Clinical trial NCT02581111
Conditions: Brain Death Organ Donors Lung Transplantation
Sponsor: Washington University School of Medicine
Start date: 2015-09-01; Completion date: 2017-09-25
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: Naloxone 8-mg IV given once after baseline ABG arm 2: Equivalent volume of saline given once
Interventions: intervention 1: Naloxone intervention 2: Normal saline
Intervention descriptions: intervention 1: Naloxone 8-mg IV bolus intervention 2: None

Protocol documents:
Prot_000.pdf: 
Study Protocol 
Naloxone for Optimizing Hypoxemia of Lung Donors (NO-HOLDS) 
 
NCT02581111 
 
 
Date: August 14, 2015 


Project Goals 
1. Evaluate whether naloxone can improve oxygenation / reverse hypoxemia in lung-eligible brain-
dead (BD) organ donors 
2. Demonstrate feasibility of prospective multi-OPO clinical trials as part of the ODRC 
Study Population (determined at initiation of OPO management) 
1. Lung-eligible BD donors (age 13-70, no established severe lung disease – e.g. COPD) 
2. Arterial hypoxemia (P:F ratio < 300 on first ABG after initial OPO stabilization) 
Study Protocol 
1. All OPO-specific donor protocols (incl. lung optimization) should be followed 
a. Does not require any other change to practice or donor management 
2. Randomization occurs for eligible donors after initial ABG (stratified by center) 
3. Naloxone 8 mg IV (or saline) given once  
a. Co-administered with a neuromuscular blocking agent (NMB)  
b. Blinding of drug vs. placebo done at each OPO with sequential unmarked syringes (prefilled 
with naloxone or saline and numbered with central code) 
Outcome Measures 
1. Change in P:F ratio to final ABG – ABG obtained on 100% FiO2, PEEP 5  
2. Change in P:F ratio to early ABG 
3. Lungs recovered / transplanted (if not – reason, e.g. hypoxemia vs. COPD, other RO) 
 
SRTR variables for O:E calculation (incl. age, race, ABO, smoker) 
 
Most of this could be abstracted post-hoc from OPO database 
 
Only study registration (with UNOS & OPO ID) entered into study-specific on-line database 
with syringe # and ABG PO2 values (redcap.wustl.edu)   
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Naloxone for Optimizing Hypoxemia of Lung Donors (NO-HOLDS) 
 
NCT02581111 
 
 
Date: August 14, 2015 
 
 


Prospectively collected data included baseline and follow-up ABGs (closest to six hours after drug 
administration and final ABG prior to procurement), as well as whether lungs were transplanted (with 
reasons for non-utilization, if not transplanted). These data were collected at the time of case 
management by Organ Procurement Coordinators and entered into a centralized study database by the 
site coordinator. Primary outcome measure was change in PaO2:FiO2 ratio (PFR, calculated by dividing 
PaO2 from ABG by FiO2) from baseline to final ABG. Secondary outcomes were early change in PFR 
(from baseline to first repeat ABG) and whether lungs were transplanted from each subject. Additional 
demographic and clinical data on donors were then abstracted from the OPO donor management 
databases following the Scientific Registry of Transplant Recipients (SRTR) standard data variables (used 
to calculate expected organ utilization rates). This additional data included important covariates used 
for adjustment of our primary and secondary endpoints, including donor age, blood type, smoking 
history, and positive serologies that could impact lung utilization.  
Based on limited available data, we estimated that naloxone would increase PFR compared to placebo 
by at least 25 mm Hg.11 This resulted in a sample size of 100 subjects per group required to provide 80% 
power to detect such an effect size. Effect of randomization group (naloxone vs. placebo) was analyzed 
using Mann-Whitney U test for PFR and Chi-square test for rate of lungs transplanted. Binary logistic 
regression was utilized to adjust the effect of treatment group for relevant covariates. Analysis of 
variance was used to evaluate for between OPO differences. Primary analyses were performed using 
intention-to-treat principles, but we also evaluated outcomes in a per-protocol analysis including only 
donors with baseline hypoxemia who received study drug as planned.