NO-HOLDS: Naloxone for Optimizing Hypoxemia Of Lung Donors

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT02581111
• Collaborator: (none)
• Enrollment: 199
• Locations: 4
• Arms: 2
• Actual Duration (Months): 24.8
• Patients Per Site: 49.8
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Brain-dead patients who provide authorization for organ donation will be randomized to naloxone or placebo if baseline arterial blood gas (ABG) after initiation of OPO (Organ Procurement Organization) management reveals hypoxemia, as defined by the ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) below 300 mm Hg, unless they have already been ruled-out for lung recovery. Investigators aim to assess whether naloxone improves oxygenation prior to organ recovery more than placebo.

Condition or Disease	Intervention/Treatment	Phase
Brain Death; Organ Donors; Lung Transplantation	Drug: Naloxone; Drug: Normal saline	Phase 2/Phase 3

Detailed Description

Naloxone has been used by many OPOs for decades to improve the pulmonary status of brain-dead organ donors (based on anecdotal evidence and small uncontrolled studies). Its efficacy in this population has never been assessed in a controlled clinical trial. The rationale for its use appears to be that it blocks the increase in capillary permeability that occurs with herniation and brain death (as demonstrated in a single sheep study of herniation). Investigators aim to rigorously test this hypothesis in a randomized placebo-controlled trial in brain-dead organ donors who have baseline hypoxemia. The primary outcome will be the acute change in oxygenation (on first follow-up ABG after naloxone as well as the final ABG prior to organ recovery). Investigators will also assess whether treatment results in more lungs being recovered and transplanted, after correcting for baseline variables such as age, blood group, smoking history, and cause of death. This study will be performed under the auspices of the Organ Donation Research Consortium and be carried out by multiple OPOs across the country. Naloxone or blinded placebo (identical syringe filled with saline) will be given after the baseline ABG shows hypoxemia (PFR - PaO2 divided by FiO2, on positive end-expiratory pressure [PEEP] of 5 and usually 100% FiO2). Naloxone and placebo will both be co-administered with a neuromuscular blocking agent (e.g. vecuronium, per center protocol) to obviate any increase in spinal reflex movements that may be potentiated by naloxone treatment. All other protocols for organ donor management should be maintained at each OPO and no other study interventions are required. Transplant centers will be informed (through DonorNet) that the organ donor being considered for lung recovery has been enrolled in this blinded clinical trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 199 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Placebo-controlled Trial of Intravenous Naloxone to Improve Oxygenation in Hypoxemic Lung-Eligible Brain-Dead Organ Donors
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Sep 22, 2017
• Actual Study Completion Date: Sep 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Naloxone Naloxone 8-mg IV given once after baseline ABG	Drug: Naloxone; Naloxone 8-mg IV bolus; Other Names: Narcan
Sham Comparator: Placebo Equivalent volume of saline given once	Drug: Normal saline; Other Names: saline

Outcome Measures

Primary Outcome Measures

1. Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG) [Baseline and at time of organ recovery, within 72 hours]

   Change in ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) from final ABG performed before organ recovery compared to baseline ABG

Secondary Outcome Measures

1. Number of Participants Who Had Lungs Transplanted [At time of organ recovery (within 72 hours)]

   Whether one or both lungs were transplanted from this organ donor (dichotomized)

2. Acute Change in Oxygenation (P/F Ratio) [Baseline and ABG at 4-6 hours after intervention]

   Change in PaO2:FiO2 ratio from ABG at 4-6 hours after randomization compared to baseline prior to randomization

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Brain-dead organ donor being managed by OPO (organ procurement organization)

• Lungs being considered for recovery and transplant

• Baseline ABG (after authorization) with P/F ratio < 300

Exclusion Criteria:

• No authorization for research

• Lungs already excluded for transplant (e.g. known chronic obstructive pulmonary disease [COPD], human immunodeficiency virus [HIV] infection)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Donor Alliance	Denver	Colorado	United States	80246
2	Louisiana Organ Procurement Agency	Metairie	Louisiana	United States	70002
3	Mid-America Transplant Services	Saint Louis	Missouri	United States	63110
4	Lifeline of Ohio	Columbus	Ohio	United States	43212

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Rajat Dhar, MD, Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol - Aug 14, 2015
• Statistical Analysis Plan - Aug 14, 2015

More Information

Publications

None provided.

• Responsible Party: Raj Dhar, Associate Professor of Neurology, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02581111
• Other Study ID Numbers: ODRC-001
• First Posted: Oct 20, 2015
• Last Update Posted: Jul 31, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Brain Death; Naloxone

Study Results

Participant Flow

Arm/Group Title	Naloxone	Placebo
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus	Equivalent volume of saline given once Normal saline
Period Title: Overall Study
STARTED	98	101
COMPLETED	96	94
NOT COMPLETED	2	7

Baseline Characteristics

Arm/Group Title	Naloxone	Placebo	Total
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus	Equivalent volume of saline given once Normal saline	Total of all reporting groups
Overall Participants	98	101	199
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.4 (13)	36.8 (13)	37 (13)
Sex: Female, Male (Count of Participants)
Female	40 40.8%	50 49.5%	90 45.2%
Male	58 59.2%	51 50.5%	109 54.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 5.1%	13 12.9%	18 9%
Not Hispanic or Latino	87 88.8%	83 82.2%	170 85.4%
Unknown or Not Reported	6 6.1%	5 5%	11 5.5%
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	15 15.3%	20 19.8%	35 17.6%
White	77 78.6%	76 75.2%	153 76.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 6.1%	5 5%	11 5.5%
Region of Enrollment (participants) [Number]
United States	98 100%	101 100%	199 100%

Outcome Measures

1. Primary Outcome

Title	Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG)
Description	Change in ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) from final ABG performed before organ recovery compared to baseline ABG
Time Frame	Baseline and at time of organ recovery, within 72 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naloxone	Placebo
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus	Equivalent volume of saline given once Normal saline
Measure Participants	96	94
Median (Inter-Quartile Range) [mm Hg]	81	80

2. Secondary Outcome

Title	Number of Participants Who Had Lungs Transplanted
Description	Whether one or both lungs were transplanted from this organ donor (dichotomized)
Time Frame	At time of organ recovery (within 72 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naloxone	Placebo
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus	Equivalent volume of saline given once Normal saline
Measure Participants	98	101
Count of Participants [Participants]	19 19.4%	19 18.8%

3. Secondary Outcome

Title	Acute Change in Oxygenation (P/F Ratio)
Description	Change in PaO2:FiO2 ratio from ABG at 4-6 hours after randomization compared to baseline prior to randomization
Time Frame	Baseline and ABG at 4-6 hours after intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naloxone	Placebo
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus	Equivalent volume of saline given once Normal saline
Measure Participants	98	101
Median (Inter-Quartile Range) [mm Hg]	71	33

Adverse Events

Time Frame	Till organ recovery (maximum of three days)
Arm/Group Title	Naloxone		Placebo
Arm/Group Description	Naloxone 8-mg IV given once after baseline ABG Naloxone: Naloxone 8-mg IV bolus		Equivalent volume of saline given once Normal saline
All Cause Mortality
	Naloxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/98 (0%)		0/101 (0%)
Serious Adverse Events
	Naloxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/98 (0%)		0/101 (0%)
Other (Not Including Serious) Adverse Events
	Naloxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/98 (0%)		0/101 (0%)

Limitations/Caveats

10 subjects were enrolled despite baseline PaO2:FiO2 ratio above 300 (i.e. protocol violations)

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.