A Study to Assess Safety,and Tolerability of 2 Doses of AZD9773 (CytoFab™) in Japanese With Severe Sepsis/Septic Shock

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01144624
• Collaborator: (none)
• Enrollment: 20
• Locations: 7
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The two co-primary objectives of this study are to assess in Japanese patients with severe sepsis and/or septic shock: 1) the safety and tolerability of two different doses of intravenous AZD9773 and 2) the PK of AZD9773.

The secondary objective is to make a preliminary assessment of the pharmacodynamics of two different doses of intravenous AZD9773 in Japanese patients with severe sepsis and/or septic shock.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Dose Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Intravenous Infusions of AZD9773 (CytoFab™) in Japanese Patients With Severe Sepsis and/or Septic Shock
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 AZD9773 250 units/kg (1 infusion) + 50 units/kg (9 infusions) (Dose Cohort 1): AZD9773 500 units/kg (1 infusion) + 100 units/kg (9 infusions) (Dose Cohort 2)	Drug: AZD9773; A single loading dose followed by 9 maintenance doses; doses to be given every 12 hours over a period of 5 days; Other Names: CytoFab™
Placebo Comparator: 2	Drug: Placebo; Intravenous infusion of a saline solution

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability of AZD9773 [28 day study period]

   Number of patients with treatment-emergent adverse events and number of patients who died over 28 days

2. Pharmacokinetics of AZD9773 [From first dose to last dose (Day 5/6 or at premature treatment discontinuation)]

   Maximum concentration at steady state (Cmax ss) for serum total and specific fabs

Secondary Outcome Measures

1. Pharmacodynamic Effects of AZD9773 on TNF-alpha [Levels taken at baseline, over the dosing period (up to Day 5/6)]

   TNF-alpha levels over approximately 6 days following the first dose

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Japanese 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. Haemopoietic or lymphoreticular malignancies not in remission.

3. Receiving radiation therapy or chemotherapy.

4. Any organ or bone marrow transplant within the past 24 weeks.

5. Absolute neutrophil count <500 per μL.

6. High dose steroids or other immunocompromising drugs.

• Concomitant diseases:

1. Deep-seated fungal infection or active tuberculosis.

2. Severe chronic liver disease associated with portal hypertension, cirrhosis, chronic ascites or Child-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 III or IV due to heart failure or any disorder.

8. Burns over > 30% of body surface area in the past 5 days.

• 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 papain, chymopapain.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Sapporo-shi	Hokkaido	Japan
2	Research Site	Kobe	Hyogo	Japan
3	Research Site	Kumamoto-Shi	Kumamoto	Japan
4	Research Site	Sumiyoshi-ku	Osaka	Japan
5	Research Site	Hachioji	Tokyo	Japan
6	Research Site	Ohta-ku	Tokyo	Japan
7	Research Site	Osaka		Japan

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Justin Lindemann, MD, AstraZeneca
• Study Director: Wayne Dankner, MD, PAREXEL International Medical Services
• Study Director: Warren Botnick, MD, PAREXEL International Medical Services

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D0620C00005 Study Report Synopsis
• redacted-CSP-D0620C00005.pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01144624
• Other Study ID Numbers: D0620C00005
• First Posted: Jun 15, 2010
• Last Update Posted: Oct 6, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by AstraZeneca: TNF neutralisation
• Additional relevant MeSH terms: Sepsis; Toxemia; Shock, Septic; Shock

Study Results

Participant Flow

Recruitment Details	Subjects were screened and enrolled at six centres in Japan.

Arm/Group Title	Dose Cohort 1	Dose Cohort 2	Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Period Title: Overall Study
STARTED	7	7	6
Received Treatment	7	7	6
Completed Treatment	7	7	6
COMPLETED	7	7	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Cohort 1	Dose Cohort 2	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	7	7	6	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.3 (10.89)	77.6 (10.45)	77.7 (17.64)	75.4 (12.78)
Sex: Female, Male (Count of Participants)
Female	3 42.9%	4 57.1%	4 66.7%	11 55%
Male	4 57.1%	3 42.9%	2 33.3%	9 45%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability of AZD9773
Description	Number of patients with treatment-emergent adverse events and number of patients who died over 28 days
Time Frame	28 day study period

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Arm 1 - Dose Cohort 1	Arm 2 - Dose Cohort 2	Arm 3 - Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	7	7	6
Number of Patients with Treatment-Emergent AEs	7 100%	7 100%	6 100%
Number of Patients who Died over 28 days	1 14.3%	0 0%	2 33.3%

2. Primary Outcome

Title	Pharmacokinetics of AZD9773
Description	Maximum concentration at steady state (Cmax ss) for serum total and specific fabs
Time Frame	From first dose to last dose (Day 5/6 or at premature treatment discontinuation)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set

Arm/Group Title	Arm 1 - Dose Cohort 1	Arm 2 - Dose Cohort 2	Arm 3 - Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	7	5	0
Cmax ss for serum total fabs	38.48	71.04
Cmax ss for serum specific fabs	1.823	3.335

3. Secondary Outcome

Title	Pharmacodynamic Effects of AZD9773 on TNF-alpha
Description	TNF-alpha levels over approximately 6 days following the first dose
Time Frame	Levels taken at baseline, over the dosing period (up to Day 5/6)

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Arm 1 - Dose Cohort 1	Arm 2 - Dose Cohort 2	Arm 3 - Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV	AZD9773 500/100 units/kg IV	Saline
Measure Participants	7	7	6
TNF-alpha level at baseline	1.000	1.690	8.810
TNF-alpha level 1-2 hours post-first dose	0.920	0.990	7.425
TNF-alpha level on Day 6 (pre-morning dose)	1.710	1.140	1.560

Adverse Events

Arm/Group Title	Dose Cohort 1		Dose Cohort 2		Placebo
Arm/Group Description	AZD9773 250/50 units/kg IV		AZD9773 500/100 units/kg IV		Saline
All Cause Mortality
	Dose Cohort 1		Dose Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Cohort 1		Dose Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		1/7 (14.3%)		1/6 (16.7%)
Cardiac disorders
Acute Myocardial Infarction	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Ventricular Tachycardia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Gastrointestinal disorders
Large Intestine Perforation	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric Cancer	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Nervous system disorders
Cerebral Infarction	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Parkinsonism	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Haemothorax	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	Dose Cohort 1		Dose Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		7/7 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	2/7 (28.6%)		1/7 (14.3%)		0/6 (0%)
Haemorrhagic Anaemia	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Cardiac disorders
Arrhythmia	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Atrial Fibrillation	0/7 (0%)		2/7 (28.6%)		0/6 (0%)
Bradycardia	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Cardiovascular Insufficiency	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Mitral Valve Incompetence	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Sinus Tachycardia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Supraventricular Extrasystoles	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Ventricular Extrasystoles	1/7 (14.3%)		2/7 (28.6%)		1/6 (16.7%)
Ventricular Tachycardia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Congenital, familial and genetic disorders
Pyloric Stenosis	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Endocrine disorders
Adrenal Insufficiency	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Eye disorders
Conjunctival Hyperaemia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Conjunctival Oedema	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastrointestinal disorders
Abdominal Compartment Syndrome	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Anal Erosion	2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Ascites	0/7 (0%)		2/7 (28.6%)		0/6 (0%)
Cheilitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Colitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Constipation	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Diarrhoea	1/7 (14.3%)		1/7 (14.3%)		3/6 (50%)
Gastric Haemorrhage	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Gastritis Erosive	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastrointestinal Haemorrhage	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastrointestinal Hypomotility	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Haematochezia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Ileus Paralytic	1/7 (14.3%)		2/7 (28.6%)		0/6 (0%)
Periodontitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Stomatitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Vomiting	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
General disorders
Catheter Site Haematoma	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Device Leakage	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Disuse Syndrome	2/7 (28.6%)		1/7 (14.3%)		1/6 (16.7%)
Fat Necrosis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Generalised Oedema	2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Injection Site Erythema	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Oedema	1/7 (14.3%)		2/7 (28.6%)		0/6 (0%)
Oedema Peripheral	1/7 (14.3%)		3/7 (42.9%)		0/6 (0%)
Pain	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Hepatobiliary disorders
Cholecystitis	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hepatic Function Abnormal	2/7 (28.6%)		0/7 (0%)		1/6 (16.7%)
Jaundice	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Infections and infestations
Abdominal Abscess	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Bacteraemia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Cellulitis Staphylococcal	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Colostomy Infection	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Fungaemia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Fungal Skin Infection	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Herpes Zoster	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Incision Site Cellulitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Infectious Peritonitis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Oral Herpes	1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Pneumonia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pneumonia Bacterial	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pneumonia Pneumococcal	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pneumonia Staphylococcal	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Postoperative Wound Infection	2/7 (28.6%)		0/7 (0%)		2/6 (33.3%)
Pseudomembranous Colitis	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Septic Shock	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Tinea Cruris	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Tracheostomy Infection	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Urinary Tract Infection	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Injury, poisoning and procedural complications
Gastrointestinal Anastomotic Leak	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Incision Site Haemorrhage	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Post Procedural Complication	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Post Procedural Haemorrhage	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Tracheal Obstruction	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Traumatic Lung Injury	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Wound Complication	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Investigations
Blood Creatine Phosphokinase Increased	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Blood Pressure Decreased	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Body Temperature Increased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
C-Reactive Protein Increased	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Heart Rate Increased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Hepatic Enzyme Increased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Pancreatic Enzymes Increased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Urine Output Decreased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
White Blood Cell Count Decreased	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Metabolism and nutrition disorders
Acidosis	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gout	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hyperglycaemia	1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Hyperkalaemia	1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Hypoalbuminaemia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Hypokalaemia	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Hyponatraemia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hypovolaemia	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Metabolic Alkalosis	2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric Cancer	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Psychiatric disorders
Delirium	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Insomnia	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Mental Disorder Due To A General Medical Condition	2/7 (28.6%)		0/7 (0%)		1/6 (16.7%)
Renal and urinary disorders
Renal Impairment	0/7 (0%)		2/7 (28.6%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/7 (0%)		2/7 (28.6%)		0/6 (0%)
Dyspnoea	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Haemoptysis	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Oropharyngeal Pain	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Pleural Effusion	5/7 (71.4%)		4/7 (57.1%)		0/6 (0%)
Pneumomediastinum	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pneumonia Aspiration	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Pneumothorax	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Productive Cough	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Pulmonary Congestion	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Pulmonary Fibrosis	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Tachypnoea	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Tracheal Oedema	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Vocal Cord Polyp	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Wheezing	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Dermatitis	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Dermatitis Contact	1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Dry Skin	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Erythema	3/7 (42.9%)		0/7 (0%)		1/6 (16.7%)
Petechiae	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Purpura	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Rash	0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Skin Erosion	1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Skin Exfoliation	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Skin Haemorrhage	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Skin Oedema	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Subcutaneous Emphysema	2/7 (28.6%)		1/7 (14.3%)		0/6 (0%)
Vascular Purpura	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Surgical and medical procedures
Dermabrasion	0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Vascular disorders
Flushing	0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hypertension	1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Jugular Vein Thrombosis	0/7 (0%)		0/7 (0%)		1/6 (16.7%)

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.