CONSERV-2: Outcomes and Safety Trial Investigating Ecallantide's Effect on Reducing Surgical Blood Loss Volume in Subjects at High Risk of Bleeding Exposed to Cardio-pulmonary Bypass During Cardiac Surgery

• Sponsor: Cubist Pharmaceuticals LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00888940
• Collaborator: (none)
• Enrollment: 243
• Locations: 34
• Arms: 2
• Duration (Months): 7
• Patients Per Site: 7.1
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

A Phase 2 Randomized Double-Blind Active-Controlled Study in Subjects Exposed to Cardio-pulmonary Bypass During Cardiac Surgery at High Risk of Bleeding

Condition or Disease	Intervention/Treatment	Phase
Bloodloss; Surgical Procedures, Operative	Drug: Ecallantide; Drug: Cyklokapron(R)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 243 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: CONSERV - 2 (Clinical Outcomes and Safety Trial to Investigate Ecallantide's Effect on Reducing Surgical Blood Loss Volume) - A Phase 2 Randomized Double-Blind Active-Controlled Study in Subjects Exposed to Cardio-pulmonary Bypass During Cardiac Surgery at High Risk of Bleeding
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ecallantide	Drug: Ecallantide; 2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion
Active Comparator: Cyklokapron(R)	Drug: Cyklokapron(R); 1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime

Outcome Measures

Primary Outcome Measures

1. Cumulative Volume of Packed Red Blood Cells Transfused [12 hours after the end of surgery]

Secondary Outcome Measures

1. Treatment-emergent Adverse Events. [Over the duration of the study.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent (by study subject) prior to any study-related procedure not part of normal medical care;

• Male or female between the ages of 18 and 85 years old, inclusive; and

• Planned cardiac surgery using cardio-pulmonary bypass, for one of the following procedures: any repeat sternotomy; surgery to repair or replace more than one valve; combined CABG plus repair or replacement of at least one valve

• If female, subject is non-lactating, and is either:Not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;Of childbearing potential but is not pregnant as confirmed by negative pregnancy test at time of screening (based on the β-subunit of HCG), and is practicing the barrier method of birth control along with one of the following methods: oral or parenteral contraceptives for three months prior to study drug administration, a vasectomized partner, or abstinence from sexual intercourse.

Exclusion Criteria:

• Planned primary CABG, single valve repair or replacement surgery, or any off pump procedure;

• Body weight <55 kg;

• Planned hypothermia (<28ºC);

• Planned transfusion in the peri-operative or post-operative periods;

• Planned transfusion of pre-operatively donated autologous blood;

• Female subjects who are pregnant or lactating;

• Planned use of desmopressin, lysine analogs (other than study medication), atrial natriuretic hormone or recombinant activated Factor VII;

• Planned use of corticosteroids in the pump prime solution;

• Ejection fraction <30% within 90 days prior to surgery;

• Evidence of a myocardial infarction within 5 days prior to surgery;

• History of stroke or transient ischemic attack within 3 months prior to surgery;

• Hypotension or heart failure requiring the use of inotropes or mechanical devices within 24 hours prior to surgery;

• Serum creatinine >2.0 mg/dL within 48 hours prior to surgery;

• Serum hepatic enzymes (aspartate aminotransferase or alanine aminotransferase) above 2.5 times the upper limit of normal for the applicable laboratory;

• Hematocrit <32% within 48 hours prior to surgery;

• Platelet count below the normal range for the applicable laboratory within 14 days prior to surgery;

• History of, or family history of, bleeding or clotting disorder (e.g. von Willebrand's Disease, idiopathic thrombocytopenia purpura) or thrombophilia such as anti-thrombin III deficiency or Factor V Leiden mutation;

• History of heparin-induced thrombocytopenia;

• Prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) >1.5 X normal range unless subject received heparin within 24 hours of test;

• Serious intercurrent illness or active infection (e.g. endocarditis, sepsis, active malignancy requiring treatment);

• Any previous exposure to ecallantide;

• Receipt of an investigational drug or device 30 days prior to participation in the current study;

• Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the subject or would preclude the subject from successful completion of the study;

• Inability to comply with the protocol for the duration of the study;

• Known allergy to any agent expected to be used in the intra-operative or post-operative periods; and

• Administration of: Eptifibatide within 6 hours prior to surgery, Tirofiban hydrochloride within 6 hours prior to surgery, (Enoxaparin sodium or other low-molecular-weight heparin <24 hours prior to surgery), Prasugrel within 10 days prior to surgery, Clopidogrel within 3 days prior to surgery, Ticlopidine within 7 days prior to surgery, Abciximab within 5 days prior to surgery, (Bivalirudin, argatroban or lepirudin within 6 hours prior to surgery), (Fondaparinux within 72 hours prior to surgery), Chlorpromazine within 7 days prior to surgery (Prophylactic use permitted for the prevention of deep vein thrombosis.)

• Planned use of heparin bonded bypass circuits;

• Known allergy or hypersensitivity to tranexamic acid or any of the other ingredients;

• Disturbance of color sense;

• Evidence of hematuria or any acute thromboses or thromboembolic diseases such as deep vein thrombosis, pulmonary embolism, or vertebral vein thrombosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardio-Thoracic Surgeons PC	Birmingham	Alabama	United States	35205
2	Universitaetsklinikum Aachen AoeR	Aachen		Germany	52074
3	Klinikum Augsburg	Augsburg		Germany	86156
4	Herz- und Gefaesszentrum Bad Bevensen	Bad Bevensen		Germany	29549
5	Universitaetsklinikum Bonn	Bonn		Germany	53105
6	Klinik und Poliklinik fuer Herz- und Thoraxchirurgie der Universitaet zu Koeln	Cologne		Germany	50937
7	St. Johannes Hospital	Dortmund		Germany	44137
8	Herzzentrum Dresden GmbH Universitaetsklinik	Dresden		Germany	01307
9	Universitaetsklinikum Erlangen	Erlangen		Germany	91054
10	Universitaetsklinikum Frankfurt	Frankfurt		Germany	60590
11	Universitaetsklinikum Freiburg	Freiburg		Germany	79106
12	Universitaetsmedizin Goettingen	Goettingen		Germany	37075
13	Universitaetsklinikum Halle (Saale)	Halle		Germany	06120
14	Universitaeres Herzzentrum Hamburg GmbH	Hamburg		Germany	20246
15	Universitaetsklinikum Heidelberg	Heidelberg		Germany	69120
16	Herzzentrum Leipzig GmbH	Leipzig		Germany	04289
17	Klinikum der Stadt Ludwigshafen gGmbH	Ludwigshafen		Germany	67063
18	Klinik fuer Herzchirurgie des Universitaetsklinikum SH	Luebeck		Germany	23538
19	Deutsches Herzzentrum Muenchen	Munich		Germany	80636
20	Universitaetsklinikum Wuerzburg	Wuerzburg		Germany	97080
21	HELIOS Klinik Wuppertal	Wuppertal		Germany	42117
22	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok		Poland	15-276
23	Szpital Uniwersytecki im. Dr. Antoniego Jurasza w Bydgoszczy	Bydgoszcz		Poland	85-094
24	Akademickie Centrum Kliniczne, Szpital AM w Gdansku	Gdansk		Poland	80-952
25	Samodzielny Publiczny Szpital Kliniczny nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach	Katowice		Poland	40-635
26	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Kraków		Poland	31-200
27	Uniwersytecki Szpital Kliniczny Nr. 3 im. Dr Seweryna Sterlinga	Lódz		Poland	91-425
28	Katedra Chorób Serca AM, Szpital Miejski im. J Strusia	Poznan		Poland	61-833
29	Samodzielny Publiczny Szpital Kliniczny Nr 2 Pomorskiej Akademii Medycznej	Szczecin		Poland	70-111
30	Wojskowy Instytut Medyczny, Centralny Szpital Kliniczny MON	Warszawa		Poland	04-414
31	Instytut Kardiologii im. Prymasa Tysiclecia Stefana Kardynała Wyszyńskiego	Warszawa		Poland	04-628
32	Samodzielny Publiczny Szpital Kliniczny nr 1 we Wroclawiu	Wroclaw		Poland	50-369
33	4 Wojskowy Szpital Kliniczny z Poliklinika SP ZOZ, Centrum Chorób Serca	Wroclaw		Poland	50-981
34	Slaskie Centrum Chorób Serca	Zabrze		Poland	41-800

Sponsors and Collaborators

• Cubist Pharmaceuticals LLC

Investigators

• Study Director: Alistair Wheeler, MD, MFPM, Cubist Pharmaceuticals LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT00888940
• Other Study ID Numbers: ECAL-CCPB-08-07
• First Posted: Apr 28, 2009
• Last Update Posted: Aug 10, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Blood Loss, Surgical; Ecallantide; Tranexamic Acid

Study Results

Participant Flow

Arm/Group Title	Ecallantide	Cyklokapron(R)
Arm/Group Description	2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion	1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime
Period Title: Overall Study
STARTED	120	122
Completed Therapy	107	106
COMPLETED	92	101
NOT COMPLETED	28	21

Baseline Characteristics

Arm/Group Title	Ecallantide	Cyklokapron(R)	Total
Arm/Group Description	2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion	1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime	Total of all reporting groups
Overall Participants	120	122	242
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.6 (8.02)	66.9 (10.88)	68.2 (9.65)
Sex: Female, Male (Count of Participants)
Female	45 37.5%	50 41%	95 39.3%
Male	75 62.5%	72 59%	147 60.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	120 100%	122 100%	242 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Cumulative Volume of Packed Red Blood Cells Transfused
Time Frame	12 hours after the end of surgery

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat = all subjects received at least one dose and analyzed according to planned treatment assignment. 3 subjects in ecallantide group not included due to no value being present

Arm/Group Title	Ecallantide	Cyklokapron(R)
Arm/Group Description	2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion	1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime
Measure Participants	106	109
Mean (Standard Deviation) [mL]	1223.2 (1334.57)	623.5 (974.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ecallantide, Cyklokapron(R)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Treatment-emergent Adverse Events.
Time Frame	Over the duration of the study.

Outcome Measure Data

Analysis Population Description

Safety population analyzed

Arm/Group Title	Ecallantide	Cyklokapron(R)
Arm/Group Description	2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion	1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime
Measure Participants	109	109
At Least 1 TEAE	100	94
At Least 1 Related TEAE	5	5
At Least 1 Severe TEAE	38	17
At Least 1 Serious TEAE	45	28
At Least 1 Related & Serious TEAE	4	1
Premature Study Drug Discontinuations Due to TEAE	2	2
Related TEAE Resulting in Discontinuation of Drug	0	0
TEAE Resulting in Death	13	4
Related TEAE Resulting in Death	0	0

Adverse Events

Arm/Group Title	Ecallantide		Cyklokapron
Arm/Group Description	2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion		1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime
All Cause Mortality
	Ecallantide		Cyklokapron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ecallantide		Cyklokapron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/109 (41.3%)		28/109 (25.7%)
Blood and lymphatic system disorders
Anaemia	0/109 (0%)	0	1/109 (0.9%)	1
Coagulopathy	0/109 (0%)	0	1/109 (0.9%)	1
Cardiac disorders
Aortic valve incompetence	0/109 (0%)	0	1/109 (0.9%)	1
Atrial fibrillation	2/109 (1.8%)	2	1/109 (0.9%)	1
Atrioventricular block complete	2/109 (1.8%)	2	1/109 (0.9%)	1
Bradycardia	1/109 (0.9%)	1	0/109 (0%)	0
Cardiac arrest	4/109 (3.7%)	4	0/109 (0%)	0
Cardiac failure	3/109 (2.8%)	3	1/109 (0.9%)	1
Cardiac tamponade	4/109 (3.7%)	4	3/109 (2.8%)	3
Cardio-respiratory arrest	0/109 (0%)	0	1/109 (0.9%)	1
Cardiogenic shock	2/109 (1.8%)	2	1/109 (0.9%)	1
Left ventricular failure	1/109 (0.9%)	1	0/109 (0%)	0
Mitral valve incompetence	0/109 (0%)	0	1/109 (0.9%)	1
Myocardial infarction	1/109 (0.9%)	1	0/109 (0%)	0
Myocardial ischaemia	1/109 (0.9%)	1	0/109 (0%)	0
Right ventricular failure	1/109 (0.9%)	1	0/109 (0%)	0
Sick sinus syndrome	1/109 (0.9%)	1	0/109 (0%)	0
Ventricle rupture	4/109 (3.7%)	4	0/109 (0%)	0
Ventricular extrasystoles	0/109 (0%)	0	1/109 (0.9%)	1
Ventricular fibrillation	4/109 (3.7%)	4	0/109 (0%)	0
Ventricular hypokinesia	1/109 (0.9%)	1	0/109 (0%)	0
Ventricular tachycardia	0/109 (0%)	0	1/109 (0.9%)	1
Gastrointestinal disorders
Gastrointestinal haemorrhage	2/109 (1.8%)	2	0/109 (0%)	0
Gastrointestinal necrosis	0/109 (0%)	0	1/109 (0.9%)	1
Pancreatic necrosis	0/109 (0%)	0	1/109 (0.9%)	1
General disorders
Impaired healing	2/109 (1.8%)	2	1/109 (0.9%)	1
Multi-organ failure	3/109 (2.8%)	3	2/109 (1.8%)	2
Hepatobiliary disorders
Cholecystitis	0/109 (0%)	0	1/109 (0.9%)	1
Hyperbilirubinaemia	1/109 (0.9%)	1	0/109 (0%)	0
Infections and infestations
Bronchopneumonia	0/109 (0%)	0	1/109 (0.9%)	1
Pneumonia	0/109 (0%)	0	1/109 (0.9%)	1
Postoperative wound infection	1/109 (0.9%)	1	0/109 (0%)	0
Pseudomembranous colitis	1/109 (0.9%)	1	0/109 (0%)	0
Sepsis	1/109 (0.9%)	1	1/109 (0.9%)	1
Septic shock	0/109 (0%)	0	1/109 (0.9%)	1
Staphylococcal infection	1/109 (0.9%)	1	0/109 (0%)	0
Staphylococcal sepsis	1/109 (0.9%)	1	0/109 (0%)	0
Stenotrophomonas infection	1/109 (0.9%)	1	0/109 (0%)	0
Wound infection	0/109 (0%)	0	2/109 (1.8%)	2
Injury, poisoning and procedural complications
Post procedural complication	1/109 (0.9%)	1	1/109 (0.9%)	1
Post procedural haemorrhage	11/109 (10.1%)	13	7/109 (6.4%)	7
Postoperative thoracic procedure complication	3/109 (2.8%)	3	0/109 (0%)	0
Vasoplegia syndrome	1/109 (0.9%)	1	0/109 (0%)	0
Investigations
Cardiac output decreased	2/109 (1.8%)	2	0/109 (0%)	0
Nervous system disorders
Cerebral haemorrhage	1/109 (0.9%)	1	0/109 (0%)	0
Cerebrovascular accident	0/109 (0%)	0	2/109 (1.8%)	2
Convulsion	0/109 (0%)	0	1/109 (0.9%)	1
Hypoxic encephalopathy	2/109 (1.8%)	2	0/109 (0%)	0
Neurological decompensation	1/109 (0.9%)	1	0/109 (0%)	0
Psychiatric disorders
Impaired self-care	1/109 (0.9%)	1	0/109 (0%)	0
Renal and urinary disorders
Renal failure	2/109 (1.8%)	2	2/109 (1.8%)	2
Renal failure acute	1/109 (0.9%)	1	1/109 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/109 (0%)	0	1/109 (0.9%)	1
Apnoea	1/109 (0.9%)	1	0/109 (0%)	0
Pneumothorax	2/109 (1.8%)	2	1/109 (0.9%)	1
Pulmonary oedema	0/109 (0%)	0	1/109 (0.9%)	1
Respiratory failure	5/109 (4.6%)	5	4/109 (3.7%)	4
Vascular disorders
Air embolism	1/109 (0.9%)	1	0/109 (0%)	0
Haemorrhage	9/109 (8.3%)	9	0/109 (0%)	0
Hypotension	0/109 (0%)	0	1/109 (0.9%)	1
Peripheral ischaemia	1/109 (0.9%)	1	0/109 (0%)	0
Other (Not Including Serious) Adverse Events
	Ecallantide		Cyklokapron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/109 (85.3%)		91/109 (83.5%)
Blood and lymphatic system disorders
Anaemia	18/109 (16.5%)	18	16/109 (14.7%)	17
Cardiac disorders
Arrhythmia	7/109 (6.4%)	7	5/109 (4.6%)	5
Atrial fibrillation	32/109 (29.4%)	32	19/109 (17.4%)	20
Tachycardia	3/109 (2.8%)	3	9/109 (8.3%)	9
Gastrointestinal disorders
Constipation	9/109 (8.3%)	9	10/109 (9.2%)	10
Diarrhoea	4/109 (3.7%)	4	8/109 (7.3%)	8
Nausea	6/109 (5.5%)	6	9/109 (8.3%)	9
Vomiting	7/109 (6.4%)	8	4/109 (3.7%)	4
General disorders
Impaired healing	6/109 (5.5%)	6	9/109 (8.3%)	9
Non-cardiac chest pain	7/109 (6.4%)	9	9/109 (8.3%)	10
Oedema peripheral	6/109 (5.5%)	6	7/109 (6.4%)	7
Injury, poisoning and procedural complications
Procedural pain	17/109 (15.6%)	18	25/109 (22.9%)	25
Metabolism and nutrition disorders
Hyperglycaemia	11/109 (10.1%)	11	15/109 (13.8%)	15
Psychiatric disorders
Sleep disorder	5/109 (4.6%)	5	6/109 (5.5%)	7
Transient psychosis	7/109 (6.4%)	7	4/109 (3.7%)	4
Renal and urinary disorders
Renal failure	3/109 (2.8%)	3	8/109 (7.3%)	8
Respiratory, thoracic and mediastinal disorders
Pleural effusion	15/109 (13.8%)	15	17/109 (15.6%)	17
Skin and subcutaneous tissue disorders
Decubitus ulcer	2/109 (1.8%)	2	6/109 (5.5%)	6
Vascular disorders
Hypertension	6/109 (5.5%)	6	10/109 (9.2%)	10
Hypotension	20/109 (18.3%)	20	20/109 (18.3%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first publication is initiated by Cubist. If the First Publication is not published within 1 year of Study conclusion or termination, Investigator shall have the right to publish and disclose the Data. Prior to any submission for publication, presentation, or communication of results or information arising from the Study, Investigator shall provide Cubist at least 90 days for review and comment upon the manuscript or other material for such publication or presentation.