Conditions: Staphylococcus Aureus
Keywords: MRSA healthcare-associated infections mupirocin iodophor resistance
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 353323
Healthy volunteers: no

Brief summary:
The Swap Out Trial is a cluster randomized controlled trial of HCA hospitals, evaluating the non-inferiority of two decolonization regimens:

Arm 1 Routine Care: ICU nasal decolonization with mupirocin twice daily for 5 days in the context of chlorhexidine for daily bathing; Arm 2 Intervention: ICU nasal decolonization with iodophor twice daily for 5 days in the context of chlorhexidine for daily bathing Note: that enrolled "subjects" represents 137 individual HCA Hospitals (representing \~235 ICUs) that have been randomized.

Detailed description:

Arms:
arm 1: ICU nasal decolonization with mupirocin twice daily for 5 days in the context of chlorhexidine for daily bathing arm 2: ICU nasal decolonization with iodophor twice daily for 5 days in the context of chlorhexidine for daily bathing

Interventions: intervention 1: Arm 1. Routine Care (Mupirocin/CHG) intervention 2: Arm 2. Iodophor/CHG Decolonization
Intervention descriptions: intervention 1: The intervention / decolonization regimen will consist of 5 days of topical intranasal mupirocin ointment (bilateral nares, twice daily) on ICU admission, in the context of continued daily baths with 2% chlorhexidine cloths. intervention 2: The intervention / decolonization regimen will consist of 5 days of topical intranasal iodophor (10% povidone-iodine nasal swabs) (bilateral nares, twice daily) on ICU admission, in the context of continued daily baths with 2% chlorhexidine cloths.

Protocol document:
Prot_002.pdf: 
 
Nasal Iodophor Antiseptic vs Nasal Mupirocin Antibiotic in the Setting of Chlorhexidine 
Bathing to Prevent Infections in Adult ICUS: A Randomized Clinical Trial 
NCT#: 03140423 
 
4/28/2017 
 
 


1 
 
Mupirocin-Iodophor Swap Out Trial - Protocol 
 
Conduct a cluster-randomized non-inferiority trial comparing mupirocin vs iodophor for nasal 
decolonization of ICU patients on S. aureus clinical cultures and all-cause bloodstream infection in the 
setting of routine chlorhexidine bathing (Mupirocin-Iodophor Swap Out Trial). 
 
1.1 Significance and Innovation 
Intensive care units (ICUs) have one of the highest rates of healthcare-associated infections due the 
patients’ severity of illness and frequent use of medical devices.1 2 3 We previously conducted a cluster-
randomized trial of decolonization in adult ICUs (REDUCE MRSA Trial) in the Hospital Corporation of America 
(HCA) health system.4 We showed that ICUs using chlorhexidine (CHG) antiseptic for routine daily bathing and 
mupirocin antibiotic for nasal decolonization of all admissions experienced a 37% reduction in methicillin-
resistant Staphylococcus aureus (MRSA) clinical cultures and a 44% reduction in all-cause bloodstream 
infection. Nasal mupirocin has been shown to be important because CHG does not clear the nasal reservoir of 
S. aureus, one of the most common and virulent healthcare-associated pathogens.5 6 7  
In response to the REDUCE MRSA Trial and other clinical trials,4 8 9 ICU decolonization has been 
adopted throughout HCA’s ICUs and broadly across the United States. However, despite evidence showing 
that the combination of mupirocin and CHG is effective in reducing all-pathogen ICU infection as well as S. 
aureus carriage and infection,4 10 11 12 many hospitals outside HCA are omitting mupirocin due to concerns of 
eliciting mupirocin resistance. We found an increase in mupirocin resistance from 10% to 17% during the 18 
month period of the REDUCE MRSA trial,13 and others have reported high rates of resistance in clinical 
settings.14 15 16 17 18 19 
Alternative agents that do not readily engender resistance to mupirocin but prevent infections are thus 
needed. This phenomenon of resistance emerging with use has been observed for many antibiotics. In 
contrast, antiseptics, such as alcohol, iodophor, and CHG, have not been shown to engender clinically 
meaningful resistance, likely due to their small molecular size.20 21 22 23 17 18 19 20 24 We did not identify CHG 
resistance in the REDUCE MRSA Trial,14 and prior studies evaluating antiseptics versus antibiotics for 
prevention of urinary tract infection or otitis media have found no evidence of antiseptic resistance.25 26 Of 
specific relevance to this study, iodophor resistance has not been reported despite over 50 years of use in 
healthcare and households.  
In this aim, we evaluate the ability of a nasal antiseptic to perform similarly to mupirocin when used in 
combination with CHG for universal ICU decolonization. This trial will be the first large-scale comparison of 
intranasal antibiotic vs. antiseptic as components of a standard decolonization regimen with CHG. It will be 
conducted as a pragmatic comparative effectiveness trial in over 100 community hospitals, and thus have 
immediate applicability to the most U.S. hospitals.  
 
1.2 Approach 
1.2.1 Study Population 
This trial is based in the HCA Healthcare (formerly Hospital Corporation of America) system, which is 
the largest private inpatient provider in the U.S., including over 168 hospitals across 23 states in the US and 
areas in the United Kingdom. Hospitals are predominantly community-based, although they range in size from 
small facilities to large complex tertiary medical centers. HCA supports an annual volume of 2 million US 
admissions and 8 million emergency department visits. Overall, 1 in 20 admissions in the U.S. occurs in an 
HCA facility.  
 
The Mupirocin-Iodophor Swap Out trial will focus on the study population of patients in adult intensive 
care units (ICUs) in HCA hospitals. All U.S. HCA hospitals with an adult ICU will be eligible to participate. 
Exclusion criteria include ICUs with an average length of stay of less than 2 days, and HCA hospitals that are 
not able to transfer or merge data into the centralized data warehouse for the baseline and intervention periods 
of the study (e.g. newly-acquired hospital that lack baseline data or hospitals not using MEDITECH as an 
electronic health system platform). The latter exclusion only applies to a small number of facilities, mostly those 
who were newly-acquired. 
 
1.2.2 Study Design  
As mentioned above, the HCA health system adopted universal ICU decolonization for adult ICUs in 
response to the results of the REDUCE MRSA Trial. HCA corporate guidance to their hospitals espouses use 


2 
 
of twice daily nasal mupirocin for the first 5 days of an ICU stay and daily chlorhexidine bathing for the duration 
of the ICU stay. The corporate campaign launched in Spring of 2013 with high compliance adoption by July 
2013. Subsequent HCA evaluations demonstrated a 24% reduction in health system ICU central line 
associated bloodstream infections attributable to universal ICU decolonization.27 
In this context, we will conduct a two-arm 18-month non-inferiority cluster randomized controlled trial of 
HCA hospitals, evaluating two regimens. Hospitals randomized to Arm 1 will be assigned to the mupirocin-
based usual care regimen for adult ICUs in the HCA health system. This will involve universal decolonization 
for all admitted patients using ICU-wide daily bathing with 2% chlorhexidine cloths for the duration of the ICU 
stay plus topical intranasal mupirocin ointment (bilateral nares) for the first five days of the ICU stay. Hospitals 
will be provided with re-training of HCA’s corporate guidance for this regimen and adherence will be tracked. 
Half of participating hospitals (minimum sample size of 60 hospitals) will be assigned this arm. We anticipate 
an average of 1.75 adult ICUs per hospital, or at least 105 ICUs in this arm. 
Hospitals randomized to Arm 2 will be assigned to the iodophor-based regimen for adult ICUs in the 
HCA health system. This will involve universal decolonization for all admitted patients using ICU-wide daily 
bathing with 2% chlorhexidine cloths for the duration of the ICU stay plus topical intranasal iodophor (10% 
povidone-iodine to bilateral nares) for the first five days of the ICU stay. Hospitals will be provided with re-
training of HCA’s corporate guidance for CHG bathing plus new training for the use of nasal iodophor. 
Adherence will be tracked. Half of participating hospitals (minimum sample size of 60 hospitals) will be 
assigned this arm. We anticipate an average of 1.75 adult ICUs per hospital, or at least 105 ICUs in this arm. 
Thus, both arms will implement some form of universal decolonization during the ICU stay.  The 
protocol will involve discontinuation of the regimen upon ICU discharge, regardless of whether the full 
intervention therapy had been applied during the ICU stay. 
 
    Table 1. Mupirocin-Iodophor Swap Out Trial Design Characteristics and Outcomes 
Study Design 
Cluster-randomized non-inferiority clinical trial 
Unit of Randomization 
Hospitals (all ICUs in a hospital will be assigned to the same regimen*) 
Study Population 
Adult ICU patients in participating HCA hospitals  
Inclusion Criteria 
Hospitals with at least 1 adult ICU, stable infection prevention initiatives and products during 
baseline period, agreement to refrain from new initiatives conflicting with the trial 
Exclusion Criteria 
ICUs with mean length-of-stay of less than 2 days. HCA hospitals having an electronic 
health record other than MEDITECH.  
Group Assignments 
 Arm 1 (N=60 hospitals) 
 Arm 2 (N=60 hospitals) 
 
Routine care: ICU decolonization with daily CHG baths and mupirocin for 5 days, twice daily 
Intervention: ICU decolonization with daily CHG baths and iodophor for 5 days, twice daily 
Study Period 
24-Month Baseline Period (Retrospective Data): May 2015 – Apr 2017 
4-Month Training and Phase In Period: May – Oct 2017 (not included in analysis) 
18-Month Intervention Period: Nov 2017 – Apr 2019 
Primary Outcome 
ICU-attributable S. aureus clinical cultures (MRSA + MSSA) 
Secondary Outcomes 
ICU attributable MRSA clinical cultures; 
ICU-attributable all-cause bloodstream infection; 
* patient-level data will be analyzed by hospital 
 
This trial will be registered with Clinicaltrials.gov, following approval by the Harvard Pilgrim Health Care 
Institutional Review Board, but prior to intervention launch. 
Randomization will occur on the hospital level. All adult ICUs in a given hospital will be assigned to the 
same regimen (Figure 1).  
 
Figure 1: Study Arms of Mupirocin-Iodophor Swap Out Trial 
 
 
 
 
 
 
 
Arm 1: Usual Care Mupirocin and Usual Care CHG (N=60) 
Universal decolonization in All Adult ICUs with 
CHG for bathing and Mupirocin for nasal decolonization 
Current HCA guidance: 
Universal decolonization 
(mupirocin-CHG) 
in all adult ICUs 
Arm 2: Nasal Iodophor and Usual Care CHG (N=60) 
Universal decolonization in All Adult ICUs with 
CHG for bathing and Iodophor for nasal decolonization 


3 
 
1.2.3 Steering Committee  
This trial will be governed by a Steering Committee that is composed of the following representatives (Table 2). 
This steering committee will be responsible for the design and conduct of this trial. 
  
Table 2. Steering Committee Members  
Institution 
Member 
Title/Expertise 
Hospital Corporation of America 
 
 
 
Kenneth Sands, MD, MPH 
Chief Epidemiologist and Chief Patient Safety 
Officer 
 
Russell Poland, PhD 
Assistant Vice President Research and 
Scientific Communications 
 
Julia Moody, MS 
Director, Infection Prevention  
CDC Prevention Epicenters 
 
 
     Harvard Pilgrim Health Care 
Richard Platt, MD MS (PI) 
Senior Investigator, Professor and Chair, Dept 
of Population Medicine  
 
Ed Septimus, MD 
Lecturer, Harvard Medical School 
Professor, Texas A&M Medical School 
Former Medical Director of Infection Prevention 
and Epidemiology Clinical Services Group, 
Hospital Corporation of America 
     UC Irvine 
Susan Huang, MD MPH (Co-PI) 
Lead Investigator; Professor and Hospital 
Epidemiologist 
     U Mass Amherst 
Ken Kleinman, PhD 
Statistician, Professor, Biostatistics 
     Stroger Hospital Cook County/  
     Rush Medical School 
Robert Weinstein, MD (PI) 
Professor of Medicine, Infectious Diseases; 
Expertise in chlorhexidine and HAI  
 
Mary Hayden, MD  
Professor of Medicine (Infectious Diseases) and 
Pathology; Expertise in microbiology 
Centers for Disease Control and 
Prevention (CDC) 
John Jernigan, MD MPH 
Division of Healthcare Quality Promotion; 
Program lead for CDC Prevention Epicenters 
 
1.2.4 Recruitment 
HCA hospitals will be recruited by HCA staff using their usual infrastructure for seeking participants for 
system-wide quality improvement projects. In particular, recruitment will be performed under the direction of Ed 
Septimus, MD (Medical Director, Infection Prevention), Julia Moody, MS (Director, Infection Prevention and 
Control), and Jason Hickok, MBA RN (Asst Vice President, Laboratory, Infection Prevention, and Research), 
with the support of Jonathan Perlin MD PhD, Chief Medical Officer of HCA. HCA health system is divided into 
two Groups (National and American), which in turn are divided into geographic divisions. Recruitment will be 
encouraged by HCA Group Presidents and HCA Division leadership. 
Hospitals recruited as participants will be provided with the trial design and a description of both arms 
of the study. They will agree to be randomized and to implement their assigned protocol. An attestation letter 
confirming commitment to the trial will be signed by the Chief Executive Officer of each participating hospital. 
We will use a centralized IRB structure with each participating hospital ceding to the Harvard Pilgrim Health 
Care IRB. 
 
1.2.5 Randomization 
Randomization will occur during Spring 2017 and participating hospitals will be notified. This will be 
done because of the requisite 3-5 month period to submit and schedule the approval of intervention protocols 
by relevant hospital committees which often meet monthly or quarterly. As per routine policy in all hospitals, no 
training or implementation activities may occur prior to obtaining requisite hospital committee approvals. This 
will allow approval to occur and appropriate training of staff to occur prior to the phase in period which will 
involve acquisition and introduction of intervention product. 
While this study is one of the largest cluster-randomized trials of hospitals, simple randomization of 120 
hospitals will not ensure balance of key variables by chance alone, and without care could even result in very 
unequal numbers of hospitals in each arm. Achieving balance on key features of the randomization units (in 
this case, hospitals) is a critical task in cluster-randomized trials, but little literature on it exists. Unlike 
individually-randomized trials, information about the clusters is often known in advance, but the number of 
clusters to be randomized can be relatively small. The existence of a priori data can mitigate the small 
numbers and help to obtain adequate balance through stratification or other methods. One attractive approach 
is to establish tuplets—matched sets (pairs, for a two-arm trial) – in which one member of each tuplet is 


4 
 
assigned to each arm. Schemes for constructing tuplets need not be guided by theory. A formal approach 
would be to calculate the Mahalanobis distance between hospitals across all key variables and choose the set 
of tuplets with the minimum average distance. In this approach, we could standardize the variables, and then 
multiply by values calibrated to reflect any difference in the importance of balancing them. Other approaches 
are more ad hoc, such as prioritizing broad classes of balance on a key variable and making pairs within these 
strata based on lower-priority variables. However, there is no “best” method of tuplet construction, only sets 
that come closer to meeting the varied needs of each trial.  
We will use methods to inform the choice of tuplet-construction scheme which we previously developed 
in the REDUCE MRSA trial. We will establish the pairs under several plausible tuplet-construction schemes, 
and use graphical methods to compare all possible realizations for balance between the arms under each 
scheme. For example, if two variables were to be balanced, we would tentatively divide the sample into two 
groups under a tuplet construction scheme and then generate a scatterplot showing the between-arm absolute 
value of the mean difference for one variable on the x-axis and the second on the y-axis for each possible 
result of the randomization. We would then divide the groups again under the same scheme, and find another 
point on the scatterplot. Repeating many times would show the typical and distribution of balance under a 
scheme. Comparing the resulting scatterplots from each tuplet-construction scheme can reveal the relative 
risks of imbalance and benefits for balance accruing to each randomization scheme, in a practical sense. One 
tuplet construction method may result in generally close balance on one key characteristic and very variable 
balance on the other, while a competing scheme has good median balance on both characteristics, but where 
each has a long tail implying a few bad-luck assignments with poor balance.  
We hope to consider balance on more than two factors, and for assessing the impact on balance in this 
case, we will use a parallel coordinates plot, a multivariate plot method. A simulated example is shown in 
Figure 2. There we show a potential result of a single tuplet construction method. The variables shown are 
volume, baseline rate of an outcome, the baseline rate of chlorhexidine use, and baseline rate of bathing. Each 
blue, red, green, or black line shows the mean difference between arms for all four variables for one potential 
realized randomization. The results show that a few randomizations, in blue, are relatively imbalanced on 
volume and outcome but balanced on chlorhexidine use and bathing, while a few others, in black, have the 
reverse pattern. The green and red realizations are approximately equally balanced across these variables. If 
we considered it more important to balance on volume and outcome, this would probably not be an ideal 
scheme.  
 
Figure 2.  
 
 
As a final note, we could consider the relative costs and benefits of strata of four, rather than tuplets, 
which are strata of two. There are sound statistical reasons to expect power to be slightly better with strata of 
four, although there is some debate on this point.  However, the balance between the arms may be worse. The 
balance is of central importance, since balance ensures that the observed effect is not confounded—
confounding requires that the confounder be out of balance between the arms. We will examine whether the 


5 
 
gain in power is strong enough, and the loss of balance slight enough, to pursue strata of four in place of 
tuplets.  
We will focus on balancing the baseline outcome values in participating hospitals, baseline adherence 
to the HCA guidance for universal decolonization with chlorhexidine and mupirocin, measures of case severity 
index, and ICU patient day volume. We will additionally consider accounting for demographics, and ICU length 
of stay. 
 
1.2.6 Phase In Timeline 
 
Trial implementation timeline is shown in Table 3. 
 
     Table 3. Implementation Timeline 
Process 
Timeline 
Collect Baseline Data 
Data collection, cleaning, and derivation of randomization variables and 
confirmation of power occurs Summer 2016-Spring 2017 
Randomization 
Randomization will occur in Spring 2017  
Notification 
Hospitals notified of randomization status to schedule the relevant hospital 
committees for approval 
Committee Approvals 
Jan-Mar 2017 
Training 
Prior to phase-in, coaching calls, training materials and computer-based 
training will be launched  
Phase In Launch 
May-October 2017: Implementation of nasal iodophor in intervention arm. Both 
arms: pharmacy tracking of nasal decolonization product and feedback reports  
Intervention Period 
November 2017 – April 2019  
 
Both arms will be provided with training and coaching conference calls and study campaign materials (Table 
4). All training and coaching scripts as well as intervention materials will be designed by the Steering 
Committee, which will meet weekly during the trial. Strategies will heavily favor mechanisms that utilize HCA’s 
current infrastructure for performance improvement and quality improvement projects. 
 
    Table 4. Intervention Elements 
Type of Element 
Leader 
Frequency/Comments 
Coaching Conference Calls 
Investigators 
Monthly during intervention 
Intervention Tool Kit 
 
 
   Campaign flyers 
Developed by Investigators/study staff 
 
   Powerpoint materials 
Developed by Investigators/study staff 
 
   Instructional materials 
Developed by Investigators/study staff 
 
Help line 
HCA leaders, study staff 
 
 
All training calls will be led by study investigators, Dr. Susan Huang (lead investigator) and Dr. Edward 
Septimus (site PI for HCA). Campaign materials will be disseminated at the start of the phase-in period, and 
will include an information packet as well as flyers and web-based information.  
 
1.2.7 Implementation 
 
Intranasal iodophor will be implemented in the intervention arm using an admission order set similar to 
the current HCA process for universal mupirocin. This arm will receive iodophor product and training during the 
Phase-In Period (Table 5). The routine care arm will receive refresher training for mupirocin and support for 
admission order processes during that period to ensure that differential compliance is not a driver of trial 
results. Both arms will receive refresher training in CHG bathing and processes.  
 
Table 5. Mupirocin-Iodophor Swap Out Trial Protocol Training Materials 
Protocol Training 
Description 
1. 
Computer Based Training 
Arm-specific protocol training module required of all staff in participating units 
2. 
Nursing Protocol 
Nursing protocol for use of mupirocin vs. iodophor 
3. 
Dos and Don’ts 
Quick reference protocol guide  
4. 
Patient Talking Points 
Talking points for common patient questions about the assigned protocol 
5. 
Frequently Asked Questions 
Staff answers to common patient questions about the protocol 
6. 
Huddle Training 
Periodic refresher training on key protocol points 
7. 
Just in Time Training 
On-the-spot training and reference guide for temporary/float nurses 
8. 
Study Related Events  
Forms for reporting study related events (iodophor) and side effects (mupirocin) 


6 
 
 
Toolkit binders with trial instructions and protocols will be provided to each unit nursing and medical director, 
infection prevention program lead, nurse education team, and Chief Nursing Officer for each participating 
hospital in each arm.  
Feedback on compliance will be provided to each hospital. Usual care hospitals will receive at least 
monthly compliance data on daily chlorhexidine bathing and use of nasal mupirocin. Iodophor-CHG hospitals 
will receive at least monthly compliance feedback on daily chlorhexidine bathing and use of nasal iodophor. 
 
Staff skills assessment forms (bathing observation checklist) will be used by peer nurses or the unit 
nursing director to ensure adherence to the assigned protocol. Nurses in HCA hospitals currently document 
bathing activities each shift. We will use this electronic documentation for compliance tracking of whether a 
CHG bath or shower was given. Compliance with nasal decolonization will be tracked through patient and unit-
specific automated pharmacy reports for administration of either product. Compliance will be assessed and fed 
back to unit champions during twice-monthly coaching calls with a goal of 85% compliance, a level we have 
previously achieved in this population. Periodic maintenance reminders will be provided in both arms and will 
reflect common lapses identified by ongoing compliance assessments.  
Study investigators will perform site visits as needed to various participating hospitals based upon 
requests for assistance, concerns about application of intervention protocols, or evidence of low compliance. 
These procedures are comparable to those used by HCA when implementing other Quality Improvement 
protocols. Oversight for the design and conduct of this trial will be provided by the Steering Committee (see 
above), which will meet weekly.  
 
1.2.8 Nasal Iodophor 
Nasal iodophor will be used for the nasal decolonization regimen for hospitals randomized to Arm 2 
(Iodophor arm), using Clorox Nasal Antiseptic Swabs, a 10% povidone-iodine product. This product is FDA 
cleared for use in the nose and the manufacturer has released guidance for routine use for decolonization. 
Thus, the use of povidone-iodine swabs in the Swap Out Trial is to apply one swab in a circular motion to each 
nostril for 30 seconds, twice daily for 5 days.   
Clorox Nasal Antiseptic Swabs has a separate set of directions for pre-operative nasal decolonization, 
which continues to use double the dose for a one-time application. Participating sites will be trained to ensure 
that they are aware of the differences in manufacturer guidance for routine ICU decolonization vs pre-operative 
indications which requires application of two swabs per nostril.  
 
1.2.9 Likelihood of Study-Related Events 
Regarding safety, we note that 10% iodophor has been the national standard of care for pre-surgical 
preparation for surgery for decades, including on mucous membranes of the nose and throat. It is also used for 
nasal decolonization prior to joint surgery, where it has been shown to be better tolerated than mupirocin.28  
The evidence for anaphylaxis for iodophor has been specifically related to contrast dye where an 
iodine-containing substance is injected directly into the bloodstream. This type of adverse event carries a 1% 
risk for direct injection into the bloodstream and is exceedingly rare in the use of iodophor for mucous 
membranes (so rare that estimates of frequency are not available). 
In addition, as part of a pilot decolonization intervention study, povidone-iodine nasal antiseptic swabs 
were applied to residents in three southern California nursing homes for 6 months. Two swabs were applied in 
a circular motion to each nostril, twice daily for 5 days every other week (total of 13 weeks of application to 
residents). Accounting for facility census and protocol adherence, a total of 22,020 applications were 
administered across all three facilities without any adverse events reported.29-30 We note that this pilot involved 
a contributed product from 3M, which was 5% povidone iodine swabs (also FDA cleared for nasal use). 
After the above pilot, as part of routine quality improvement, one of the nursing homes continued the 
use of nasal iodophor, but changed to a 10% povidone-iodine product (Clorox) and used one swab per nostril 
per application instead of 2 swabs per nostril per application. This was due to the fact that nursing staff felt that 
the two-swab-per-nostril regimen was redundant in application. Accounting for facility census and protocol 
adherence, a total of 1,987 applications were administered without any report of adverse events. Given the 
interest in a simpler regimen, we asked to evaluate whether the effect on nasal decolonization of S. aureus 
was similar between the prior 5% povidone-iodine two-swab regimen and the 10% one-swab povidone-iodine 
swab regimen. Nasal and skin cultures were taken from residents confirmed nearly identical reductions in 
MRSA with the 5% povidone-iodine two-swab regimen and the 10% one-swab povidone-iodine swab regimen.  


7 
 
1.2.10 Monitoring Study-Related Events 
 
To monitor the occurrence of study-related events, a Study-Related Events Submission Form will be 
provided to Arm 2 facilities to document all events possibly related to use of iodophor, as part of study 
procedures. Clinical staff will be required to provide specific details regarding the event such as the body parts 
affected, the agent related to the event, a description of the reaction, and the corrective action that was taken 
to resolve the event. Clinical staff will be instructed to report all events to their designated nurse manager or 
director who will securely fax Study-Related Event Forms (iodophor). All clinical decision-making related to 
study related events will be at the discretion of the treating physician, not trial investigators or study staff, as is 
routine for quality improvement protocols.  
Facilities will be asked to submit Study-Related Event Submission Forms as events are found. We will 
use our regular trial coaching calls to prompt facilities to report on schedule. Call attendance will be tracked. In 
the event that a facility is unable to attend, study staff will follow up to obtain a status update. A database will 
be used to document reported study-related events that take place in participating facilities. This tool will 
enable the project staff to closely track and assess any events deemed to be associated with the trial. The user 
will be able to document specific details regarding the event, and it will allow the user to keep a case open if 
the event is ongoing or close a case if the event is resolved.  
Additionally, a Side-Effects Form for mupirocin-related events will be provided to Arm 1 facilities. 
Clinical staff at Arm 1 facilities will be asked to document and report all events possibly related to use of 
mupirocin, providing the same type of information as requested in the iodophor form. While nasal mupirocin is 
not part of the intervention, this information is requested so that the frequency and severity of mupirocin-related 
events can be compared to that of iodophor.  
 
1.2.11 Outcomes  
Individual level data from patients in all participating ICUs will be obtained from the HCA corporate data 
warehouse, including demographics, census (including ICU patient days), bathing queries, pharmacy (nasal 
decolonization product administration), diagnostic and procedure codes (enabling comorbidity score 
assessment), and microbiology testing results.  
The primary outcome will be S. aureus clinical cultures (MRSA and MSSA) attributed to the 
participating ICU (>2 days into the ICU stay until 2 days after ICU discharge). Secondary outcomes intended 
for primary manuscript, include: 1) ICU-attributable MRSA clinical cultures, 2) ICU-attributable all-cause 
bloodstream infection.  
Table 6. Mupirocin-Iodophor Swap Out Trial Outcomes 
Outcome 
Metric 
Primary Trial Outcome 
ICU-attributable S. aureus clinical cultures (MRSA + MSSA) 
Secondary Trial Outcomes 
 
ICU-attributable MRSA clinical cultures 
ICU-attributable all-cause bloodstream infection 
 
1.2.12 Data Collection 
Descriptive data, outcome data and variables for addressing confounding will be derived from 
microbiology, census, pharmacy, and claims data from participating hospitals. The following data elements will 
be collected (Table 6) using encrypted study IDs. 
 
    Table 6. Data Elements  
Source Data 
Result Types 
Elements 
Microbiology:  
Finalized Results 
All positive and negative 
cultures 
Pathogen name (if culture is positive), patient identifier, date of 
collection, body site of collection, antimicrobial susceptibility 
Census Data 
Line item per admission 
Patient identifier, hospital admission date, hospital discharge 
date, ICU vs. non-ICU charge code by calendar date, age in 
years, gender  
Claims Data  
Line item per admission 
For case mix adjustment: 
Diagnosis codes (ICD9-ICD10) 
Procedure codes (ICD9/ICD10/CPT codes)  
Pharmacy 
Mupirocin and iodophor 
dispensing 
Patient identifier, date range dispensed, ICU location 


8 
 
Nursing Queries 
Bathing responses 
Data on whether a bath was given, and if yes, with a CHG or 
non-CHG bathing soap product. 
 
We will use claims data to collect diagnostic and procedure codes that will be used for case mix adjustment for 
both hospital-wide, ICU-specific, and post-ICU outcomes. Case mix will be assessed using a comorbidity score 
(e.g. Elixhauser score) as well as evaluating the individual components of that score (e.g. diabetes, renal 
disease) and evidence of major surgery. 
 
1.2.13 Statistical Analysis and Power 
The primary analysis will be an as-randomized proportional hazards model to evaluate for noninferiority 
at a margin of 10% (difference in relative hazard). Model terms will include arm, period (baseline vs. 
intervention) and an arm by period interaction term to assess whether the difference in relative hazard between 
the baseline and intervention period differs significantly between the two arms. Clustering within hospital will be 
accounted for using shared frailties, i.e., a random intercept for each hospital, and, if it should become 
technologically feasible, an additional random intercept for each ICU within hospital and for repeated hospital 
stays for each person.   
• 
Null hypothesis (H0): the change in relative hazard of clinical culture of S. aureus in the 
Iodophor-CHG arm is higher than (inferior to) the change in the Mupirocin-CHG arm by more 
than 10%  
• 
Alternative hypothesis (H1): the change in relative hazard of clinical culture of S. aureus in the 
Iodophor-CHG arm is higher than (inferior to) the Mupirocin-CHG arm by 10% or less 
 
Phase-in period data will not be included in the analysis.  
To be explicit, the primary analysis will take the form of 𝜆𝜆𝑖𝑖𝑖𝑖(𝑡𝑡) = 𝜆𝜆0(𝑡𝑡)𝑒𝑒𝛽𝛽1𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖+𝛽𝛽2𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖+𝛽𝛽3𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖∗𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖+𝛾𝛾𝑖𝑖  
where 𝜆𝜆𝑖𝑖𝑖𝑖(𝑡𝑡) is the time 𝑡𝑡 of the S. aureus clinical culture for person 𝑗𝑗 at hospital 𝑖𝑖. The baseline hazard 
function for time 𝑡𝑡, 𝜆𝜆0(𝑡𝑡), is shared by all people; 𝛾𝛾𝑖𝑖is the frailty shared by patients at hospital 𝑖𝑖. The linear 
predictor in the exponent functions as in a linear model, where 𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖 indicates the treatment arm of person 𝑗𝑗 
in hospital 𝑖𝑖 is the iodophor arm, and 𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖 indicates that person 𝑗𝑗 in hospital 𝑖𝑖 was seen in the intervention 
period. Thus 𝛽𝛽3 is the estimated differential effect of iodophor relative to mupirocin in the intervention period 
compared to baseline. While software is currently not able to include frailties for multiple visits per person or for 
multiple ICUs per hospital on the scale of the data, we will include them if this should become possible by the 
time the trial is analyzed. 
 
The primary outcome of the trial is ICU-attributable S. aureus clinical cultures (MRSA + MSSA) where 
ICU-attributable is defined as S. aureus cultures occurring in specimens collected from study cohort patients 
from the 3rd day of an ICU stay through 2 days after ICU discharge. This outcome will be assessed using an 
as-randomized unadjusted proportional hazards model as described above with two-sided significance set at 
alpha = 0.05, consistent with FDA standards of non-inferiority (https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/non-inferiority-clinical-trials). The pre-specified non-inferiority 
margin, we repeat, is 10%. 
 
There is reason to suspect that nasal iodophor may be inferior to mupirocin due to FDA clearance 
based upon suppression versus cidal kill for S. aureus, which is the reason for the non-inferiority trial. 
However, conversely, if iodophor is found to be non-inferior, we are declaring the a priori intent to assess for 
superiority because of evidence of mupirocin-resistant S. aureus strains where none is expected to exist for 
iodophor. For this reason, if iodophor is found to be non-inferior in the primary outcome of the trial, we will also 
report the pre-specified assessment of superiority which is already performed in the primary analysis. 
 
Secondary non-inferiority outcomes include 1) ICU-attributable MRSA clinical cultures and 2) ICU-
attributable all-cause bloodstream infection. These will be assessed using an as-randomized unadjusted 
proportional hazards model as described above.  We will use two-sided significance tests set at alpha = 0.05 
for each outcome to determine possible inferiority with greatest possible sensitivity, again with a non-inferiority 
margin of 10%. Due to the above antibiotic-resistance rationale to suspect possible superiority, if non-inferiority 
is met for these secondary outcomes, we will perform a pre-specified assessment of superiority at a two-tailed 
significance set at alpha = 0.025, which accounts for the multiple comparisons of two outcomes. To be clear, 
the non-inferiority tests are not adjusted for multiple testing, while the superiority tests, if they are performed, 
will be adjusted for multiple testing, for conservatism. 


9 
 
 
Additional analyses will include as-treated and adjusted models, which will be reported as point 
estimates with confidence intervals without p-values. The reason for including these analyses is to provide 
additional information related to the trial outcomes for reader assessment of potential confounders. The reason 
to not include them in a formal multiple comparisons adjustment is because these analyses are non-
independent evaluations related to the as-randomized unadjusted analyses.  
While 140 HCA hospitals are eligible for recruitment, we have HCA corporate commitment to assure 
the participation of at least 120 hospitals.  Power was assessed using simulation methods.  We simulated 
hospitals using information from HCA regarding ICU size and from a prior trial (REDUCE MRSA Trial) 
regarding likely rates of S. aureus in the baseline period.   With 120 hospitals, we will have 82% power to 
detect non-inferiority within a hazard ratio of 1.1, based upon 2014 HCA ICU-attributable S. aureus clinical 
cultures of 4.8 cases per 1,000 ICU-days. While the intent is to confirm non-inferiority, we assume that 
iodophor will eradicate 5% more S. aureus than mupirocin due to existing mupirocin resistance. We estimate 
that total ICU patients in the intervention period will be ~171,500 patients who stay >2 ICU days. 
 
 
 
 


10 
 
References 
 
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Associated Infections Program. Targeted versus universal decolonization to prevent ICU infection. N Engl J 
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Climo MW, Yokoe DS, Warren DK, Perl TM, Bolon M, Herwaldt LA, Weinstein RA, Sepkowitz KA, Jernigan 
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10  Schweizer ML, Chiang HY, Septimus E, Moody J, Braun B, Hafner J, Ward MA, Hickok J, Perencevich EN, 
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with surgical site infections among patients undergoing cardiac, hip, or knee surgery. JAMA. 2015 Jun 
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11  O'Grady S, Hirji Z, Pejcic-Karapetrovic B, Fung S, Dedier H, Takata-Shewchuk J, Zhang K, Conly J. A 
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12  Bode LG, Kluytmans JA, Wertheim HF, Bogaers D, Vandenbroucke-Grauls CM, Roosendaal R, Troelstra 
A, Box AT, Voss A, van der Tweel I, van Belkum A,Verbrugh HA, Vos MC. Preventing surgical-site 
infections in nasal carriers of Staphylococcus aureus. N Engl J Med. 2010 Jan 7;362(1):9-17.  
13  Lolans K, Haffenreffer K, Avery TR, Kleinman K, Li H, Kaganov RE, Lankiewicz J, Moody J, Septimus E, 
Weinstein RA, Hickok J, Jernigan J, Perlin JB, Huang SS, Platt R, Hayden MK. Chlorhexidine (CHG) and 
mupirocin susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) isolates in the REDUCE-
MRSA trial. IDWeek: A Joint Meeting of the Infectious Disease Society of America, Society for Healthcare 
Epidemiology of America, HIV Medicine Association, and the Pediatric Infectious Disease Society. 
Philadelphia, PA. October 8-12, 2014. 
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15  Robicsek A, Beaumont JL, Thomson RB, Govindarajan G, Peterson LR. Topical therapy for methicillin-
resistant Staphylococcus aureus colonization: impact on infection risk. Infect Control Hosp Epidemiol 
2009;30:623-32. 
16  Upton A, Lang S, Heffernan H. Mupirocin and Staphylococcus aureus: a recent paradigm of emerging 
antibiotic resistance. J Antimicrob Chemother 2003;51: 613-7. 
17  Vivoni AM, Santos KR, de-Oliveira MP, Giambiagi-deMarval M, Ferreira AL, Riley LW, Moreira BM. 
Mupirocin for controlling methicillin-resistant Staphylococcus aureus: lessons from a decade of use at a 
university hospital. Infect Control Hosp Epidemiol. 2005 Jul;26(7):662-7. 


11 
 
 
18  Harbarth S, Dharan S, Liassine N, Herrault P, Auckenthaler R, Pittet D. Randomized, placebo-controlled, 
double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant 
Staphylococcus aureus. Antimicrob Agents Chemother 1999;43:1412-6. 
19  Simor AE, Stuart TL, Louie L, et al. Mupirocin-resistant, methicillin-resistant Staphylococcus aureus strains 
in Canadian hospitals. Antimicrob Agents Chemother 2007;51:3880-6. 
20  Fleischer W, Reimer K. Povidone-iodine in antisepsis--state of the art. Dermatology.1997;195 Suppl 2:3-9. 
21  Sheldon AT Jr. Antiseptic "resistance": real or perceived threat? Clin Infect Dis. 2005 Jun 1;40(11):1650-6. 
22  van Meurs SJ, Gawlitta D, Heemstra KA, Poolman RW, Vogely HC, Kruyt MC. Selection of an optimal 
antiseptic solution for intraoperative irrigation: an in vitro study. J Bone Joint Surg Am. 2014;96(4):285-91. 
23  Reimer K, Wichelhaus TA, Schäfer V, Rudolph P, Kramer A, Wutzler P, Ganzer D, Fleischer W. 
Antimicrobial effectiveness of povidone-iodine and consequences for new application areas. 
Dermatology. 2002;204 Suppl 1:114-20. 
24  Capriotti K, Capriotti JA. Topical iodophor preparations: chemistry, microbiology, and clinical utility. 
Dermatol Online J. 2012;18(11):1. 
25  Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical 
antiseptic versus a topical antibiotic in the treatment of otorrhoea. Clin Otolaryngol Allied Sci. 1990 
Feb;15(1):7-10. 
26  Freeman RB, Smith WM, Richardson JA, Hennelly PJ, Thurm RH, Urner C, Vaillancourt JA, Griep RJ, Bromer L. 
Long-term therapy for chronic bacteriuria in men. U.S. Public Health Service cooperative study. 
Ann Intern Med. 1975 Aug;83(2):133-47. 
27  Septimus E, Hickok J, Moody J, Kleinman K, Avery TR, Huang SS, Platt R, Perlin J. Closing the Translation 
Gap: Toolkit Based Implementation of Universal Decolonization in Adult Intensive Care Units Reduces 
Central Line Associated Bloodstream Infections in 95 Community Hospitals. Clin Infect Dis. 2016 May; 
63(2):172-7. 
28  Maslow J, Hutzler L, Cuff G, Rosenberg A, Phillips M, Bosco J. Patient experience with mupirocin or 
povidone-iodine nasal decolonization. Orthopedics. 2014 Jun;37(6):e576-81.  
29  McKinnell JA,* Miller LG,* Singh R,  Kleinman K, Peterson E,  Evans KD, Dutciuc TD,  Heim L, Gombosev 
A,  Estevez M,  Launer B, Tjoa T,  Tam S,  Bolaris MA, Huang SS. Prevalence and Factors Associated with 
Multidrug Resistant Organism (MDRO) Colonization in Three Nursing Homes. Infect Control Hosp 
Epidemiol. 2016. In press. 
30  Miller LG, McKinnell JA, Singh R, Kleinman K, Gombosev A, Dutciuc T, Evans K, Tjoa T, Heim L, Launer B, 
Bolaris M, Ramsay K, Kim D, Estevez M, Peterson E, Huang SS. Reduction of MDRO Colonization in 
Nursing Home Residents with Routine Use of Chlorhexidine Bathing and Nasal Iodophor (Project 
PROTECT). IDWeek (5th Annual Joint Meeting of IDSA, SHEA, HIVMA, and PIDS), October 26-30, 2016 
(New Orleans, LA). 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Nasal Iodophor Antiseptic vs Nasal Mupirocin Antibiotic in the Setting of Chlorhexidine 
Bathing to Prevent Infections in Adult ICUS: A Randomized Clinical Trial 
NCT#: 03140423 
8/14/2019 


1 
Mupirocin-Iodophor Swap Out Trial 
Statistical Analysis Plan 
Ken Kleinman, ScD 
August 14, 2019 
Background 
Universal decolonization of all adult ICU patients with daily chlorhexidine (CHG) baths is widely 
implemented as ICU standard of care with and without nasal mupirocin due to several trials 
including the REDUCE MRSA Trial. This 43-hospitals trial showed a relative 37% reduction in 
ICU-associated methicillin resistant S. aureus (MRSA) clinical cultures and a relative 44% 
reduction in all-cause bloodstream infections. 
Combined use of CHG with mupirocin is driven by the fact that Staphylococcus aureus is a 
common community and healthcare-associated pathogen responsible for disease in ICU 
settings. Nevertheless, the variability in mupirocin resistance in various geographic areas (near 
zero to >15%) has led intensivists to be circumspect in whether they implement universal CHG 
bathing alone or with universal mupirocin. While the majority of MRSA are still susceptible to 
mupirocin, the concern about whether mupirocin resistance will continue to rise has led to 
interest in finding alternative effective agents. 
For this reason, the Mupirocin-Iodophor Swap Out Trial was undertaken as a cluster 
randomized non-inferiority trial in 137 HCA Healthcare hospitals with hospitals randomized to: 
Arm 1: Mupirocin-CHG (Usual Care) 
Hospitals will continue daily bathing with chlorhexidine plus twice daily intranasal application 
of mupirocin ointment upon admission to all ICUs and continuing for 5 days or until 
discharge from the ICU.  
Arm 2: Iodophor-CHG  
Hospitals will continue daily bathing with chlorhexidine, but switch from mupirocin to twice 
daily intranasal application of 10% povidone-iodine (iodophor).  
Trial Outcomes 
Trial outcomes are found in the below table. 
  Mupirocin-Iodophor Swap Out Trial Outcomes 
Outcome 
Metric 
Primary Trial Outcome 
ICU-attributable S. aureus clinical cultures (MRSA + 
MSSA) 
Secondary Trial Outcomes 
(primary manuscript) 
ICU-attributable MRSA clinical cultures 
ICU-attributable all-cause bloodstream infection 
Other pre-specified secondary 
exploratory analyses for later 
manuscripts 
Mupirocin and iodophor resistance in MRSA isolates 
1


2 
Analysis 
The primary analysis will be an as-randomized proportional hazards model to evaluate for non-
inferiority at a margin of 10% (difference in relative hazard). Model terms will include arm, period 
(baseline vs. intervention) and an arm by period interaction term to assess whether the 
difference in relative hazard between the baseline and intervention period differs significantly 
between the two arms.  Clustering within hospital will be accounted for using shared frailties, 
i.e., a random intercept for each hospital, and, if it should become technologically feasible, an
additional random intercept for each ICU within hospital and for repeated hospital stays for each
person.
•
Null hypothesis (H0): the change in relative hazard of clinical culture of S. aureus in the
Iodophor-CHG arm is higher than (inferior to) the change in the Mupirocin-CHG arm by
more than 10%
•
Alternative hypothesis (H1): the change in relative hazard of clinical culture of S. aureus
in the Iodophor-CHG arm is higher than (inferior to) the Mupirocin-CHG arm by 10% or
less
Phase-in period data will not be included in the analysis. 
To be explicit, the primary analysis will take the form of 𝜆𝜆𝑖𝑖𝑖𝑖(𝑡𝑡) =
𝜆𝜆0(𝑡𝑡)𝑒𝑒𝛽𝛽1𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖+𝛽𝛽2𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖+𝛽𝛽3𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖∗𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖+𝛾𝛾𝑖𝑖  where 𝜆𝜆𝑖𝑖𝑖𝑖(𝑡𝑡) is the time 𝑡𝑡 of the S. aureus clinical 
culture for person 𝑗𝑗 at hospital 𝑖𝑖. The baseline hazard function for time 𝑡𝑡, 𝜆𝜆0(𝑡𝑡), is shared by all 
people; 𝛾𝛾𝑖𝑖is the frailty shared by patients at hospital 𝑖𝑖. The linear predictor in the exponent 
functions as in a linear model, where 𝐴𝐴𝐴𝐴𝑚𝑚𝑖𝑖𝑖𝑖 indicates the treatment arm of person 𝑗𝑗 in hospital 𝑖𝑖 
is the iodophor arm, and 𝑃𝑃𝑃𝑃𝑟𝑟𝑖𝑖𝑖𝑖 indicates that person 𝑗𝑗 in hospital 𝑖𝑖 was seen in the intervention 
period. Thus 𝛽𝛽3 is the estimated differential effect of iodophor relative to mupirocin in the 
intervention period compared to baseline. While software is currently not able to include frailties 
for multiple visits per person or for multiple ICUs per hospital or for multiple periods per hospital 
on the scale of the data, we will include them if this should become possible by the time the trial 
is analyzed. 
The primary outcome of the trial is ICU-attributable S. aureus clinical cultures (MRSA + MSSA) 
where ICU-attributable is defined as S. aureus cultures occurring in specimens collected from 
study cohort patients from the 3rd day of an ICU stay through 2 days after ICU discharge. This 
outcome will be assessed using an as-randomized unadjusted proportional hazards model as 
described above with two-sided significance set at alpha = 0.05, consistent with FDA standards 
of non-inferiority (https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/non-inferiority-clinical-trials). The pre-specified non-inferiority margin, we repeat, is 
10%. 
There is reason to suspect that nasal iodophor may be inferior to mupirocin due to FDA 
clearance based upon suppression versus cidal kill for S. aureus, which is the reason for the 
non-inferiority trial. However, conversely, if iodophor is found to be non-inferior, we are declaring 
the a priori intent to assess for superiority because of evidence of mupirocin-resistant S. aureus 
strains where none is expected to exist for iodophor. For this reason, if iodophor is found to be 
non-inferior in the primary outcome of the trial, we will also report the pre-specified assessment 
of superiority which is already performed in the primary analysis. 
2


3 
Secondary non-inferiority outcomes include 1) ICU-attributable MRSA clinical cultures and 2) 
ICU-attributable all-cause bloodstream infection. These will be assessed using an as-
randomized unadjusted proportional hazards model as described above.  We will use two-sided 
significance tests set at alpha = 0.05 for each outcome to determine possible inferiority with 
greatest possible sensitivity, again with a non-inferiority margin of 10%. Due to the above 
antibiotic-resistance rationale to suspect possible superiority, if non-inferiority is met for these 
secondary outcomes, we will perform a pre-specified assessment of superiority at a two-tailed 
significance set at alpha = 0.025, which accounts for the multiple comparisons of two outcomes. 
To be clear, the non-inferiority tests are not adjusted for multiple testing, while the superiority 
tests, if they are performed, will be adjusted for multiple testing, for conservatism. 
Additional analyses will include as-treated and adjusted models, which will be reported as point 
estimates with confidence intervals without p-values. The reason for including these analyses is 
to provide additional information related to the trial outcomes for reader assessment of potential 
confounders. The reason to not include them in a formal multiple comparisons adjustment is 
because these analyses are non-independent evaluations related to the as-randomized 
unadjusted analyses.  
Power and Sample Size 
While 140 HCA hospitals are eligible for recruitment, we have HCA corporate 
commitment to assure the participation of at least 120 hospitals. Power was assessed using 
simulation methods.  We simulated hospitals using information from HCA regarding ICU size 
and from a prior trial (REDUCE MRSA Trial) regarding likely rates of S. aureus in the baseline 
period. With 120 hospitals, we will have 82% power to detect non-inferiority within a hazard ratio 
of 1.1, based upon 2014 HCA ICU-attributable S. aureus clinical cultures of 4.8 cases per 1,000 
ICU-days. While the intent is to confirm non-inferiority, we assume that iodophor will eradicate 
5% more S. aureus than mupirocin due to existing mupirocin resistance. We estimate that total 
ICU patients in the intervention period will be ~171,500 patients who stay >2 ICU days. 
NOTE: This statistical analytic plan was updated post-completion of the trial, but prior to 
accessing the trial dataset for cleaning or analysis. It was updated in response to the Harrington 
et al. (NEJM 2019;381:285-6) publication on “New Guidelines for Statistical Reporting in the 
Journal.” 
3