CEASE: Comparative Evaluation of Albumin and Starch Effects in Acute Lung Injury (ALI)

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00796419
• Collaborator: (none)
• Enrollment: 31
• Locations: 4
• Arms: 2
• Duration (Months): 94
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are similar conditions in which the lungs are critically injured by another inflammatory process in the body. Together they affect more than 150,000 people per year in the United States, with mortality approaching 50% and a financial burden estimated to exceed $5 billion. Fluid overload, weight gain, and reduced oncotic pressure (low blood proteins) are associated with prolonged need for mechanical ventilation and mortality in patients with ALI/ARDS. Historical studies have provided conflicting evidence for benefits with colloid or diuretic therapy in ALI/ARDS, but recent clinical trials have demonstrated significant improvements in blood oxygen levels. The mechanisms of these benefits are not yet certain, but appear to relate to albumin's (a protein medicine) specific ability to influence injury and inflammation in the lungs, thus improving the ability for the lung to repair and exchange oxygen.

The purpose of this project is to determine the effects of therapies that affect blood proteins on their ability to change the way the lungs and cardiovascular system (heart and blood vessels) function. Special measurements will be taken to understand how these protein medicines change the ability of the lung and whole body to recover from widespread injury, with additional measures of specific heart and lung function. This clinical trial randomizes ALI/ARDS patients with low blood protein levels to receive albumin (a natural blood protein that is known to influence inflammation) or hetastarch (a synthetic blood protein) with diuretic therapy targeted to improve respiratory function. Therapeutic effects on respiratory function and blood oxygen levels, extravascular lung water, oncotic pressure, lung fluid removal, and heart function will be characterized. This trial will advance our understanding of treatment of ALI/ARDS and the factors that affect fluid balance in the lungs of these patients.

Funding Source - FDA Office of Orphan Products Development (OOPD)

Condition or Disease	Intervention/Treatment	Phase
Lung Injury, Acute (ALI); Respiratory Distress Syndrome, Acute (ARDS)	Drug: 5% human albumin; Drug: 6% hetastarch	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase III Study Comparing Albumin and Hetastarch Therapy in Acute Lung Injury
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Intravenous 5% human albumin	Drug: 5% human albumin; Intravenous administration of 250 milliliters (mL) 5% human albumin every 8 hours for 5 days
Experimental: 2 Intravenous 6% hetastarch	Drug: 6% hetastarch; Intravenous administration of 250mL 6% hetastarch every 8 hours for 5 days

Outcome Measures

Primary Outcome Measures

1. Change in Extravascular Lung Water (EVLW) [Baseline to Day 5 (120 hours)]

   Quantity of extravascular lung water (EVLW) measured by transpulmonary thermodilution. Higher measurements of EVLW per kilogram of body weight indicate increased lung injury. Normal values for EVLW are thought to be less than 10 mL/kg.

Secondary Outcome Measures

1. Change in Oxygenation (PaO2/FiO2 Ratio) [Baseline, Day 1]

   Change in arterial oxygenation measured by arterial blood gas analysis. The partial pressure of O2 in arterial blood to fraction of inspired oxygen ratio (PaO2/FiO2) is a ratio of partial pressure arterial oxygen to fractional inspired inspired oxygen. This ratio is used as an indicator of hypoxemia (low blood oxygen). A PaO2/FiO2 ratio of 200-300 indicates mild ARDS, 100-200 indicates moderate ARDS, and less than 100 indicates severe ARDS.

2. Ventilator-free Days [Day 30]

   The 'ventilator free survival days' in a 30-day period is a previously validated method of comparing groups with respect to mechanical ventilator requirements while adjusting for mortality. This variable represents the number of days in the 30-day period following baseline that the patient is alive and not requiring mechanical ventilation.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Consensus clinical definition of ALI or ARDS:

• Partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (PaO2 / FiO2) ratio ≤ 200 (ARDS) or ≤ 300 (ALI), and;

• Bilateral infiltrates on chest x-ray, and;

• No clinical evidence of congestive heart failure, and;

• Pulmonary artery occlusion pressure (PAOP) ≤ 18 mm Hg, if a pulmonary arterial catheter is present

• Serum total protein concentration < 6.0 g/dL.

• Endotracheal intubation and mechanical ventilation ≥ 24 hours.

Exclusion Criteria:

• Hemodynamic instability within the prior 24 hours: (either of the following)

• Ongoing fluid resuscitation defined as > 2 liters of crystalloid boluses or > 4 units of blood products transfused in the prior 24-hour period.

• Vasopressor support exceeding any of the following:

• Dopamine or dobutamine > 5 mcg/kg/min, or in combination at any dose; or

• Any other vasoactive agent (i.e. epinephrine, norepinephrine, phenylephrine)

• Significant renal disease (either of the following at the time of screening):

• End-stage renal disease, or

• Renal insufficiency with serum creatinine ≥ 3.0 mg/dL or urine output < 500cc/24 hrs

• Allergy to albumin, hetastarch or furosemide.

• Increased risk for bleeding:

• Within 72 hours of any surgical procedure requiring use of the operating room, or

• Any current or previously diagnosed bleeding disorder, or

• History of any intracranial abnormality (including, but not limited to, intracranial arteriovenous malformations, subdural/subarachnoid/intracerebral hemorrhage, intracranial mass lesions) or traumatic brain injury with Glasgow Coma Scal (GCS) < 9 in the prior 14 days, or

• Prothrombin time international normalized ratio (INR) > 2.0, partial thromboplastin time (PTT) > 1.5 times control, platelet count < 50,000/cc3

• Risk for worsening pulmonary edema due to systolic heart failure.

• Technical pulse contour analysis limitations:

• Absence of central venous catheter, clinical arterial vascular disease, severe hypothermia (core temperature < 94°F), weight < 40 kg or > 250 kg, clinically significant bleeding diathesis.

• Failure of the patient or nearest relative to provide informed consent.

• Refusal of the patient's attending physician to provide consent to participate.

• Age < 18 years.

• Pregnancy.

• Inability to quantify urine output (e.g. absence of bladder or bladder catheter).

• Significant hypokalemia (K+ < 3.5 meq/L), hypernatremia (Na+ > 155 meq/L) or hypomagnesemia (Mg < 1.0 meq/L)

• Patient meets criteria for weaning mechanical ventilation:

• Required FiO2 ≤ 0.40 and positive end-expiratory pressure (PEEP) ≤ 5, and;

• Spontaneous tidal volumes > 5 ml / kg, and;

• Spontaneous respiratory rate < 20 / minute, and;

• Capable of spontaneous ventilation on continuous positive airway pressure (CPAP)=5, pressure support (PS)=5.

• Expected survival ≤ 120 hours.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Grady Memorial Hospital	Atlanta	Georgia	United States	30303
2	Emory Crawford Long Hospital	Atlanta	Georgia	United States	30308
3	Emory University Hospital	Atlanta	Georgia	United States	30322
4	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: Greg S Martin, MD, MSc, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Greg S. Martin, M.D., M.Sc., Professor, Emory University
• ClinicalTrials.gov Identifier: NCT00796419
• Other Study ID Numbers: IRB00002187; R01FD003440; 622-2000
• First Posted: Nov 24, 2008
• Last Update Posted: Apr 28, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Greg S. Martin, M.D., M.Sc., Professor, Emory University: Acute lung injury (ALI); Acute respiratory distress syndrome (ARDS); Respiratory failure
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Lung Injury; Acute Lung Injury; Wounds and Injuries; Hydroxyethyl Starch Derivatives

Study Results

Participant Flow

Recruitment Details	Critically ill, mechanically ventilated intensive care patients with Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS) and low blood protein levels were recruited from four hospitals in the Southeast United States between May 1, 2009 and October 31, 2015.
Pre-assignment Detail	Not all consented subjects were treated due to changes in eligibility between the consent and treatment periods or subject withdrawal from the study after consent but prior to treatment. 31 individuals gave consent to participate in the study, however, 4 did not begin the study intervention, resulting in 27 who started treatment.

Arm/Group Title	Intravenous 5% Human Albumin	Intravenous 6% Hetastarch
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250 milliliters (mL) 5% human albumin every 8 hours for 5 days	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250 milliliters (mL) 6% hetastarch every 8 hours for 5 days
Period Title: Overall Study
STARTED	13	14
COMPLETED	13	13
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Intravenous 5% Human Albumin	Intravenous 6% Hetastarch	Total
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 5% human albumin every 8 hours for 5 days	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 6% hetastarch every 8 hours for 5 days	Total of all reporting groups
Overall Participants	13	14	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (16)	50 (16)	49 (15)
Sex: Female, Male (Count of Participants)
Female	8 61.5%	9 64.3%	17 63%
Male	5 38.5%	5 35.7%	10 37%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 15.4%	0 0%	2 7.4%
Not Hispanic or Latino	11 84.6%	14 100%	25 92.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
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	4 30.8%	9 64.3%	13 48.1%
White	7 53.8%	5 35.7%	12 44.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 15.4%	0 0%	2 7.4%
Region of Enrollment (participants) [Number]
United States	13 100%	14 100%	31 114.8%

Outcome Measures

1. Primary Outcome

Title	Change in Extravascular Lung Water (EVLW)
Description	Quantity of extravascular lung water (EVLW) measured by transpulmonary thermodilution. Higher measurements of EVLW per kilogram of body weight indicate increased lung injury. Normal values for EVLW are thought to be less than 10 mL/kg.
Time Frame	Baseline to Day 5 (120 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous 5% Human Albumin	Intravenous 6% Hetastarch
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 5% human albumin every 8 hours for 5 days	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 6% hetastarch every 8 hours for 5 days
Measure Participants	13	14
Baseline	18.5 (7.1)	17.7 (5.9)
Hour 120	16.0 (7.3)	15.1 (3.6)

2. Secondary Outcome

Title	Change in Oxygenation (PaO2/FiO2 Ratio)
Description	Change in arterial oxygenation measured by arterial blood gas analysis. The partial pressure of O2 in arterial blood to fraction of inspired oxygen ratio (PaO2/FiO2) is a ratio of partial pressure arterial oxygen to fractional inspired inspired oxygen. This ratio is used as an indicator of hypoxemia (low blood oxygen). A PaO2/FiO2 ratio of 200-300 indicates mild ARDS, 100-200 indicates moderate ARDS, and less than 100 indicates severe ARDS.
Time Frame	Baseline, Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous 5% Human Albumin	Intravenous 6% Hetastarch
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 5% human albumin every 8 hours for 5 days	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 6% hetastarch every 8 hours for 5 days
Measure Participants	13	14
Baseline	191.3 (53.8)	157.3 (63.0)
Day 1	213.4 (95.5)	165.4 (50.8)

3. Secondary Outcome

Title	Ventilator-free Days
Description	The 'ventilator free survival days' in a 30-day period is a previously validated method of comparing groups with respect to mechanical ventilator requirements while adjusting for mortality. This variable represents the number of days in the 30-day period following baseline that the patient is alive and not requiring mechanical ventilation.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous 5% Human Albumin	Intravenous 6% Hetastarch
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 5% human albumin every 8 hours for 5 days	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 6% hetastarch every 8 hours for 5 days
Measure Participants	13	14
Median (Inter-Quartile Range) [days]	23	23

Adverse Events

Time Frame	Adverse events (AEs) will be determined daily from enrollment to 72 hours after the last dose of study drug or any study-related procedure. All deaths, unexpected serious adverse events (SAEs), and worsening renal function (as defined as creatinine greater than or equal to 3.0 mg/dL or urine output less than 500cc/24 hrs) will be followed until 30 days after enrollment in this study.
Adverse Event Reporting Description	For purposes of this study, an AE is defined as any unfavorable or unintended change in structure, function, signs, or symptoms different from what is expected in the clinical course of an ALI patient and temporally associated with the use of any study drug (albumin, hetastarch or furosemide) or the performance of a study procedure, regardless of any causal relationship to the study.
Arm/Group Title	Intravenous 5% Human Albumin		Intravenous 6% Hetastarch
Arm/Group Description	Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 5% human albumin every 8 hours for 5 days		Recipients of continuous infusion intravenous furosemide and administration of intravenous 250mL 6% hetastarch every 8 hours for 5 days
All Cause Mortality
	Intravenous 5% Human Albumin		Intravenous 6% Hetastarch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		3/14 (21.4%)
Serious Adverse Events
	Intravenous 5% Human Albumin		Intravenous 6% Hetastarch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		5/14 (35.7%)
Cardiac disorders
Cardiac arrest	0/13 (0%)	0	1/14 (7.1%)	1
General disorders
Re-hospitalization	1/13 (7.7%)	1	0/14 (0%)	0
Shock	0/13 (0%)	0	2/14 (14.3%)	2
Bleeding	0/13 (0%)	0	1/14 (7.1%)	1
Focal weakness	0/13 (0%)	0	1/14 (7.1%)	1
Death	1/13 (7.7%)	1	3/14 (21.4%)	3
Hepatobiliary disorders
Acute hepatic injury	0/13 (0%)	0	1/14 (7.1%)	1
Renal and urinary disorders
Acute kidney injury	1/13 (7.7%)	1	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/13 (0%)	0	1/14 (7.1%)	1
Acute respiratory distress/failure	1/13 (7.7%)	1	0/14 (0%)	0
Other (Not Including Serious) Adverse Events
	Intravenous 5% Human Albumin		Intravenous 6% Hetastarch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)		6/14 (42.9%)
Blood and lymphatic system disorders
Bleeding/coagulopathy	0/13 (0%)	0	4/14 (28.6%)	6
Increase in serum amylase or lipase	0/13 (0%)	0	1/14 (7.1%)	1
Cardiac disorders
Myocardial ischemia	0/13 (0%)	0	1/14 (7.1%)	1
Pericardial effusion	1/13 (7.7%)	1	0/14 (0%)	0
Tachycardia	1/13 (7.7%)	1	0/14 (0%)	0
General disorders
Systemic hypotension	4/13 (30.8%)	7	3/14 (21.4%)	3
Systemic hypertension	1/13 (7.7%)	1	0/14 (0%)	0
Infections and infestations
Secondary infection or sepsis	0/13 (0%)	0	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders
Worsening pulmonary edema or lung injury	2/13 (15.4%)	2	1/14 (7.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.