomized, Blinded, ODSH Arm
All Cause Mortality
	Open Label		Placebo Comparator: 0.9% Sodium Chloride		ODSH Treatment Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Open Label		Placebo Comparator: 0.9% Sodium Chloride		ODSH Treatment Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		4/65 (6.2%)		2/69 (2.9%)
Cardiac disorders
Cardiopulmonary failure	0/13 (0%)		1/65 (1.5%)		0/69 (0%)
Gastrointestinal disorders
Retroperitoneal haematoma	0/13 (0%)		0/65 (0%)		1/69 (1.4%)
Upper gastrointestinal haemorrhage	0/13 (0%)		0/65 (0%)		1/69 (1.4%)
Nervous system disorders
Guillain-barre syndrome	0/13 (0%)		1/65 (1.5%)		0/69 (0%)
Ischaemic stroke	0/13 (0%)		1/65 (1.5%)		0/69 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/13 (0%)		1/65 (1.5%)		0/69 (0%)
Chronic obstructive pulmonary disease	0/13 (0%)		1/65 (1.5%)		0/69 (0%)
Respiratory failure	1/13 (7.7%)		0/65 (0%)		0/69 (0%)
Other (Not Including Serious) Adverse Events
	Open Label		Placebo Comparator: 0.9% Sodium Chloride		ODSH Treatment Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		13/65 (20%)		48/69 (69.6%)
Gastrointestinal disorders
Diarrhoea	0/13 (0%)		3/65 (4.6%)		4/69 (5.8%)
Constipation	0/13 (0%)		1/65 (1.5%)		4/69 (5.8%)
Hepatobiliary disorders
ALT Increased	0/13 (0%)	0	7/65 (10.8%)	8	26/69 (37.7%)	33
AST Increased	0/13 (0%)	0	6/65 (9.2%)	6	22/69 (31.9%)	29

Limitations/Caveats

PGX-ODSH-2006, Ph II in patients with exacerbation of COPD. There were no safety issues. An interim analysis demonstrated lack of efficacy for the primary and secondary endpoints; therefore, Cantex terminated the study on August 11, 2009.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Confidentiality and Non-Disclosure Agreement