LIPS-A: Lung Injury Prevention Study With Aspirin

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01504867
• Collaborator: Beth Israel Deaconess Medical Center (Other), Montefiore Medical Center (Other), Vanderbilt University Medical Center (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 400
• Locations: 16
• Arms: 2
• Actual Duration (Months): 44
• Patients Per Site: 25
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary hypothesis was that early aspirin administration will decrease the rate of developing acute lung injury during the first 7 days after presentation to the hospital.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome	Drug: Aspirin; Drug: Lactose powder	Phase 2

Detailed Description

Acute respiratory distress syndrome (ARDS) remains a life-threatening critical care syndrome characterized by alveolar-capillary membrane injury and hypoxemic respiratory failure. The median time to onset of ARDS is 2 days after hospital presentation. Therefore, the period between hospital presentation and the development of ARDS presents a brief window of opportunity for ARDS prevention.

This was a multicenter, double-blind, placebo-controlled, parallel-group, Phase 2b, randomized clinical trial. Development of ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission. The first dose of study drug or placebo was administered within 24 hours after presentation to the hospital. Important co-interventions were standardized across sites using a web-based tool, Checklist for Lung Injury Prevention. Study participants were screened daily for receipt of mechanical ventilation and determination of the partial pressure of arterial oxygen (PaO2) or oxygen saturation to fraction of inspired oxygen ratio (SpO2:FIO2). If the participant's SpO2:FIO2 ratio was consistently below 315, hypoxemia was confirmed with measurement of arterial blood gas. Chest radiographs for all intubated patients with a SpO2:FIO2 of 300 or less were independently reviewed by both site investigator and a member of the trial's executive committee. Study participants who died or were discharged from the hospital before day 7 without meeting criteria for ARDS were adjudicated as not having ARDS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: LIPS-A: Lung Injury Prevention Study With Aspirin
• Actual Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aspirin This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	Drug: Aspirin; 325mg loading dose once on study day 1, followed by 81mg dose once daily on study days 2-7. Administered by mouth or down nasal gastric tube.
Placebo Comparator: Placebo This group received matching lactose powder filled capsules on days 1-7.	Drug: Lactose powder; Matching lactose powder filled capsules will be administered on days 1-7.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days [Within seven days from hospital presentation]

   ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission.

Secondary Outcome Measures

1. Hospital Mortality [28 days]

2. Number of Participants With ARDS or Mortality Within 7 Days [within 7 days]

3. Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization [approximately 7 days]

4. Mean Number of Days Participants Were Ventilator-Free To Day 28 [baseline, Day 28]

5. Number of Subjects Admitted to Intensive Care Unit (ICU) [7 days]

6. Mean Hospital Length of Stay [approximately 7 days]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult patients (age > 18) admitted to the hospital through the emergency department (ED)

• At high risk of developing acute lung injury (ALI) Lung Injury Prediction Score (LIPS) greater than or equal to 4

Exclusion Criteria:

• Anti-platelet therapy on admission or within 7 days prior to admission

• Presented to outside hospital ED > 12 hrs before arrival at site's facility

• Inability to obtain consent within 12 hours of hospital presentation

• Admitted for elective surgery

• Acute lung injury prior to randomization

• Receiving mechanical ventilation through a tracheostomy tube prior to current hospital admission (patient who is ventilator dependent)

• Presence of bilateral pulmonary infiltrates on admission if he or she has a history of bilateral pulmonary infiltrates (as evidenced by previous x-rays) that can reasonably explain the current degree of pulmonary infiltrates present.

• Presentation due to pure heart failure and no other known risk factors for ALI.

• Allergy to aspirin or non steroidal anti inflammatory drugs (NSAIDs)

• Bleeding disorder

• Suspected active bleeding or judged to be at high risk for bleeding

• Active peptic ulcer disease (within past 6 months)

• Severe chronic liver disease

• Inability to administer the study drug

• Expected hospital stay < 48 hours

• Admitted for comfort or hospice care

• Patient, surrogate or physician not committed to full support. (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)

• Not anticipated to survive > 48 hours

• Previously enrolled in this trial

• Enrolled in a concomitant intervention trial

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Univeristy	Stanford	California	United States	94305
2	Bridgeport Hospital	Bridgeport	Connecticut	United States	06610
3	University of Florida	Gainsville	Florida	United States	32610
4	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224
5	University of Illinois at Chicago	Chicago	Illinois	United States	60612
6	University of Louisville Medical Center	Louisville	Kentucky	United States	40202
7	Massachusetts General Hospital	Boston	Massachusetts	United States	021114
8	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
9	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
10	University of Michigan	Ann Arbor	Michigan	United States	48109
11	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
12	Montefiore Medical Center	Bronx	New York	United States	10467
13	Duke University Medical Center	Durham	North Carolina	United States	27710
14	Wake Forest University Medical Center	Winston Salem	North Carolina	United States	27517
15	Temple University School of Medicine	Philadelphia	Pennsylvania	United States	19140
16	Harborview Medical Center	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Mayo Clinic
• Beth Israel Deaconess Medical Center
• Montefiore Medical Center
• Vanderbilt University Medical Center
• National Heart, Lung, and Blood Institute (NHLBI)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Daryl Kor, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daryl J. Kor, M.D., PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01504867
• Other Study ID Numbers: 10-004856; U01HL108712-01; KL2RR024151; K23HL112855; UL1TR000433
• First Posted: Jan 6, 2012
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Daryl J. Kor, M.D., PI, Mayo Clinic: Acute Respiratory Distress Syndrome; Acute Lung Injury; ARDS; ALI; aspirin; prevention
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Aspirin

Study Results

Participant Flow

Recruitment Details	Participants were recruited between 1/2/2012 and 11/17/2014 at multiple US academic hospitals.

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Period Title: Overall Study
STARTED	202	198
COMPLETED	195	195
NOT COMPLETED	7	3

Baseline Characteristics

Arm/Group Title	Aspirin	Placebo	Total
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.	Total of all reporting groups
Overall Participants	195	195	390
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	57.0	57.0	57
Sex: Female, Male (Count of Participants)
Female	88 45.1%	99 50.8%	187 47.9%
Male	107 54.9%	96 49.2%	203 52.1%
Region of Enrollment (participants) [Number]
United States	195 100%	195 100%	390 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Developed Acute Respiratory Distress Syndrome (ARDS) Within 7 Days
Description	ARDS was defined by Berlin criteria (modified to require invasive mechanical ventilation) within 7 days of hospital admission.
Time Frame	Within seven days from hospital presentation

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Number [participants]	20 10.3%	17 8.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments	The primary outcome significance level was adjusted for multiple testing associated with the interim analysis. Its significance level is 92.6%
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Wald
	Comments	This was a large sample (Wald) test estimated using a conditional logistic regression model with site as a stratification variable.

2. Secondary Outcome

Title	Hospital Mortality
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Number [participants]	14 7.2%	14 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.99
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Number of Participants With ARDS or Mortality Within 7 Days
Time Frame	within 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Number [participants]	27 13.8%	21 10.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Number of Subjects With Mechanical Ventilation at Any Time During Hospitalization
Time Frame	approximately 7 days

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Number [participants]	51 26.2%	41 21%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Mean Number of Days Participants Were Ventilator-Free To Day 28
Time Frame	baseline, Day 28

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Mean (Standard Deviation) [days]	24.9 (7.4)	25.2 (7.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Number of Subjects Admitted to Intensive Care Unit (ICU)
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Number [participants]	115 59%	98 50.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Mean Hospital Length of Stay
Time Frame	approximately 7 days

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Aspirin	Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.	This group received matching lactose powder filled capsules on days 1-7.
Measure Participants	195	195
Mean (Standard Deviation) [days]	8.8 (10.3)	9.0 (9.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	12 months
Arm/Group Title	Aspirin		Placebo
Arm/Group Description	This arm received a 325mg loading dose of aspirin on study day one, followed by 81mg of aspirin on days 2-7.		This group received matching lactose powder filled capsules on days 1-7.
All Cause Mortality
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/195 (2.1%)		8/195 (4.1%)
Blood and lymphatic system disorders
Hematoma	1/195 (0.5%)	1	0/195 (0%)	0
Anemia due to Upper GI Bleeding	0/195 (0%)	0	1/195 (0.5%)	1
Hemoptysis	0/195 (0%)	0	1/195 (0.5%)	1
Low Hemoglobin	0/195 (0%)	0	1/195 (0.5%)	1
Cardiac disorders
Chest Pain	1/195 (0.5%)	1	0/195 (0%)	0
Pulseless Electrical Activity	0/195 (0%)	0	1/195 (0.5%)	2
Gastrointestinal disorders
Bleeding Stress Ulcer	1/195 (0.5%)	1	0/195 (0%)	0
Gastrointestinal bleeding	1/195 (0.5%)	1	2/195 (1%)	2
Infections and infestations
Pneumonia/Sepsis	0/195 (0%)	0	1/195 (0.5%)	1
Nervous system disorders
Hydrocephalus	0/195 (0%)	0	1/195 (0.5%)	1
Renal and urinary disorders
Urinary Tract Infection	0/195 (0%)	0	1/195 (0.5%)	1
Skin and subcutaneous tissue disorders
Skin Infection	0/195 (0%)	0	1/195 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Aspirin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/195 (6.7%)		5/195 (2.6%)
Blood and lymphatic system disorders
Bleeding	2/195 (1%)	2	0/195 (0%)	0
Thrombocytopenia	2/195 (1%)	2	0/195 (0%)	0
Cerebral Hemorrhage	1/195 (0.5%)	1	0/195 (0%)	0
Hematoma	1/195 (0.5%)	1	1/195 (0.5%)	1
Low Hemoglobin	0/195 (0%)	0	1/195 (0.5%)	1
Cardiac disorders
NSTEMI	1/195 (0.5%)	1	0/195 (0%)	0
Gastrointestinal disorders
Gastrointestinal Bleeding	2/195 (1%)	2	0/195 (0%)	0
Mild Indigestion	1/195 (0.5%)	1	0/195 (0%)	0
Vomiting	0/195 (0%)	0	1/195 (0.5%)	1
Infections and infestations
Pneumonia	0/195 (0%)	0	1/195 (0.5%)	1
Renal and urinary disorders
Rectal Bleeding	1/195 (0.5%)	1	0/195 (0%)	0
Urosepsis	1/195 (0.5%)	1	0/195 (0%)	0
Renal Failure Requiring Dialysis	0/195 (0%)	0	1/195 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	1/195 (0.5%)	1	0/195 (0%)	0
Surgical and medical procedures
Right Hip Resection	1/195 (0.5%)	1	0/195 (0%)	0
Vascular disorders
Elevated Blood Pressure	1/195 (0.5%)	1	0/195 (0%)	0
Nose Bleed	1/195 (0.5%)	1	0/195 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.