A Study to Compare the Efficacy and Safety of 2 Dosing Regimens of IV Infusions of AZD9773 (CytoFab™) With Placebo in Adult Patients With Severe Sepsis and/or Septic Shock

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01145560
• Collaborator: (none)
• Enrollment: 300
• Locations: 52
• Arms: 3
• Duration (Months): 19
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary purpose of this study to evaluate the effect of two different doses of AZD9773 (CytoFab™) versus placebo on ventilator free days (VFDs) over the first 28 days after the start of dosing with AZD9773 in patients with severe sepsis and/or septic shock, who are already receiving appropriate standard of care treatment for sepsis.

Condition or Disease	Intervention/Treatment	Phase
Severe Sepsis; Septic Shock	Drug: AZD9773; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A MultiCentre, Randomized, Double-blind, Placebo-controlled Phase IIb Study to Compare the Efficacy and Safety of Two Dosing Regimens of Intravenous Infusions of AZD9773 (CytoFab™) in Adult Patients With Severe Sepsis and/or Septic Shock
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 AZD9773 250/50 units/kg	Drug: AZD9773; A single loading dose following by up to 9 maintenance doses; doses to be given every 12 hours over a period of 5 days; Other Names: CytoFab™
Experimental: 2 AZD9773 500/100 units/kg	Drug: AZD9773; A single loading dose following by up to 9 maintenance doses; doses to be given every 12 hours over a period of 5 days; Other Names: CytoFab™
Placebo Comparator: 3	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Ventilator-free Days (VFDs) Over 28 Days [Over 28 days following first dose]

   Number of ventilator-free days (VFDs)

Secondary Outcome Measures

1. 7-day Mortality [Over 7 days following first dose]

   Number of patients who died over 7 days

2. 28-day Mortality [Over 28 days following first dose]

   Number of patients who died over 28 days

3. Safety and Tolerability [All study visits (over 90 days following first dose)]

   Number of patients with treatment-emergent adverse events

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults with a first episode of sepsis during this hospitalisation and objective evidence of infection that requires parenteral antibiotics.

• At least 2 of 4 SIRS criteria in the 24 hours before organ dysfunction (must include either fever OR elevated white blood cells [WBC])

• Cardiovascular or respiratory dysfunction.

Exclusion Criteria:

• Immunocompromising comorbidities or concomitant medications:

1. Advanced human immunodeficiency virus (HIV) infection (CD4 ≤50/mm3).

2. Stage III or IV cancer.

3. Haemopoietic or lymphoreticular malignancies not in remission.

4. Receiving radiation therapy or chemotherapy.

5. Stem cell, organ or bone marrow transplant in the past 6 months.

6. Absolute neutrophil count <500 per μL.

7. High dose steroids or other immunocompromising drugs.

• Concomitant diseases:

1. Deep seated fungal infection or active tuberculosis.

2. Cirrhosis with portal hypertension or Childs-Pugh Class C.

3. History of chronic hypercarbia, respiratory failure in past 6 months or use of home oxygen in the setting of severe chronic respiratory disease.

4. Neuromuscular disorders that impact breathing/spontaneous ventilation.

5. Quadriplegia.

6. Cardiac arrest in the past 30 days.

7. New York Heart Association functional Class IV due to heart failure or any disorder.

8. Burns over > 30% of body surface area.

• Medication and allergy disqualifications.

1. Treatment with anti-TNF agents within the last 8 weeks.

2. Previously received ovine derived products (CroFab™, DigiFab™).

3. Sheep product allergy or allergy to latex, papain, chymopapain.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Blacktown	New South Wales	Australia
2	Research Site	Wollongong	New South Wales	Australia
3	Research Site	Herston	Queensland	Australia
4	Research Site	Nambour	Queensland	Australia
5	Research Site	Woollongabba	Queensland	Australia
6	Research Site	Adelaide	South Australia	Australia
7	Research Site	Clayton	Victoria	Australia
8	Research Site	Footscray	Victoria	Australia
9	Research Site	Fremantle	Western Australia	Australia
10	Research Site	Antwerpen		Belgium
11	Research Site	Brussels		Belgium
12	Research Site	Genk		Belgium
13	Research Site	Godinne		Belgium
14	Research Site	Liege		Belgium
15	Research Site	Ottignies		Belgium
16	Research Site	Edmonton	Alberta	Canada
17	Research Site	Vancouver	British Columbia	Canada
18	Research Site	Victoria	British Columbia	Canada
19	Research Site	Winnipeg	Manitoba	Canada
20	Research Site	Halifax	Nova Scotia	Canada
21	Research Site	Ottawa	Ontario	Canada
22	Research Site	Windsor	Ontario	Canada
23	Research Site	Quebec		Canada
24	Research Site	Hradec Kralove		Czech Republic
25	Research Site	Praha		Czech Republic
26	Research Site	Usti Nad Labem		Czech Republic
27	Research Site	Kuopio		Finland
28	Research Site	Tampere		Finland
29	Research Site	Angers		France
30	Research Site	Dijon		France
31	Research Site	La Roche Sur Yon		France
32	Research Site	Limoges		France
33	Research Site	Montauban		France
34	Research Site	Nantes		France
35	Research Site	Nimes		France
36	Research Site	Orleans		France
37	Research Site	Paris		France
38	Research Site	Poitiers		France
39	Research Site	Saint-michel		France
40	Research Site	Toulon		France
41	Research Site	Toulouse		France
42	Research Site	Tours		France
43	Research Site	Vandoeuvre Les Nancy		France
44	Research Site	Oviedo	Asturias	Spain
45	Research Site	Sabadell	Barcelona	Spain
46	Research Site	Barcelona	Cataluna	Spain
47	Research Site	Terrassa	Cataluna	Spain
48	Research Site	Valencia	Comunidad Valenciana	Spain
49	Research Site	Santiago de Compostela	Coruna	Spain
50	Research Site	Palma de Mallorca	Islas Baleares	Spain
51	Research Site	Getafe	Madrid	Spain
52	Research Site	Madrid		Spain

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Gordon Bernard, MD, Vanderbilt University
• Study Director: Warren Botnick, MD, Parexel
• Study Director: Justin Lindemann, MD, AstraZeneca
• Study Director: Wayne Dankner, MD, Parexel
• Study Director: Jiri Juchelka, MD, Parexel

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR-D0620C00003.pdf
• redacted-CSP-D0620C00003.pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01145560
• Other Study ID Numbers: D0620C00003
• First Posted: Jun 16, 2010
• Last Update Posted: Oct 6, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by AstraZeneca: severe sepsis; TNF neutralisation; septic shock patients
• Additional relevant MeSH terms: Sepsis; Toxemia; Shock, Septic; Shock

Study Results

Participant Flow

Recruitment Details	Subjects were screened and enrolled from approximately 100 centres worldwide.

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Period Title: Overall Study
STARTED	100	100	100
Received Treatment	99	98	99
Completed Treatment	69	85	78
COMPLETED	96	96	98
NOT COMPLETED	4	4	2

Baseline Characteristics

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo	Total
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline	Total of all reporting groups
Overall Participants	100	100	100	300
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.4 (15.76)	66.6 (14.61)	64.1 (15.25)	65.0 (15.21)
Sex: Female, Male (Count of Participants)
Female	40 40%	40 40%	32 32%	112 37.3%
Male	60 60%	60 60%	68 68%	188 62.7%

Outcome Measures

1. Primary Outcome

Title	Ventilator-free Days (VFDs) Over 28 Days
Description	Number of ventilator-free days (VFDs)
Time Frame	Over 28 days following first dose

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis set

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	100	100	100
Median (Full Range) [Days]	21.0	17.5	19.0

2. Secondary Outcome

Title	7-day Mortality
Description	Number of patients who died over 7 days
Time Frame	Over 7 days following first dose

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis set

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	100	100	100
Number [Participants]	9 9%	9 9%	10 10%

3. Secondary Outcome

Title	28-day Mortality
Description	Number of patients who died over 28 days
Time Frame	Over 28 days following first dose

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis set

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	100	100	100
Number [Participants]	15 15%	27 27%	20 20%

4. Secondary Outcome

Title	Safety and Tolerability
Description	Number of patients with treatment-emergent adverse events
Time Frame	All study visits (over 90 days following first dose)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	AZD9773 250/50 Units/kg	AZD9773 500/100 Units/kg	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	100	97	99
Number [Participants]	86 86%	87 87%	92 92%

Adverse Events

Adverse Event Reporting Description	One patient received incorrect dose of AZD9773, which explains the difference between the 2 AZD9773 dose groups for the patients in the following tables for adverse events.
Arm/Group Title	AZD9773 250/50 Units/kg		AZD9773 500/100 Units/kg		Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV		AZD9773 500/100 units/kg IV		Saline
All Cause Mortality
	AZD9773 250/50 Units/kg		AZD9773 500/100 Units/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD9773 250/50 Units/kg		AZD9773 500/100 Units/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/100 (28%)		27/97 (27.8%)		31/99 (31.3%)
Cardiac disorders
Acute Myocardial Infarction	0/100 (0%)		0/97 (0%)		1/99 (1%)
Arrhythmia	0/100 (0%)		1/97 (1%)		0/99 (0%)
Atrial Fibrillation	0/100 (0%)		0/97 (0%)		2/99 (2%)
Cardiac Arrest	0/100 (0%)		1/97 (1%)		1/99 (1%)
Cardiac Failure Acute	0/100 (0%)		1/97 (1%)		0/99 (0%)
Cardiogenic Shock	0/100 (0%)		1/97 (1%)		0/99 (0%)
Sick Sinus Syndrome	0/100 (0%)		1/97 (1%)		0/99 (0%)
Endocrine disorders
Inappropriate Antidiuretic Hormone Secretion	0/100 (0%)		1/97 (1%)		0/99 (0%)
Gastrointestinal disorders
Abdominal Pain	0/100 (0%)		0/97 (0%)		1/99 (1%)
Diarrhoea	1/100 (1%)		0/97 (0%)		0/99 (0%)
Gastrointestinal Fistula	1/100 (1%)		0/97 (0%)		0/99 (0%)
Gastrointestinal Haemorrhage	1/100 (1%)		2/97 (2.1%)		1/99 (1%)
Gastrointestinal Necrosis	1/100 (1%)		1/97 (1%)		0/99 (0%)
Intestinal Infarction	1/100 (1%)		0/97 (0%)		0/99 (0%)
Intestinal Ischaemia	0/100 (0%)		1/97 (1%)		2/99 (2%)
Intestinal Perforation	0/100 (0%)		0/97 (0%)		1/99 (1%)
Pancreatic Fistula	0/100 (0%)		1/97 (1%)		0/99 (0%)
Vomiting	1/100 (1%)		0/97 (0%)		0/99 (0%)
Abdominal Wall Abscess	0/100 (0%)		0/97 (0%)		1/99 (1%)
General disorders
Multi-Organ Failure	0/100 (0%)		3/97 (3.1%)		3/99 (3%)
Pyrexia	0/100 (0%)		0/97 (0%)		1/99 (1%)
Hepatobiliary disorders
Biliary Tract Disorder	0/100 (0%)		0/97 (0%)		1/99 (1%)
Cholecystitis	0/100 (0%)		0/97 (0%)		1/99 (1%)
Cytolytic Hepatitis	0/100 (0%)		1/97 (1%)		0/99 (0%)
Hepatic Failure	0/100 (0%)		1/97 (1%)		0/99 (0%)
Hepatic Function Abnormal	0/100 (0%)		1/97 (1%)		0/99 (0%)
Hepatic Lesion	0/100 (0%)		1/97 (1%)		0/99 (0%)
Immune system disorders
Drug Hypersensitivity	1/100 (1%)		0/97 (0%)		0/99 (0%)
Infections and infestations
Aspergillosis	0/100 (0%)		0/97 (0%)		1/99 (1%)
Device Related Sepsis	1/100 (1%)		0/97 (0%)		1/99 (1%)
Empyema	1/100 (1%)		0/97 (0%)		0/99 (0%)
Encephalitis Herpes	1/100 (1%)		0/97 (0%)		0/99 (0%)
Endocarditis	1/100 (1%)		0/97 (0%)		0/99 (0%)
Fungal Oesophagitis	1/100 (1%)		0/97 (0%)		0/99 (0%)
Infection	0/100 (0%)		1/97 (1%)		0/99 (0%)
Infectious Peritonitis	0/100 (0%)		1/97 (1%)		1/99 (1%)
Meningitis Staphylococcal	0/100 (0%)		1/97 (1%)		0/99 (0%)
Pneumonia	0/100 (0%)		2/97 (2.1%)		5/99 (5.1%)
Sepsis	2/100 (2%)		1/97 (1%)		1/99 (1%)
Septic Shock	2/100 (2%)		2/97 (2.1%)		1/99 (1%)
Systemic Candida	0/100 (0%)		1/97 (1%)		0/99 (0%)
Tracheobronchitis	0/100 (0%)		1/97 (1%)		0/99 (0%)
Injury, poisoning and procedural complications
Splenic Rupture	0/100 (0%)		0/97 (0%)		1/99 (1%)
Subdural Haematoma	0/100 (0%)		0/97 (0%)		1/99 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile Duct Cancer	0/100 (0%)		1/97 (1%)		0/99 (0%)
Colon Cancer	0/100 (0%)		0/97 (0%)		1/99 (1%)
Oesophageal Carcinoma	0/100 (0%)		0/97 (0%)		1/99 (1%)
Rectal Cancer	1/100 (1%)		0/97 (0%)		0/99 (0%)
Nervous system disorders
Autonomic Nervous System Imbalance	0/100 (0%)		1/97 (1%)		0/99 (0%)
Cerebral Infarction	0/100 (0%)		1/97 (1%)		0/99 (0%)
Convulsion	1/100 (1%)		0/97 (0%)		0/99 (0%)
Critical Illness Polyneuropathy	0/100 (0%)		0/97 (0%)		1/99 (1%)
Guillain-Barre Syndrome	1/100 (1%)		0/97 (0%)		0/99 (0%)
Hepatic Encephalopathy	0/100 (0%)		1/97 (1%)		0/99 (0%)
Ischaemic Stroke	0/100 (0%)		0/97 (0%)		1/99 (1%)
Polyneuropathy	1/100 (1%)		0/97 (0%)		0/99 (0%)
Psychiatric disorders
Abnormal Behaviour	1/100 (1%)		0/97 (0%)		0/99 (0%)
Renal and urinary disorders
Renal Failure	0/100 (0%)		0/97 (0%)		1/99 (1%)
Renal Failure Acute	0/100 (0%)		1/97 (1%)		0/99 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	1/100 (1%)		0/97 (0%)		0/99 (0%)
Acute Respiratory Distress Syndrome	0/100 (0%)		1/97 (1%)		0/99 (0%)
Haemoptysis	0/100 (0%)		1/97 (1%)		0/99 (0%)
Hypoxia	0/100 (0%)		1/97 (1%)		0/99 (0%)
Pleural Effusion	0/100 (0%)		1/97 (1%)		0/99 (0%)
Pneumonia Aspiration	0/100 (0%)		0/97 (0%)		3/99 (3%)
Pneumothorax	0/100 (0%)		2/97 (2.1%)		1/99 (1%)
Pulmonary Embolism	0/100 (0%)		0/97 (0%)		1/99 (1%)
Respiratory Distress	0/100 (0%)		0/97 (0%)		1/99 (1%)
Respiratory Failure	4/100 (4%)		0/97 (0%)		1/99 (1%)
Respiratory Gas Exchange Disorder	0/100 (0%)		1/97 (1%)		0/99 (0%)
Skin and subcutaneous tissue disorders
Rash Vesicular	1/100 (1%)		0/97 (0%)		0/99 (0%)
Vascular disorders
Air Embolism	1/100 (1%)		0/97 (0%)		0/99 (0%)
Extremity Necrosis	0/100 (0%)		1/97 (1%)		1/99 (1%)
Ischaemia	0/100 (0%)		0/97 (0%)		1/99 (1%)
Shock	2/100 (2%)		1/97 (1%)		0/99 (0%)
Other (Not Including Serious) Adverse Events
	AZD9773 250/50 Units/kg		AZD9773 500/100 Units/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/100 (74%)		71/97 (73.2%)		68/99 (68.7%)
Blood and lymphatic system disorders
Anaemia	20/100 (20%)		18/97 (18.6%)		22/99 (22.2%)
Thrombocytopenia	5/100 (5%)		4/97 (4.1%)		4/99 (4%)
Cardiac disorders
Atrial Fibrillation	11/100 (11%)		14/97 (14.4%)		8/99 (8.1%)
Gastrointestinal disorders
Constipation	7/100 (7%)		11/97 (11.3%)		9/99 (9.1%)
Diarrhoea	12/100 (12%)		9/97 (9.3%)		14/99 (14.1%)
Nausea	5/100 (5%)		2/97 (2.1%)		7/99 (7.1%)
Vomiting	5/100 (5%)		2/97 (2.1%)		5/99 (5.1%)
General disorders
Generalised Oedema	6/100 (6%)		2/97 (2.1%)		4/99 (4%)
Oedema	4/100 (4%)		2/97 (2.1%)		5/99 (5.1%)
Oedema Peripheral	3/100 (3%)		3/97 (3.1%)		5/99 (5.1%)
Pyrexia	6/100 (6%)		5/97 (5.2%)		5/99 (5.1%)
Infections and infestations
Pneumonia	5/100 (5%)		4/97 (4.1%)		7/99 (7.1%)
Urinary Tract Infection	2/100 (2%)		6/97 (6.2%)		7/99 (7.1%)
Metabolism and nutrition disorders
Fluid Overload	3/100 (3%)		5/97 (5.2%)		3/99 (3%)
Hyperglycaemia	2/100 (2%)		1/97 (1%)		5/99 (5.1%)
Hyperkalaemia	6/100 (6%)		3/97 (3.1%)		5/99 (5.1%)
Hypernatraemia	6/100 (6%)		3/97 (3.1%)		4/99 (4%)
Hypoalbuminaemia	4/100 (4%)		1/97 (1%)		5/99 (5.1%)
Hypoglycaemia	5/100 (5%)		5/97 (5.2%)		2/99 (2%)
Hypokalaemia	10/100 (10%)		9/97 (9.3%)		5/99 (5.1%)
Hypophosphataemia	5/100 (5%)		2/97 (2.1%)		6/99 (6.1%)
Psychiatric disorders
Agitation	6/100 (6%)		7/97 (7.2%)		8/99 (8.1%)
Anxiety	6/100 (6%)		1/97 (1%)		7/99 (7.1%)
Confusional State	7/100 (7%)		4/97 (4.1%)		5/99 (5.1%)
Insomnia	5/100 (5%)		3/97 (3.1%)		11/99 (11.1%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	6/100 (6%)		7/97 (7.2%)		4/99 (4%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	4/100 (4%)		5/97 (5.2%)		6/99 (6.1%)
Rash	5/100 (5%)		3/97 (3.1%)		4/99 (4%)
Vascular disorders
Hypertension	5/100 (5%)		5/97 (5.2%)		7/99 (7.1%)
Hypotension	4/100 (4%)		5/97 (5.2%)		5/99 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.