Clinical trial NCT03861767
Conditions: Aging
Keywords: Prehabilitation
Sponsor: Matthew Neal MD
Start date: 2019-04-15; Completion date: 2022-09-23
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this project is to determine the effect of various interventions to improve patient outcome as defined by hospital free days at day 90 for adult patients undergoing elective surgery. Within this project, multiple studies may be conducted.

The structure of this project permits:

* the testing of multiple treatments at the same time within the same patient
* the use of early study results to provide better treatment options to future patients
* the removal of treatments which are shown to be less effective than the other treatments
* the addition of new treatments

The first study to be conducted under this project (IRB STUDY19090186) is the Strategies to Promote ResiliencY (SPRY) clinical trial (IRB PRO18060038).

The SPRY clinical trial will determine the effectiveness of Metformin on improving surgical outcomes among nondiabetic older adults who are scheduled for elective surgery.

Detailed description:

Arms: arm 1: LD-SC (low-dose, short course)

Participants take Metformin ER 500 mg daily for 7-28 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 2: LD-IC (low-dose, intermediate course)

Participants take Metformin ER 500 mg daily for 29-90 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 3: LD-LC (low-dose, long course)

Participants take Metformin ER 500 mg daily for 90+ days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 4: ID-SC (intermediate-dose, short course)

Participants take Metformin ER 1000 mg daily for 7-28 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 5: ID-IC (intermediate-dose, intermediate course)

Participants take Metformin ER 1000 mg daily for 29-90 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 6: ID-LC (intermediate-dose, long course)

Participants take Metformin ER 1000 mg daily for 90+ days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 7: HD-SC (high-dose, short course)

After a 7 day run-in of Metformin ER 1000 mg, participants take Metformin ER 1500 mg daily for 7-28 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 8: HD-IC (high-dose, intermediate course)

After a 7 day run-in of Metformin ER 1000 mg, participants take Metformin ER 1500 mg daily for 29-90 days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 9: HD-LC (high-dose, long course)

After a 7 day run-in of Metformin ER 1000 mg, participants take Metformin ER 1500 mg daily for 90+ days prior to their elective surgical procedure as determined by the patient's scheduling of their surgery. Participants take this same dose of Metformin ER for 90 days after their surgical procedure. arm 10: Participants are randomized to receive dose matched placebo to take daily for either short-, intermediate-, or long-course.
Interventions: intervention 1: Metformin ER intervention 2: Placebo
Intervention descriptions: intervention 1: tablet intervention 2: Matched placebo in doses of 1, 2 and 3 tablets to coincide with the 500, 1000, and 1500 mg arms.

Protocol documents:
ICF_002.pdf: 
SPRY Consent Cover Page 
 
 
UPMC 
Strategies to Promote ResiliencY (SPRY)-An Adaptive Randomized Clinical 
Trial of Metformin in High Risk Surgical Patients 
NCT  NCT03861767 
Matthew D. Neal, MD FACS 
9-22-2021 
 


 
 
                                                                          Page 1 of 15                                           
 
 
 Department of Critical Care Medicine 
School of Medicine 
 
600 Scaife Hall 
3550 Terrace Street 
Pittsburgh, PA 15261 
412-647-6965 
ccm.pitt.edu 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
STUDY TITLE: Strategies to Promote ResiliencY (SPRY)-An Adaptive Randomized 
Clinical Trial of Metformin in High Risk Surgical Patients 
 
PRINCIPAL INVESTIGATOR:  
Dr. Matthew Neal 
University of Pittsburgh 
Departments of Surgery, Critical Care Medicine, and the Clinical and Translational 
Science Institute 
F1271.2 PUH  
200 Lothrop Street 
Pittsburgh, PA  15213 
Phone: 412.647.1158 
 
SPRY Team Clinical Research Coordinator 
412.383.1573 
SOURCE OF SUPPORT: UPMC Internal Funds 
KEY INFORMATION: 
You are being invited to consider joining a research study. Participation in a research 
study is always voluntary. The first part of this form is a summary of the study. Please 
also read the Detailed Information section that follows before making a decision about 
participation in this study. 
 
Why are researchers doing this study? 
Increasing age is a risk factor for having complications after surgery. There are some 
studies suggesting metformin, a medication often used for diabetes, may be able to 
reduce inflammation as well as have other effects which may help with complications. 
 
In this study, we want to look at whether or not metformin is able to improve your 
outcome and reduce complications after elective surgery.  


 
 
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What is involved in this study? 
You will be randomly assigned to receive one of 3 doses of metformin (500 mg, 1000 
mg, or 1500 mg) or one of three doses of placebo (sugar pills). You will take this study 
drug starting tomorrow and continue to take this study drug for 90 days after your 
surgery. 
If you participate in this study, you may have blood samples taken at up to 5 timepoints 
while you take the study drug. This blood would be stored without identifiers. 
 
You may also complete questionnaires during this study. 
 
What are some reasons I might choose to volunteer? 
Researchers are conducting this study because they do not know if metformin might be 
helpful. Their goal is to determine what might help future patients.   
 
What risks are involved in the study? 
For those people who are assigned to take metformin, some people may experience 
mild stomach and digestive system side effects as outlined in the ‘Potential Risks and 
Discomforts’ section which follows. These are usually temporary and resolve with 
continued use of metformin.  
 
Other minor risks are noted in the ‘Potential Risks and Discomforts’ section. 
 
What other things should I consider? 
You will not be charged for costs associated with the study drug or for any procedures 
required by the study. Costs associated with your routine medical care, including your 
elective surgery and hospital stay, will still be your responsibility or that of your 
insurance provider. 
 
Will being in this study help me? 
For those assigned to the placebo group, no direct benefit is expected. For those who 
will be taking metformin, it is not known if there will be any direct benefit to you.  
 
What are my choices if I decide not to be in this study? 
If you decide not to join the study, this will have no effect on your elective surgery.  
 
DETAILED INFORMATION 
 
INTRODUCTION: 
This study is being conducted to determine if people taking metformin have better 
outcomes and fewer complications after having elective surgery compared to people not 
taking metformin.  Metformin is a medication commonly given by doctors to reduce 
blood sugar in people with diabetes (a disease where you have higher than normal 
blood sugar).  The use of metformin in this research study is investigational.  
“Investigational” means that the use of metformin for the purpose of improving outcome 
after surgery is not approved by the United States Food and Drug Administration.  


 
 
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In this consent form, “you” and “your” always refers to the subject and “we” always 
refers to the study team.  
You are being asked to participate in this research study as you are scheduled for an 
elective surgical procedure in a UPMC facility as part of your routine care.  You may be 
eligible for participation in this research study if you are at least 60 years of age and do 
not have diabetes.  You may also be eligible if you are younger than 60 years of age 
and have certain chronic medical conditions.  Women enrolled into this study must be 
post-menopausal, which means that you have not had a menstrual period within the last 
12 months.  
DESCRIPTION OF THE RESEARCH 
A total of up to 2,000 men and women may be enrolled into this research study over the 
next two years at the University of Pittsburgh/UPMC.  
Your study participation will begin on the day you are seen in the clinic for the pre-
operative evaluation prior to your surgery.  As part of this study, you will take a study 
drug prior to your operation and then for ninety (90) days after the date of your surgery. 
Medical record information may be collected for approximately a year after your 
completion of the study drug. 
WHEN THE INVESTIGATOR IS ALSO THE CARE-PROVIDER: 
For some of you, your physician is involved as an investigator in this research study. 
Before agreeing to participate, or at any time during your study participation, you may 
discuss your care with another doctor who is not associated with this research study. 
You are not under any obligation to participate in any research study offered by your 
physician. 
STUDY PROCEDURES: 
If you decide to take part in this research study, certain research procedures may occur.   
Clinic Visit Before Your Surgery: 
• You may answer questions regarding your demographic details (date of birth, 
race, etc.) 
• You may answer a few general questions about your medical history, allergies, 
and your use of alcohol to verify that you are eligible to participate in this study.   
• You may be asked to provide contact information (name, phone number, mailing 
address, e-mail address) for you, your spouse/partner, and maybe for another 
friend/relative.   This contact information is collected as the study team may need 
to contact you throughout the study.  If the study team cannot reach you, they 
would then try to reach one of the other individuals you have identified for the 
study team.   


 
 
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• You may have a blood sample drawn.  Blood will be drawn to store some blood 
for future testing to be able to compare how aspects of your blood change as you 
progress through the study. The blood would likely be drawn by putting a needle 
into a vein in your arm.  About four (4) tablespoons of blood may be taken for this 
study at the same time as blood is drawn for testing required for your surgery if 
needed.  Your blood would be drawn by a nurse or another skilled medical 
professional.  The blood draw should take about ten minutes. Other blood 
samples may be taken at other times during the study.  When possible, these 
blood samples would be drawn at the same time as standard of care blood is 
drawn. 
• You will be randomly assigned by chance to receive one of the following study 
drugs to take one time daily by mouth: 
• 500 mg (1 pill) metformin extended release (ER)  
• 1000 mg (2 pills) metformin extended release (ER)  
• 1500 mg (3 pills) metformin extended release (ER)  
• Placebo (1 pill) 
• Placebo (2 pills) 
• Placebo (3 pills) 
A placebo is a sugar pill that looks like a metformin pill but does not contain any active 
drug.  At the beginning of the study, an individual has a 37% (37 in 100) chance of 
receiving placebo and a 63% (63 in 100) chance of receiving one of the three metformin 
doses.  Once an individual is assigned to receive placebo or metformin, the individual 
takes this study drug for the duration of the study.   
As this study is designed to enroll people over 2 years, the likelihood that those who 
participate at a later time will receive metformin or placebo will change based on the 
number of individuals who have participated in the study up to that point. 
If you are assigned to either the 1500 mg metformin extended release dose or the 3 pill 
placebo option, you will take 2 pills for the first 7 days.  Starting on day eight, you will 
then take 3 pills.  The reason to begin with the lower dose is that this will help to reduce 
possible side effects if you are taking metformin.   
Both you and the study team will not know if you are taking metformin or placebo during 
the study.  In the event of an emergency, it is possible for the study team to learn what 
study drug you are taking.  
You should start to take the study drug the morning after your pre-operative clinic visit.  
You should take the study drug every day.  You should take the study drug with food to 
minimize GI effects. You should bring your current study drug pill bottle with you on the 
date of your surgery.  Depending upon when your surgery is scheduled, the UPMC 
Investigational Drug Service may need to send you additional study drug by mail.  It is 
important that you take all the study drug in the current study drug pill bottle before 
starting to take study drug from a new study drug pill bottle received in the mail.  
You should continue to take the study drug through the day of your elective surgical 


 
 
                                                                          Page 5 of 15                                           
 
procedure and for 90 days following the date of your surgery.  The study drug will only 
be available to you during the study.   
• You will be given a wallet card that indicates that you are participating in this 
study.  This card lists that you may be taking metformin.  You should carry this 
wallet card with you and show this wallet card to any health care professional you 
see while you are taking the study drug.   
• We may contact your PCP and other members of your health care team to let 
them know of your involvement in this study. These communications could occur 
at various times throughout your study participation.  
• As part of the process for you to decide to participate in this study, you will speak 
with one of the investigators involved with this study.  If the investigator cannot 
promptly come to your clinic location, this interaction may occur via phone or via 
remote video conference.   The purpose of your conversation with the 
investigator is for the investigator to ensure that you understand what is involved 
in study participation and to ensure all your questions have been answered.  
Following the conversation with the investigator, either in person or by 
telephone/video conference, this informed consent will be signed by you and by 
the investigator.  A copy of the informed consent will be given to you.  
These research procedures will likely take place in the clinic where you are having your 
office visit before surgery.  The research procedures may add approximately 45 minutes 
to your visit.  
Prior to the day of surgery, ideally within 48 hours of study enrollment: 
• You may receive a phone call from a member of the Long-Term Outcomes Core 
team.  The purpose of this phone call is to remind you of the importance of 
bringing your study drug pill bottle with you when you come to the hospital for 
your elective surgery.   
• During this phone call, a member of the Long-Term Outcomes Core may ask you 
some questions about your general health and to assess your thinking and 
memory.  This phone call should take about 15 minutes. 
Day of surgery: 
• You should give your study drug pill bottle to hospital staff personnel when you 
arrive at the hospital for your surgery.  Your study drug pill bottle will be kept by 
hospital personnel while you are in the hospital.  You will continue to take the 
study drug while you are in the hospital.   
• You may have a blood sample drawn from the intravenous (IV) line that is 
inserted in your arm for your surgery or directly from a vein.  About four (4) 
tablespoons of blood may be taken.  Your blood would be drawn by a nurse or 
another skilled medical professional.  The blood draw should take less than ten 
minutes.  
• We may review your medical records and collect information related to your 
surgery and the medications you receive for your surgery as well as your general 


 
 
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health.  We may continue to review and collect this kind of information while you 
are in the hospital.  
These research activities should take about 25 minutes.  
After surgery: 
• You may have blood drawn from the intravenous (IV) line that was inserted in 
your arm for your surgery or directly from a vein.  About three and a half (3.5) 
tablespoons of blood may be taken at this time.  Your blood would be drawn by a 
nurse or another skilled medical professional.  The blood draw should take less 
than ten minutes and should occur in your hospital room.     
During your hospital stay: 
• You will continue to receive the study drug during your hospital stay.  We may 
decide to suspend giving you the study drug if you have certain types of 
difficulties as a result of your surgery.   
Day 3 after surgery or immediately prior to hospital discharge if earlier than Day 3: 
• 
You may have blood drawn from the intravenous (IV) line inserted in your arm for 
your medical care or directly from a vein.  About three and a half (3.5) 
tablespoons of blood may be taken at this time.  Your blood would be drawn by a 
nurse or another skilled medical professional.  The blood draw should take less 
than ten minutes. 
Day of hospital discharge: 
• You should be given another pill bottle containing the same study drug as before 
your surgery.  You should continue to take the study drug for a total of 90 days 
since the date of your surgery.   
These research procedures should take about 15 minutes and would take place in your 
room at the hospital before you leave the hospital to go home.  
Follow-up visit approximately 2-3 weeks after surgery (Usual Care): 
• You may have blood drawn from a vein in your arm.  About three and a half (3.5) 
tablespoons of blood may be taken for this study.  Your blood would be drawn by 
a skilled medical professional.  The blood draw should take about ten minutes 
and would take place in the clinic where you see your doctor or in a nearby 
UPMC location. 
Phone call 30 days (+/- 7 days) after surgery: 
All subjects participating in this study may receive a phone call from the Long Term 
Outcomes Core who may ask you questions about your general health, your taking of 
the study drug, your general level of physical activity, and about whether you have seen 


 
 
                                                                          Page 7 of 15                                           
 
any doctors/been to the hospital since your surgery.  This phone call should take about 
10-15 minutes.  
Phone call 90 days (+ 28 days) after surgery: 
The Long-Term Outcomes Core may contact you via telephone to ask you the same 
kinds of questions as asked during the 30-day call.  You may also be asked some 
questions to assess your memory, attention, and thinking skills.  
This phone call should take about 30-35 minutes.   
For those subjects who completed their 90-day questionnaires via phone call with the 
Long-Term Outcomes Core, you will be reminded to discard the wallet card.   
 
CONTINUED ACCESS TO MEDICAL RECORD INFORMATION  
We also would like to have permission to collect medical record information for over one 
year from the time you stop taking the study drug.  We would collect information related 
to your general health such as test results, treatments, and doctor’s notes as well as 
information about any hospital admissions and emergency department visits.  In order 
to collect this medical record information from non-UPMC facilities, you may be asked to 
sign a separate authorization which would permit the sharing of your non-UPMC 
protected health information with the study team.   
DATA RETENTION and BLOOD SAMPLES 
All of the samples collected during this study will be placed in a specimen bank.  The 
purpose of the specimen bank is to collect and store these samples for future research 
studies related to aging as well as to study various types of diseases and conditions.  
Your samples will be kept forever. Your past, current and future medical record 
information stored at UPMC will be available to be matched with your biological 
samples.   This data will be stored in a controlled-access database.  Your data, which 
may include your health information, your biological samples, and genetic data 
generated from your samples will be stored with a unique ID number but will not be 
stored with your name.  Your samples may be used by other investigators here at the 
University of Pittsburgh and UPMC and may be shared with other researchers, industry, 
or with a federal repository without additional consent from you.   
Research data will be maintained for at least 7 years following closure of this research 
study.  
Analysis of these samples may include genetic analysis as previously described. 
Any genetic information obtained from these studies will not be entered into your 
medical records.  No clinically relevant results will be returned to you.  
As the research questions to be asked are unknown and as the meaning and 


 
 
                                                                          Page 8 of 15                                           
 
significance of the results of any future unspecified testing of the biospecimens 
collected under this research study is unknown, personal results will not be disclosed to 
research subjects.   
Your samples and research data collected in this study may contribute to a new 
discovery or treatment.   In some instances, these discoveries or treatments may be of 
commercial value and may be sold, patented, or licensed by the investigators and the 
University of Pittsburgh for use in other research or the development of new products. 
You will not retain any property rights, nor will you share in any money that the 
investigators, the University of Pittsburgh, or their agents may realize.  
POTENTIAL RISKS AND DISCOMFORTS 
Metformin: The known risks are effects on your stomach and digestive system such as 
gas, loss of appetite, nausea, vomiting, diarrhea, and decreased levels of B12 
(cobalamin).  
 
These side effects are usually temporary and resolve with continued use of metformin. 
 
There is a rare risk of something called lactic acidosis. This is the build-up of something 
called lactate in your blood. Lactate in your blood normally is harmful if there too much. 
Early signs of this are changes in your breathing and belly pain. Always call the study 
team if you have any concern.  
 
You should not participate in this study if you know you have an allergy to metformin.  
 
As with all medications, in very rare cases, the use of metformin may result in an 
allergic reaction. Some symptoms of allergic reactions include rash, difficulty breathing, 
wheezing, sudden drop in blood pressure, swelling around the mouth, throat or eyes, a 
fast pulse, sweating. Please seek emergency treatment immediately if you experience 
these kinds of symptoms and then alert the study doctor and study staff if you have 
these symptoms as a very serious allergic reaction may be life-threatening. 
 
The study drug could interact with other drugs such as carbonic anhydrase inhibitors, 
gliptins, and cimetidine.   
 
Blood sampling: You may experience temporary discomfort, bruising, pain at the blood 
draw site, and fainting (rare risk).  
 
Surveys/questionnaires: Individuals completing questionnaires/surveys may 
experience mild frustration or boredom in completing these assessments.   
 
Breach of confidentiality: It is possible that someone could find out that you were in 
this study and could find out information about you.  Every effort will be made to prevent 
this from happening.  To protect your confidentiality, we will remove your name and 
other personal identifiers from the samples and from the medical record information we 


 
 
                                                                          Page 9 of 15                                           
 
obtain.  This information will be identified by a code.  
 
 
Although every reasonable effort has been taken, confidentiality during Internet 
communication activities cannot be guaranteed and it is possible that additional 
information beyond that collected for research purposes may be captured and used by 
others not associated with this study. Text messages are not encrypted or secure during 
their transmission, and could be intercepted. 
Risks associated with gene studies: The risks associated with gene studies include 
the potential for a breach of confidentiality which could affect future insurability, 
employability, or reproduction plans, or have a negative impact on family relationships 
and/or result in paternity suits or stigmatization. 
In addition, there is a Federal law, called the Genetic Information Nondiscrimination Act 
(GINA), that generally makes it illegal for health insurance companies and group health 
plans to use genetic information in making decisions regarding your eligibility or 
premiums. GINA also makes it illegal for employers with 15 or more employees to use 
your genetic information when making decisions regarding hiring, promoting, firing, or 
setting the terms of employment. This new Federal law does not protect you against 
genetic discrimination by companies that sell life, disability, or long-term care insurance. 
To facilitate communication during the study, this study will use e-mails to update the 
study team of your progress in the study.  This may include the use of your name and 
other personal identifiers to ensure accurate information.  Although every reasonable 
effort has been taken, confidentiality during Internet communication activities cannot be 
guaranteed and it is possible that additional information beyond that collected for 
research purposes may be captured and used by others not associated with this study.   
As with any experimental procedure, there may be adverse events or side effects that 
are currently unknown and certain of these unknown risks could be permanent, severe 
or life-threatening. 
ANTICIPATED BENEFITS TO SUBJECTS 
For those subjects assigned to the placebo group (no metformin will be taken), no direct 
benefit from study participation is expected.  For those subjects who will be taking 
metformin, it is not known if there will be any direct benefit to you from being in the 
research study. 
ALTERATIVE TREATMENTS 
There are no alternative procedures which may be of benefit to you if you choose not to 
participate in this research study. 


 
 
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NEW INFORMATION 
You will be promptly notified if any new information we learn during this research study 
may cause you to change your mind about continuing to participate in the study. 
COSTS AND PAYMENTS 
If you agree to take part in this research study, you and/or your insurance will not have 
to pay for the study drug or any tests that are being done only for the research study.  
However, you are still responsible for paying for elective surgery and hospital admission 
as well as other care you would normally receive.  This includes treatments and tests 
you would need even if you were not in this study.  These costs will be billed to you 
and/or your insurance. 
If you complete the entire study, you may be paid up to $200 in return for your time and 
effort associated with research study involvement. These funds will be provided to you 
as $50 payments 4 times throughout the study: 
$50 following the clinic visit before surgery 
$50 following the hospital stay 
$50 following the phone call at roughly 30 days after surgery 
$50 following the phone call/visit at roughly 90 days after surgery  
In addition, if you participate in the Microbiome Sub-study, you will be paid $20 for each 
of the stool samples and rectal swab collected for this study for a total of $80 over the 
course of the study.   
You will receive this compensation via a reloadable debit card.  The debit card is not 
loaded with funds until you coordinate with the study team to load the card with funds. 
Since you are being compensated for your participation in this study, your name, 
address, and social security number will be released to the Accounting Office.  If you 
are not comfortable with providing your social security number for use by the 
Accounting Office, taxes will automatically be removed from the payment.  
USE AND DISCLOSURE OF PROTECTED HEALTH INFORMATION 
We are also requesting your authorization or permission to review your medical records. 
This research study may involve the recording of past, current and/or future identifiable 
medical information from your hospital and/or other (e.g. physician office) records to 
determine whether you meet the conditions for participation in this study.  The 
information that may be recorded will include information concerning your medical 
history, results of lab tests, diagnostic procedures, the reason for your elective surgical 
procedure, and the type of medical insurance you have.  In addition, medical record 
information related to your hospital stay for your elective surgery and any follow-up 
visits may be recorded to assess the effects of the study drug.  As part of this research 


 
 
                                                                          Page 11 of 15                                           
 
study, some information that we obtain from you may be placed into your medical 
records held at UPMC, including the results of any testing performed specifically for this 
research study. This authorization to provide identifiable information available to 
members of the study team is valid for an indefinite period of time. 
In addition to the Principal Investigator listed on the first page of this consent form and 
the other investigators involved in this study and the study team, the following 
individuals will or may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research study: 
• Authorized representatives of the University of Pittsburgh Office of Research 
Protections for the purpose of monitoring the appropriate conduct of this research 
study.  
• Authorized representatives of UPMC or other affiliated health care providers for 
the purpose of (1) fulfilling orders made by the investigators for hospital and 
health care services (e.g., diagnostic procedures) associated with research study 
participation; (2) addressing correct payment for tests and procedures ordered by 
the investigators; and/or (3) for internal hospital operations (e.g., quality 
assurance). 
• 
Authorized representatives of the U.S. Food and Drug Administration (FDA) and other 
regulatory agencies may review and/or obtain your identifiable information (which may 
include your identifiable medical record information) related to your participation in this 
research study for the purpose of monitoring the accuracy of the research data. 
 
We will protect your privacy and the confidentiality of your records, as described in this 
document, but cannot guarantee the confidentiality of your research records, including 
information obtained from your medical records, once your personal information is 
disclosed to others outside UPMC or the University.  
In addition, coded data about your participation in this study will be shared with Berry 
Consultants, LLC, a collaborator, and an external Data Safety and Monitoring Board 
(DSMB).  The DSMB will review this coded data for the purpose of overseeing study 
progress and evaluating the potential risks to subjects associated with study 
participation.  
We may send your de-identified muscle biopsy samples for analysis to investigators at 
the University of Pittsburgh and/or to other collaborators such as the University of Utah 
for analysis. The linkage document containing your name and your study ID will not be 
shared with these research teams. Descriptors such as your age and gender may be 
shared but no identifiable information.  
We may share your responses from the EQ-5D questionnaires with your health care 
providers. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as 
required by US Law. This website will not include information that can identify you. At 


 
 
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most, the website will include a summary of the results. You can search this website at 
any time. 
 
MEDICAL CARE FOR RESEARCH RELATED INJURY 
If you believe that the research procedures have resulted in an injury to you, 
immediately contact the Principal Investigator who is listed on the first page of this form. 
Emergency medical treatment for injuries solely and directly related to your participation 
in this research study will be provided to you by the hospitals of UPMC. Your insurance 
provider may be billed for the costs of this emergency treatment, but none of those 
costs will be charged directly to you. If your research-related injury requires medical 
care beyond this emergency treatment, you will be responsible for the costs of this 
follow-up care. Currently, there is no plan for any additional financial compensation. You 
do not, however, waive any legal rights by signing this form. 
VOLUNTARY PARTICIPATION  
Your participation in this research study is entirely voluntary.  You may want to discuss 
this study with your family and friends and your personal physician before agreeing to 
participate.  If there are any words you do not understand, feel free to ask us.  The 
investigators will be available to answer your current and future questions.  
Whether or not you provide your consent for participation in this research study will 
have no effect on your current or future relationship with the University of Pittsburgh. 
Whether or not you provide your consent for participation in this research study will 
have no effect on your current or future medical care at a UPMC hospital or affiliated 
health care provider or your current or future relationship with a health care insurance 
provider. 
As both your doctor and a research investigator, s/he is interested both in your medical 
care and the conduct of this research study. Before agreeing to participate in this 
research study, or at any time during your study participation, you may discuss your 
care with another doctor who is not associated with this research study. You are not 
under any obligation to participate in any research study offered by your doctor. 
To formally withdraw your consent for participation in this research study, you should 
provide a written and dated letter of this decision to the principal investigator of this 
research study at the address listed on the first page of this form. 
RIGHT TO WITHDRAW 
It is possible that you may be removed from the research study by the researchers if, for 
example, 


 
 
                                                                          Page 13 of 15                                           
 
• You do not or cannot take the study drug properly. 
• The researcher feels it is in your best interest not to continue in  
the study.  
• The funding for the study is not continued. 
• There may be other reasons to remove you from the study not identified at      
               present. 
In the event of study withdrawal, you will be asked to return the study drug pill bottle to 
the study team using a pre-paid mailing envelope.  
Upon your withdrawal from this study, you should participate in additional monitoring 
follow-up procedures that are being conducted to measure the safety of the study drug. 
All information obtained from you up until the date of your withdrawal from the study will 
be maintained in a coded fashion.  No further data will be collected following your 
withdrawal from the study.  Your blood and stool samples which have been placed into 
storage may continue to be used for analysis, but no further samples will be collected 
from you for this study.  
VOLUNTARY CONSENT TO PARTICIPATE: 
The above information has been explained to me and all of my current questions have 
been answered.  I understand that I am encouraged to ask questions, voice concerns or 
complaints about any aspect of this research study during the course of this study, and 
that such future questions, concerns or complaints will be answered by a qualified 
individual or by the investigator listed on the first page of this consent document at the 
telephone number given.  
I understand that I may always request that my questions, concerns or complaints be 
addressed by a listed investigator.  I understand that I may contact the Human Subjects 
Protection Advocate of the IRB Office, University of Pittsburgh (1-866-212-2668) to 
discuss problems, concerns, and questions; obtain information; offer input; or discuss 
situations that occurred during my participation. By signing this form, I agree to 
participate in this research study and provide my authorization to share my medical 
records with the study team. A copy of this consent form will be given to me. 
___________________________________         
Printed Name of Participant           
 
_________________________________            ____________ 
 
__________ 
Signature of Participant 
 
 
                Date  
 
 
Time 
 
INVESTIGATOR CERTIFICATION: 


 
 
                                                                          Page 14 of 15                                           
 
I certify that I have explained the nature and purpose of this research study to the 
above-named individual(s), and I have discussed the potential benefits and possible 
risks of study participation. Any questions the individual(s) have about this study have 
been answered, and we will always be available to address future questions, concerns 
or complaints as they arise. I further certify that no research component of this protocol 
was begun until after this consent form was signed. 
 
___________________________________        _____________________ 
Printed Name of Person Obtaining Consent          Role in Research Study 
 
_________________________________            ____________ 
 
__________ 
Signature of Person Obtaining Consent                Date  
 
 
Time  
 
 
 
 


 
 
                                                                          Page 15 of 15                                           
 
 
 

Prot_000.pdf: 
 
 
 
 
 
Domain-Specific Appendix: 
Metformin 
 
 
Strategies to Promote ResiliencY (SPRY)- 
An Adaptive Randomized Clinical Trial of 
Metformin in High Risk Surgical Patients 
UPMC REMAP: Randomized, Embedded, 
Multifactorial Adaptive Platform Trial for 
Optimizing Surgical Outcomes 
NCT 03861767 
 
IRB approved  January 17, 2020 


UPMC REMAP Metformin Domain-Specific Appendix Version 6 dated 15 October 2019 
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Summary 
In this domain of the UPMC REMAP trial, participants with elective surgery at UPMC facilities will be 
randomized to receive the following Metformin doses or placebo:  
• 
Placebo 
• 
500mg ER daily 
• 
1000mg ER daily 
• 
1500mg ER daily 


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UPMC REMAP: Metformin Duration Domain Summary  
Interventions 
• 
Placebo 
• 
3 different doses of Metformin,  
• 
3 different pre-operative dosing durations: short (7-28 days), intermediate (29-90 
days); long (over 90 days) 
• 
Metformin continued for 90 days after surgery 
Strata 
Analysis and Response Adaptive Randomization are by strata (surgical type) to allow for 
strata-by-intervention interaction 
Evaluable 
Interactions 
Intervention-intervention interactions will be evaluated between interventions in this 
domain and the complimentary interventions in the ERAS Domain  
Timing 
of 
Reveal 
Randomization with Immediate Reveal and Delayed Initiation (with reveal and initiation only 
occurring after consent or agreement for participation is obtained) 
Inclusions 
Patients are eligible for this domain only if they have been included in the Master Protocol 
inclusion criteria 
Domain-
Specific 
Exclusions 
Domain exclusions: 
 
• 
The treating clinician believes that participation in the domain would not be in the 
best interest of the patient 
• 
Pre-existing diabetes type I or II 
• 
Women of child-bearing potential 
• 
Presently taking metformin or prior use in the past 6 months 
• 
Evidence of an absolute or relative contraindication to Metformin therapy 
o 
Known allergy to metformin 
o 
Acute or chronic metabolic acidosis with or without coma 
o 
Hemodialysis, end-stage renal disease, or GFR < 45 in the prior 30 days 
o 
Ongoing treatment with therapy known to have significant drug-drug 
interaction with metformin (carbonic anhydrase inhibitors, cimetidine, 
gliptins) 
o 
History of lactic acidosis 
o 
History of excessive alcohol intake 
o 
Severe hepatic dysfunction 
 
Outcome 
measures 
Primary REMAP endpoint: hospital free days at day 90 after the surgical encounter  
Secondary REMAP endpoints refer to Core Protocol  
Secondary domain endpoints: 
1. Gastrointestinal distress causing discontinuation of the medication 
2. Lactic acidosis 
3. Hepatic dysfunction 
Serious Adverse Events (SAE) as defined in CORE protocol 


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TABLE OF CONTENTS 
1. 
ABBREVIATIONS ................................................................................................................. 6 
2. 
PROTOCOL APPENDIX STRUCTURE ..................................................................................... 7 
3. 
Metformin DOMAIN-SPECIFIC APPENDIX VERSION ............................................................. 7 
3.1. 
Version History ........................................................................................................................ 7 
4. 
Metformin DOMAIN GOVERNANCE .................................................................................... 8 
4.1. 
Domain Members ................................................................................................................... 8 
4.2. 
Contact Details ...................................................................................................................... 10 
5. 
Metformin DOMAIN-SPECIFIC WORKING GROUP AUTHORIZATION ................................... 11 
6. 
BACKGROUND AND RATIONALE ........................................................................................ 11 
6.1. 
Domain Definition ................................................................................................................. 11 
6.2. 
Domain-specific Background ................................................................................................ 11 
6.2.1. 
Guideline Recommended Use of Metformin and Potential Applications ................ 12 
6.2.2. 
Metformin Mechanisms of Action. ........................................................................... 13 
6.2.3. 
Association of Metformin with Longevity in Small Clinical Trials ............................. 13 
6.2.4. 
Metformin Safety Profile .......................................................................................... 13 
7. 
DOMAIN OBJECTIVES ........................................................................................................ 14 
8. 
TRIAL DESIGN .................................................................................................................... 15 
8.1. 
Population ............................................................................................................................. 15 
8.2. 
Eligibility Criteria ................................................................................................................... 15 
8.2.1. 
Inclusion Criteria for this Domain ............................................................................. 15 
8.2.2. 
Exclusion Criteria from this Domain ......................................................................... 15 
8.3. 
Interventions ......................................................................................................................... 16 
8.3.1. 
Research Testing ....................................................................................................... 16 
8.3.2. 
Study Drug Intervention ............................................................................................ 16 
8.3.3. 
Timing of Initiation of Intervention ........................................................................... 17 
8.3.4. 
Duration of Administration of Study Drug ................................................................ 17 
8.3.5. 
Temporary Suspension of Study Drug ....................................................................... 17 
8.3.6. 
Suspension of Study Drug at the Direction of the Treating Clinician ........................ 17 
8.3.7. 
Collection of Blood Samples ..................................................................................... 18 
8.3.8. 
Collection of Samples for Microbiome Sub-study .................................................... 18 
8.3.9. 
Collection of questionnaires ..................................................................................... 19 


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8.3.10. 
Muscle Biopsy Sub-Study .......................................................................................... 21 
8.4. 
Endpoints .............................................................................................................................. 23 
8.4.1. 
Primary Endpoint ...................................................................................................... 23 
8.4.2. 
Secondary Endpoints................................................................................................. 23 
9. 
TRIAL CONDUCT ................................................................................................................ 24 
9.1. 
Domain-specific Data Collection ........................................................................................... 24 
9.1.1. 
Clinical Data Collection ............................................................................................. 24 
9.2. 
Criteria for Discontinuation .................................................................................................. 24 
9.3. 
Blinding ................................................................................................................................. 24 
9.3.1. 
Blinding ..................................................................................................................... 24 
9.3.2. 
Unblinding ................................................................................................................. 24 
10. 
STATISTICAL CONSIDERATIONS.......................................................................................... 24 
10.1. 
Domain-specific Stopping Rules ............................................................................................ 24 
10.2. 
Strata ..................................................................................................................................... 25 
10.3. 
Timing of Revealing of Randomization Status ...................................................................... 25 
10.4. 
Interactions with Interventions in Other Domains ............................................................... 25 
10.5. 
Post-trial Sub-groups............................................................................................................. 26 
11. 
ETHICAL CONSIDERATIONS ................................................................................................ 26 
11.1. 
Data Safety and Monitoring Board ....................................................................................... 26 
11.2. 
Potential Domain-specific Adverse Events ........................................................................... 26 
11.3. 
Domain-specific Consent Issues ............................................................................................ 26 
12. 
GOVERNANCE ISSUES ........................................................................................................ 27 
12.1. 
Funding of Domain ................................................................................................................ 27 
12.2. 
Domain-specific Declarations of Interest .............................................................................. 27 
13. 
REFERENCES ...................................................................................................................... 28 
 


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1. ABBREVIATIONS  
eGFR: estimated Glomerular Filtration Rate 
ERAS: Enhanced Recovery after Surgery 
GFR: Glomerular Filtration Rate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. PROTOCOL APPENDIX STRUCTURE 
The structure of this protocol is different to that used for conventional trials because this trial is 
highly adaptive and can best be described as ‘modular’ in its protocol design. With competing 
treatment interventions nested within a domain, both interventions and domains will change over 
time.  While all adaptations are pre-specified, the structure of the protocol is designed to allow the 
trial to evolve over time, for example, by the introduction of new domains or interventions or both 
and commencement of the trial in new clinics. 
The protocol has multiple modules, in brief, comprising a Core Protocol (overview and design 
features of the study) and multiple Domain-Specific Appendices (DSA) (detailing all interventions 
currently being studied in each domain). 
The Core Protocol contains all information that is generic to the trial, irrespective of the clinic in 
which the trial is conducted and the domains or interventions that are being tested. The Core 
Protocol is void domain and intervention specifics, statistical analysis plans, and simulation specifics.  
The Core Protocol may be amended, but it is anticipated that such amendments will be infrequent.  
Information about the intervention(s) to be examined, within each domain, is covered in a DSA. 
These Appendices are anticipated to change over time, with removal and addition of options within 
an existing domain, at one level, and removal and addition of entire domains, at another level. Each 
addition of a new domain and/or new intervention to an existing domain in a DSA will be subject to a 
separate ethics application for approval.  
Although the analysis model will change over time in accordance with the domain and intervention 
trial adaptations, this information is contained in the Statistical Analysis and Simulations Appendices. 
Each modification will be subject to approval from the Trial Steering Committee (TSC) in conjunction 
with advice from the Data Safety and Monitoring Board (DSMB). 
3. METFORMIN DOMAIN-SPECIFIC APPENDIX VERSION 
The version of the Metformin Domain-Specific Appendix is in this document’s header and on the 
cover page. 
3.1. Version History  
Version 1: 
Proposed on 16 July 2018 


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Version 2: Proposed on 20 January 2019 
Version 3: Proposed on 25 June 2019 
Version 4: Proposed on 17 July 2019 
Version 5: Proposed on 31 July 2019 
Version 6: Proposed on 15 October 2019 
4. METFORMIN DOMAIN GOVERNANCE  
4.1. Domain Members 
Chair:  
  
 
Derek C. Angus, MD, MPH 
Professor and Chair, Critical Care Medicine 
The Mitchell P. Fink Chair in Critical Care Medicine 
 
Members: 
Scott M. Berry, PhD 
President and Senior Statistical Scientist 
Berry Consultants LLC 
 
Timothy Billiar, MD 
George Vance Foster Professor and Chair, Department of Surgery 
Distinguished Professor of Surgery 
Vice-President and Chief Academic Officer, University of Pittsburgh Physicians 
Associate Medical Director, UPMC International and Commercial Services Division 
 
Philip E. Empey, PharmD, PhD 
Assistant Professor 
Pharmacy and Therapeutics 
 
Stephen A. Esper, MD, MBA 
Assistant Professor 


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Director of Perioperative Services 
UPMC Department of Anesthesiology  
 
 
Toren Finkel, MD, PhD 
Professor of Medicine, Division of Cardiology 
G. Nicholas Beckwith III and Dorothy B. Beckwith Chair in Translational Medicine 
Director, Aging Institute of UPMC and Pitt 
 
 
Timothy Girard, MD 
Associate Professor of Critical Care Medicine 
University of Pittsburgh  
 
Jennifer M. Holder-Murray, MD, FACS 
Assistant Professor of Surgery 
Vice Chair for Quality Integration, Department of Surgery 
Co-Director, Enhanced Recovery Program, UPMC 
 
A. Murat Kaynar, MD, MPH 
Associate Professor 
Departments of Critical Care Medicine and Anesthesiology 
Program Director, Anesthesiology Critical Care Medicine Fellowship 
 
Oscar C. Marroquin, MD, FACC 
Chief Clinical Analytics Officer, UPMC Health Services Division 
Assistant Professor of Medicine, Epidemiology, and Clinical and Translation Sciences 
 
Matthew D. Neal, MD FACS 
Assistant Professor of Surgery and Critical Care Medicine 
Attending Surgeon, Division of Trauma and Acute Care Surgery 
University of Pittsburgh Medical Center  
 
Anne B. Newman, MD, MPH 
Chair, Department of Epidemiology 


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Katherine M. Detre Endowed Chair, Population Health Sciences 
Director, Center for aging and Population Health 
Professor, Epidemiology, Medicine, and Clinical and Translational Science Institute 
 
Jeffery Romoff 
President and Chief Executive Officer 
UPMC 
 
 
Matthew R. Rosengart, MD, MPH 
Associate Professor, Surgery and Critical Care Medicine 
Co-Director, Surgical Trauma Intensive Care Unit, UPMC Presbyterian 
 
Christopher W. Seymour, MD, MSc 
Assistant Professor                                                                             
Departments of Critical Care and Emergency Medicine   
University of Pittsburgh School of Medicine 
The CRISMA Center 
 
Jennifer Vates, MS-RA 
Senior Project Manager, UPMC REMAP 
Department of Critical Care Medicine 
 
Brian Zuckerbraun, MD, FACS 
Chief, Division of General/Trauma and Acute Care Surgery 
Professor of Surgery 
 
 
4.2. Contact Details 
 
Jennifer Rectosh 
 
Administrative Assistant 
 
Trauma/General Surgery 


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412-692-2850 
 
5. Metformin DOMAIN-SPECIFIC WORKING GROUP AUTHORIZATION 
The Metformin Domain-Specific Working Group (DSWG) have read the appendix and authorize it as 
the official Domain-Specific Appendix for the study entitled UPMC REMAP. Signed on behalf of the 
committee, 
 
 
Chair  
 
 
 
 
Date 
 
 
Dr. Derek Angus 
 
 
 
 
 
6. BACKGROUND AND RATIONALE 
6.1. Domain Definition 
This is a domain within the UPMC REMAP to test the effectiveness of different doses and durations 
of metformin in nondiabetic patients with elective surgical encounters at UPMC who meet eligibility 
criteria.  
6.2. Domain-specific Background  
Our population is aging.  Aging is associated with altered inflammatory and immune responses.  This 
altered response has been termed “inflammaging”, and has been attributed to age-related diseases 
and treatment complications.   Surgical stress is less well tolerated in older patients.  Therapies 
aimed at pre-habilitation and ameliorating the response of individuals to such stressors hold the 
promise of improving outcomes in patients undergoing operative procedures.  Pharmacological pre-
habilitation possesses the potential of altering the response of older and at risk individuals towards 
that of younger and healthier individuals.  Metformin is one such therapy based on a combination of 
exciting pre-clinical and clinical data demonstrating enhanced longevity and a pleiotropic modulation 
of inflammatory response. 
 


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6.2.1. Guideline Recommended Use of Metformin and Potential Applications 
Metformin is considered first line therapy for patients with type II diabetes mellitus with 
hyperglycemia that cannot be controlled with lifestyle alone. Unlike other oral medications, 
metformin is favored for its insulin sensitizing effects resulting in improved glycemic control, weight 
loss, and overall improvement of metabolic syndrome. Over the past fifteen years, metformin has 
received significant attention for its other potential therapeutic uses and has been found to 
decrease the rate of age related illness progression improving longevity, especially in the setting of 
cancer. Additionally, recent clinical trials across multiple disease states have shown metformin to 
decrease all-cause mortality in diabetic and non-diabetic patients 1–3. Although the mechanisms by 
which metformin affects longevity is an active area of both basic science and clinical research, it 
clearly has anti-inflammatory properties both independent and dependent of glycemic control 4.  
 


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6.2.2. Metformin Mechanisms of Action. 
The underlying mechanisms of action of metformin are under active investigation. A leading 
hypothesis is that cellular mitochondria are the primary site of metformin in activity. Metformin 
decreases intracellular AMP and increases 5’-AMP-activated protein kinase (AMPK) resulting in three 
main downstream effects 2. First and foremost, there is a decrease in gluconeogenesis, decreasing 
serum glucose levels, and improving insulin resistance. Secondly, mitochondrial AMPK activation 
inhibits mechanistic target of rapamycin (mTOR), which decreases mitotic activity and therefore has 
anti-tumor affects influencing mitochondrial homeostasis.  Finally, downstream protein synthesis 
inhibition results in decreased production of both pro-inflammatory cytokines and reactive oxygen 
species (ROS) through activation of the thioredoxin antioxidant system decreasing DNA damage 
2,4,11,12. The anti-inflammatory effects of metformin, in addition to glycemic control, are thought to 
be the leading cause of the proposed anti-aging and cardiovascular protection of metformin 11. 
While this clinical benefit is established in diabetic patients, the anti-inflammatory mechanism of 
action is, at least in part, independent of glycemic control. Therefore, as in prevention and treatment 
of cancer, metformin has properties that can help control inflammation in all patients with systemic 
inflammation. 
6.2.3. Association of Metformin with Longevity in Small Clinical Trials 
Recently, there have been multiple prospective clinical trials exploring the effect metformin in non-
diabetic and diabetic patients. Patients were treated with standard clinical doses of metformin 
ranging from 250mg-2000mg three times days from 14 days to 48 weeks continuing to demonstrate 
an excellent safety profile. The metformin was very well tolerated with the primary side effect (30-
60% of subjects) was self-limited gastrointestinal discomfort including mild diarrhea and anorexia 
1,13,14. Across multiple disease states, metformin has been shown to decrease appetite stimulating 
glucagon like peptide-1, decrease low density lipid profiles, decrease the mitotic rate in breast 
cancer, and improve liver pathology in patients with non-alcoholic steatotic hepatitis 1,3,13,15–17. As 
discussed above, some of these changes are attributed to the anti-glycemic and anti-tumor effects of 
metformin, yet the anti-inflammatory role cannot be underestimated. However, the effects of 
metformin on non-diabetics and longevity remain unexplored. 
6.2.4. Metformin Safety Profile  
The safety profile of metformin is well established. However, there are also safety concerns 
regarding metformin with reports of hepatic damage and lactic acidosis, although these are 


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rare. More commonly, metformin can cause diarrhea and other gastrointestinal-related adverse 
effects, taste disturbances, headaches and muscle weakness. 
 
7. DOMAIN OBJECTIVES  
The objective of this domain is to determine the effectiveness of different doses and durations of 
metformin in select patients evaluated prior to elective surgery at UPMC. 
The interventions that will be compared are: 
• 
Varied doses of metformin (500, 1000, and 1500mg ER) started at the pre-operative clinic 
before elective surgical encounter at UPMC vs. placebo with continuation for 90 days post-
op 
• 
Varied pre-op duration of metformin (short-7-28 days; intermediate-29-90 days; and long- 
90+ days) as dictated by the individual’s clinical course 
We hypothesize that the elective surgical patients will experience more hospital free days at day 90 
after the surgical encounter after administration of metformin vs. placebo. 
We hypothesize that longer course of metformin will lead to more hospital free days at day 90 after 
the surgical encounter compared to a shorter course. 
We hypothesize that the higher dose of metformin will lead to more hospital free days at day 90 
after the surgical encounter compared to lower doses of metformin or placebo, and the effect will 
depend on the type of surgical procedure (and corresponding inflammatory insult). This is termed a 
strata-by-intervention interaction. 
We hypothesize that metformin treatment will alter the complexity and diversity of the microbiome 
as compared to placebo (microbiome sub-study). 
We hypothesize that metformin treatment will alter muscle strength as compared to placebo (Motor 
Assessment Group). 
We hypothesize that metformin treatment will alter striated muscle fiber structure (Muscle Sub-
Study) and correlate with decreased muscle strength as compared to placebo (Motor Assessment 
Group).  


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8. TRIAL DESIGN 
This domain will be conducted as part of a UPMC REMAP trial for Optimizing Surgical Outcomes. 
Treatment allocation will be adaptive, as described in the Core Protocol.  
8.1. Population 
The REMAP enrolls patients with elective surgical encounters admitted to UPMC facilities. Up to 
2000 patients will be enrolled. 
8.2. Eligibility Criteria 
Participants are included in the platform if they have all the REMAP-level inclusions and none of the 
REMAP-level exclusion criteria.  
8.2.1. Inclusion Criteria for this Domain 
Patients are eligible for this domain only if they have been scheduled for elective surgery at UPMC 
facilities and are being evaluated pre-operatively prior to surgery. 
Other criteria include: 
• 
Age >= 60 years 
• 
Age < 60 but evidence of comorbidity risk as represented by a Charlson Comorbidity Index  
of >  2 in 12 months prior to enrollment 
• 
Able to take an oral medication in non-crushable pill form 
• 
Women must be post-menopausal, which is defined as not having a menstrual period within 
the last 12 months 
8.2.2. Exclusion Criteria from this Domain 
Patients will be excluded from this domain, at the time of randomization, if: 
• 
The treating clinician believes that participation in the domain would not be in the best 
interest of the patient 


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• 
Pre-existing diabetes type I or II 
• 
Women of child-bearing potential 
• 
Presently taking metformin or prior use in the past 6 months 
• 
Evidence of an absolute or relative contraindication to Metformin therapy 
o Known allergy to metformin 
o Acute or chronic metabolic acidosis with or without coma 
o Hemodialysis, end-stage renal disease, or GFR < 45 in the prior 30 days 
o Ongoing treatment with therapy known to have significant drug-drug interaction 
with metformin (carbonic anhydrase inhibitors, cimetidine, gliptins) 
o History of lactic acidosis 
o History of excessive alcohol intake 
o Severe hepatic dysfunction 
8.3. Interventions 
8.3.1. Research Testing and Study-related Communications 
The study team may contact the patient’s health care providers (including their PCP) to notify of 
patient’s involvement in the study. These communications may occur at various times throughout 
the study.  
8.3.2. Study Drug Intervention 
Patients will be randomly assigned to intention to receive one of the following study interventions.  
• 
Placebo 
• 
Metformin 500mg ER 
• 
Metformin 1000mg ER  
• 
Metformin 1500mg ER 
The dosing of and route of administration of metformin are not specified in the protocol but the 
following guidance is provided: 
• 
Doses will be oral 
• 
Subjects will be instructed to take a dose once daily and complete all dispensed medication 
from the provided pill bottle 


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Metformin should be discontinued if the patient experiences a serious adverse event (SAE) that is 
thought to be related to the study drug and may be discontinued at the discretion of the treating 
clinician if continued treatment is not in the best interest of the patient. 
8.3.3. Timing of Initiation of Intervention  
The intervention is to begin on the day following the evaluation of the eligible and consented subject 
at the pre-operative clinic/surgeon’s office. Daily oral doses will continue through the hospital 
admission for elective surgery. For patients without side effects, dosing will continue daily for 90 
days after the surgical encounter. 
 
Patients will be contacted between the pre-operative clinic/surgeon’s office visit and surgery to 
evaluate study drug compliance as well as any adverse events associated with the study drug. 
8.3.4. Duration of Administration of Study Drug 
The duration of Metformin therapy is a complimentary research question in this domain. In the short 
course intervention, subjects will receive the study drug (metformin or placebo) within 7-28 days 
prior to the elective surgical encounter. In the intermediate course therapy, subjects will receive the 
study drug for 29-90 days prior to surgery.  In the long course therapy, patients receive a longer 
course of study drug prior to surgery when the pre-operative evaluation occurs far enough in 
advance (e.g., >3 month). All patients will receive study drug for 90 days after the surgical encounter. 
8.3.5. Temporary Suspension of Study Drug 
If the patient should experience any of the following, study drug administration will be temporarily 
discontinued for 48 hours: 
• 
Procedure involving the administration of contrast dye 
8.3.6. Suspension of Study Drug at the Direction of the Treating Clinician 
Study drug administration may be suspended at the direction of the treating clinician in the event a 
patient should experience a medical condition where it is felt there is a predisposition to renal 
impairment and/or tissue hypoxia.  


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8.3.7. Collection of Blood Samples 
As part of this domain, blood samples may be collected over the course of a patient’s participation in 
this domain.  These blood samples will be processed and aliquoted for long-term storage in a 
biorepository which will permit the analysis of such aliquots at a future unspecified date.  Collection 
of blood samples from patients participating in this domain will be attempted at the following 
timepoints: 
 
• 
Pre-op clinic visit 
• 
Day of surgery (often in pre-op holding area) 
• 
After surgery  
• 
Post-op Day 3 or immediately prior to hospital discharge if sooner 
• 
Post-op clinic visit  
 
Where possible, blood samples will be piggy-backed at the time of clinical draws or will be taken 
through established intravenous lines to minimize patient discomfort. If there is concern the 
collection of blood samples via the established intravenous line may jeopardize the patency of this 
line, the blood sample may be drawn directly from a patient’s vein. Blood samples will be processed 
via standard operating procedures and aliquoted to permit long-term storage.  These blood samples 
will be maintained by the Department of Critical Care Medicine for an indefinite period of time.  
Each aliquot will bear a unique code number which will permit matching to coded medical record 
information, while guarding patient identity.  Aliquots may be used by investigators within the 
University of Pittsburgh/UPMC as well as by external investigators.  Any request for the use of 
aliquots banked in the biorepository will need to be reviewed and approved by the Biorepository 
Steering Committee. 
 
8.3.8. Collection of Samples for Microbiome Sub-study 
 
There is interest to determine how the microbiome may change over the course of this study.  For 
this reason, up to 1000 subjects participating in this domain may be asked to participate in a 
microbiome sub-study.  This sub-study will attempt to collect stool samples of participants at 3 
timepoints: 
 


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• 
prior to surgery 
• 
during the inpatient hospital admission or following hospital discharge and within 5 days of 
surgery 
• 
temporal to the post-op visit  
Those stool samples collected prior to and after the inpatient hospital admission should be returned 
to study personnel via pre-paid mailing envelopes. Subjects participating in the microbiome sub-
study may also undergo a rectal swab on the day of surgery.   
 
8.3.9. Collection of questionnaires 
To examine cognitive and/or motor changes over the course of the study, subjects may complete a 
series of questionnaires.  All subjects participating in this domain will be scheduled to have 
questionnaires completed via telephone interaction prior to their surgery and 30 days (+/- 7 days) 
after their index surgery.   
 
The following questionnaires should be completed during the telephone call prior to the index 
surgery: 
• 
EQ-5D (quality of life) 
• 
MoCA-BLIND 
• 
Functional Activities Questionnaires (FAQ) 
 
 
The following questionnaires should be completed during the 30-day telephone call:  
 
• 
Post-discharge resource use questionnaire  
• 
EQ-5D (quality of life) 
• 
Return to work questionnaire 
 
In order to assess motor function, up to 1/3 of subjects who are over the age of 65 and living within 
20 miles of the primary research offices may be asked to attend a 90 day (+ 28 day) in-person visit 
(Motor Assessment Group).  This visit should include questionnaires similar to those completed 
during the 30-day telephone call as well as motor assessments, specifically: 


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• 
Post-discharge resource use questionnaire  
• 
EQ-5D (quality of life) 
• 
Return to work questionnaire 
• 
Functional Activities Questionnaires (FAQ) 
• 
NIH Toolbox  
o Cognition Battery 
o 2 Minute Walk Test 
o Grip Strength  
On a case-by-case basis, the study team may determine it best to collect these questionnaires via 
telephone interaction.  
For those subjects who do not attend the 90 day in-person visit, the following questionnaires will be 
completed via telephone interaction at 90 days post-op (+ 28 days): 
• 
Hospital readmission questionnaire (primary endpoint) 
• 
EQ-5D (quality of life) 
• 
Return to work questionnaire 
• 
Functional Activities Questionnaires (FAQ) 
• 
Cognitive battery (MoCA-BLIND, Hayling, and phone CAM) 
To avoid in-study learning by patients, alternative versions will be administered for those 
questionnaires used at multiple timepoints.  
If someone should indicate by their answer on the EQ-5D that they are extremely anxious or 
depressed, a member of the LTOC team will ask if the subject has discussed these feelings with their 
health care providers.  If yes, no further action is taken. 
Regarding monitoring for anxiety or depression in subjects as per the queries on the interviews,  if 
the patient answers no, then a written communication would be sent to the patient’s PCP and 
surgeon for the SPRY-related procedure to communicate the subject’s ‘feeling extremely anxious or 
depressed’ response on the EQ-5D, the context of the EQ-5D administration (that is, administered in 
conjunction with a research study). The PI and study team would also be notified of the patient’s 
response. 
 


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8.3.10. Muscle Biopsy Sub-Study 
In collaboration with Dr. Micah Drummond of the University of Utah, who focuses his 
research on the cellular and molecular mechanisms of muscle growth, we intend to explore 
Metformin’s effect on striated muscle growth and structure.  Muscle atrophy is a common 
occurrence within an aged population, often attributed to the decreased mobility and 
disuse seen in older adults. This finding may be accelerated after surgery and prolonged 
immobility.  Dr. Drummond is currently investigating as part of a randomized clinical trial 
whether Metformin may mitigate muscle atrophy through its ability to improve insulin 
sensitivity via AMPK pathway blockade. Dr. Drummond’s clinical trial18 compares metformin 
to placebo for individuals on bed rest for five consecutive days.   
All subjects from the Motor Assessment Group who are willing are eligible for the 
Microbiome and Muscle Biopsy Sub-studies. We intend to expand upon Dr. Drummond’s 
work by enrolling up to 200 subjects from the SPRY study to assess the potential effect of 
Metformin on striated muscle tissue structure.  This will be particularly relevant to assess in 
our patient cohort who are at risk for accelerated muscle atrophy after surgical 
stress.  Subjects involved in this sub-study may have up to 2 muscle biopsy samples taken at 
2 separate timepoints- on the day of elective surgery while the patient is under anesthesia 
and during the Visit at 90 days (+ 28 days) after surgery following the administration of 
lidocaine.  The 90-day muscle biopsy will occur in either the Radiology Procedure Unit B or 
on the 8th floor of Montefiore Hospital. 
Determining Metformin’s effect on muscle tissue may be evaluated by measuring muscle 
fiber cross sectional area and correlating to muscle strength.  In addition, the myogenic 
potential of sample myotubes may be evaluated.  
In addition, as changes in muscle mitochondrial respiration are often seen with muscle 
atrophy, there is interest to examine this aspect and Metformin’s potential effect.   
 
 


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To further examine this aspect, Drs. Forman, Newman, and Finkel would like to be able to 
retain some of the above-referenced samples from the up to 200 subjects from whom 
muscle biopsies are obtained to investigate questions related to mitochondrial respiration 
using fresh muscle tissue as well as to use frozen tissue for questions about lipid and protein 
metabolism. 
Muscle biopsies will be performed by physicians on the study team experienced in muscle 
biopsies, specifically Drs. Neal, Rosengart, Zuckerbraun, and Forman. 
The muscle sample collection procedure involves using a needle to take a small piece of 
muscle tissue from the outside of the patient’s upper leg, about 4-6 inches above the knee. 
Following cleaning of the skin, Lidocaine will be injected to minimize any pain. A small 
incision about the size of this dash  “__” (1/4th of an inch) will be made in the skin, through 
which a needle about the size of the letter “O” is slowly inserted into the muscle.  A piece of 
the muscle (0.125-0.5 gram) is then removed with the needle, the skin is closed with a steri-
strip and a light dressing is applied then a pressure wrap is placed over the dressing.   
For patients involved in the Muscle Biopsy Sub-Study, anti-coagulant medications will be 
held per their standard of care pre-op directions for the biopsy conducted on the day of 
surgery. For the 90-day muscle biopsy, patients will be advised to hold: 
1.Apixaban, Rivaroxaban, Dabigatran, Edoxaban (also known as Eliquis, Xarelto, Pradaxa, 
Savaysa)—48 hours 
 
2. Aspirin, coated or uncoated (also known as Bayer, Bufferin, Exedrin, Ecotrin, Ascriptin)---5 
days 
 
3. Clopidogrel, Ticgrelor, or Pragruel (also known as Plavix, Brilinta, Effient)---5 days 
 
4. Warfarin (also known as Coumadin)---5 days 
 
5. Aggrenox (also known as Dipyridamole and Persantine)---5 days 
 
6. Ticlid (also known as Ticlopidine)---5 days 
 
7. Agrylin or Xagrid (also known as Anagrelide)---5 days 
 


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The study team will confirm the patient has held these medications prior to performing the 
muscle biopsy.  
 
Appropriate post-biopsy care instructions will be provided to patients and a contact person 
in case they experience signs or symptoms of concern. 
 
The study team will also assure patients receive post-op care instructions from the clinical 
team as need per their surgery and length of stay.  
 
For both biopsies timepoints, technicians working under the direction of the study team will 
process the specimens.  Some of these muscle samples (or a portion of the sample) may be 
retained for local use and storage while the remainder of the samples may be analyzed by 
collaborators such as the University of Utah.  These technicians will be responsible for the 
processing of tissue for local use as well as for the shipping of shipping of the frozen muscle 
biopsy samples and associated research data to collaborators such as the University of Utah, 
an identified collaborator, in batches. Dr. Drummond will not store this tissue for long-term 
use. 
 
8.4. Endpoints 
8.4.1. Primary Endpoint 
The primary endpoint for this domain is the REMAP primary outcome of hospital free days at 90 days 
after the elective surgical encounter.   
8.4.2. Secondary Endpoints 
All secondary endpoints as specified in the Core Protocol. 
The domain-specific secondary outcome measures (occurring during the index elective surgical 
procedure), include: 
• 
Hypoglycemia 
• 
Gastrointestinal intolerance 
• 
SAE as defined in Core Protocol 
• 
1 year mortality 


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9. TRIAL CONDUCT 
9.1. Domain-specific Data Collection 
9.1.1. Clinical Data Collection 
Patients who are randomized in this domain will have the following data collected: 
• 
Treatment allocation at the time of enrollment 
• 
Successful dispensing of study medication 
• 
Gastrointestinal intolerance 
• 
SAE as defined in Core Protocol  
9.2. Criteria for Discontinuation  
Refer to Core Protocol for discontinuation criteria for the participation in UPMC REMAP. 
9.3. Blinding  
9.3.1. Blinding 
We will attempt blinding in the following ways. All medication tablets will be void of dosage amounts 
or stamps that identify dose. Each patient will have the number of pills appropriate to the dose to 
which they are randomized. For placebo patients, we will randomly select whether they receive 1, 2, 
or 3 tablets, all of which will be placebo. Placebo pills will appear identical to study drug in color, 
size, shape, and markings, to the extent legally possible.  
9.3.2. Unblinding  
N/A 
10. STATISTICAL CONSIDERATIONS 
10.1. 
Domain-specific Stopping Rules 
If a Platform Conclusion (as defined in the Core Protocol) of equivalence in the primary endpoint is 
demonstrated, the DSMB and the TSC may consider continuation of randomization if clinically 
relevant differences in secondary endpoints have not been demonstrated and it is considered 


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plausible that clinically relevant differences in one or more secondary endpoints may be capable of 
being demonstrated. In all other respects, the stopping rules for this domain are those outlined in 
the Core Protocol.  
In general, the following futility stopping rules shall apply to this domain: 
• 
Drop dose t within duration k if the probability that it is better than placebo by clinically 
significant difference (OR of .8) is less than 15%: Pr(𝑒^(𝛾_(𝑘,𝑡) )<.8)<.15  
• 
Stop enrolling to duration k if all doses have been dropped in that duration 
• 
Stop domain for futility if all doses/durations have been stopped 
 
The following rules shall apply to define success stopping for this domain:  
• 
Pool all active enrolling durations within each dose.  Estimate pooled effect within each 
dose.   
• 
Posterior Probability Best Dose is better than placebo > Success threshold   
• 
Success threshold is based on O'Brien Fleming stopping bounds and multiplicity correction 
for 3 doses.   
More detailed stopping rules may be found in the Statistical Analysis Plan associated with the Core 
Protocol. 
10.2. 
 Strata  
Both analysis of the treatment effect and the Response Adaptive Randomization (RAR) will utilize the 
stratum of surgical clinics in this domain. 
10.3. 
Timing of Revealing of Randomization Status 
The revealing of allocation status and administration of interventions is not specified to occur during 
the trial. 
10.4. 
Interactions with Interventions in Other Domains 
An a priori interaction with the ERAS Domain is considered possible and will be incorporated into the 
statistical models used to analyze this domain. 


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10.5. 
Post-trial Sub-groups 
Domain-specific post-hoc sub-groups will be used in analysis following the conclusion of one or more 
interventions within the domain. The a priori sub-groups of interest include: 
• 
Patients eligible due to comorbidity (and not age criteria) 
• 
Pre-operative exposure duration anticipated to be (eg. <28, 29-90, >90 days) 
• 
Surgical procedure type 
 
11. ETHICAL CONSIDERATIONS 
11.1. 
Data Safety and Monitoring Board  
The DSMB should be aware that the superiority, inferiority, or equivalence of different interventions 
with respect to the primary endpoint is possible, and if equivalence is demonstrated, the optimal 
treatment may be based on secondary endpoints.  
11.2. 
Potential Domain-specific Adverse Events 
The drug used in this domain has a known toxicity profile and adverse events are rare.  
Domain-specific harms related to metformin include: 
• 
Gastrointestinal intolerance 
• 
Hypersensitivity 
• 
Lactic acidosis 
• 
Hemolytic anemia 
• 
Malabsorption 
11.3. 
Domain-specific Consent Issues 
Metformin is approved and is in common use in many countries.  
The use of prolonged courses of metformin is widely used for diabetes and the doses proposed in 
this trial are well within the standard range. Clinics will be able to opt out of this domain for all 
patients at that site if they believe that this intervention is not part of reasonable care of patients 


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evaluated for elective surgery. Additionally, clinicians may choose not to enroll individual patients if 
they feel that participation is not the patient’s best interests.  
12. GOVERNANCE ISSUES 
12.1. 
Funding of Domain 
The SPRY trial is funded by UPMC.  
12.2. 
Domain-specific Declarations of Interest 
All investigators involved in UPMC REMAP will maintain a registry of interests with UPMC. These are 
updated periodically and publicly accessible on the study website. 


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13. REFERENCES 
1.    Loomba, R. et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic 
steatohepatitis. Aliment Pharmacol Ther 29, 172–182 (2009). 
2.    Pernicova, I. & Korbonits, M. Metformin--mode of action and clinical implications for diabetes and 
cancer. Nat Rev Endocrinol 10, 143–156 (2014). 
3.    Glueck, C. J. et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density 
lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. 
Metab Clin Exp 50, 856–861 (2001). 
4.    Algire, C. et al. Metformin reduces endogenous reactive oxygen species and associated DNA 
damage. Cancer Prev Res (Phila Pa) 5, 536–543 (2012). 
5.    Naito, Y. et al. Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during 
and after upper abdominal surgery. Anesthesiology 77, 426–431 (1992). 
6.    Jansson, K. et al. Intraperitoneal cytokine response after major surgery: higher postoperative 
intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source 
of the postoperative inflammatory reaction. Am J Surg 187, 372–377 (2004). 
7.    Lin, E., Calvano, S. E. & Lowry, S. F. Inflammatory cytokines and cell response in surgery. 
Surgery 127, 117–126 (2000). 
8.    Kato, M. et al. Elevated plasma levels of interleukin-6, interleukin-8, and granulocyte colony-
stimulating factor during and after major abdominal surgery. J Clin Anesth 9, 293–298 (1997). 
9.    Alazawi, W., Pirmadjid, N., Lahiri, R. & Bhattacharya, S. Inflammatory and immune responses to 
surgery and their clinical impact. Ann Surg 264, 73–80 (2016). 
10.    Keel, M. et al. Endotoxin tolerance after severe injury and its regulatory mechanisms. J Trauma 
41, 430–7; discussion 437 (1996). 
11.    Hou, X. et al. Metformin reduces intracellular reactive oxygen species levels by upregulating 
expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res 
Commun 396, 199–205 (2010). 
12.    de Luca, C. & Olefsky, J. M. Inflammation and insulin resistance. FEBS Lett 582, 97–105 
(2008). 


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13.    Garrett, C. R. et al. Survival advantage observed with the use of metformin in patients with type 
II diabetes and colorectal cancer. Br J Cancer 106, 1374–1378 (2012). 
14.    Giovannucci, E. et al. Diabetes and cancer: a consensus report. Diabetes Care 33, 1674–1685 
(2010). 
15.    Niraula, S. et al. Abstract PD03-06: Clinical and Biologic Effects of Metformin in Early Stage 
Breast Cancer. Cancer Res 70, PD03-06-PD03-06 (2010). 
16.    Mannucci, E. et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in 
obese nondiabetic subjects. Diabetes Care 24, 489–494 (2001). 
17.    Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl 
Environ Microbiol 80, 5935–5943 (2014). 
18. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 
(US). 2019 Jan 20 -Identifier NCT03107884 Role of Metformin on Muscle Health of Older Adults; 
Available from:https://clinicaltrials.gov/ct2/show/NCT03107884 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
Strategies to Promote ResiliencY - 
Metformin Trial Statistical Analysis Plan: 
An Adaptive Randomized Clinical Trial of Metformin in High-Risk 
Surgical Patients 
 
UPMC REMAP: Randomized, Embedded, Multifactorial Adaptive 
Platform Trial for Optimizing Surgical Outcomes 
 
 
 
 
 
 
 
 
 
 
 
Version: 1.0 
 
          NCT03861767  
 
          06 September 2023 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. UPMC REMAP – SPRY - Metformin domain SAP Version ........................................................ 4 
1.1. Version history .............................................................................................................. 4 
2. 
SAP Authors ........................................................................................................................ 4 
3. 
Introduction ................................................................................................................ 5 
4. 
Design Considerations ...................................................................................................... 5 
5. 
Unblinding .................................................................................................................. 6 
6. 
Interventions .............................................................................................................. 6 
7. 
Disease States .................................................................................................................... 7 
8. 
Analysis Populations ................................................................................................. 8 
9. 
Endpoints ................................................................................................................... 9 
9.1. Primary Endpoint .......................................................................................................... 9 
9.2. Secondary Endpoints ................................................................................................... 9 
10. 
Graphical Data Summaries ...................................................................................... 10 
11. 
Descriptive Statistics ............................................................................................... 11 
12. 
Treatment Delivery ................................................................................................... 12 
13. 
Analytic Approach ................................................................................................... 12 
13.1. Primary Analysis of Primary Endpoint ......................................................................... 12 
13.1.1. Proportional Odds Assumption ............................................................................... 16 
13.2. Analytic Approach for Secondary Endpoints ............................................................... 16 
13.2.1. Descriptive Statistics for Secondary Dichotomous Endpoints .................................. 18 
13.3. Subgroup Analyses .................................................................................................... 18 
13.4. Exploratory Analyses .................................................................................................. 19 
13.5. Missing Data Approach ............................................................................................ 19 
13.6. Multiple Comparisons .............................................................................................. 19 


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SIGNATURE PAGE 
Approvers: 
9/7/2023 
Matthew D. Neal, MD FACS 
Date 
 
 
 
 
 
 
 
9/6/2023 
 
Melanie Quintana, PhD 
Date 


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1. UPMC REMAP – SPRY - METFORMIN DOMAIN SAP VERSION 
 
The version is in this document’s header and on the cover page. 
 
1.1. 
Version history 
 
Version 1: 
Finalized on 06 September 2023. 
 
2. 
SAP AUTHORS 
 
Jason Kennedy, Cheryl Moore, Matthew Neal, Melanie Quintana, Katherine Reitz, Kert Viele, 
Hasan Nassereldine 


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3. 
INTRODUCTION 
 
The population is aging. Over 50 million Americans are greater than 65 years of age.1 Associated with, 
but independent of aging, the cumulative effects of medical, social, and environmental stressors lead to 
frailty.2–4 The physiologic stress associated with the surgical treatment of disease is an age and frailty 
accelerating physiologic stressor, progressing frailty and further depleting resilience.5,6 As such, aging 
and frail patients, whom undergo over one third of all surgical interventions, have an increased risk of 
postoperative morbidity and mortality for all levels of physiologic surgical stress.4,7–11 
 
Strategies to Promote ResiliencY (SPRY) aimed to use the age and frailty inducing surgical intervention as 
an efficient experimental model to stabilize or even reduce frailty and the associated adverse 
postoperative outcomes. Using a randomized, embedded, multifactorial, adaptative platform (REMAP)12 
trial strategy, we hypothesized that the pleiotropic and anti-inflammatory properties of metformin 
administered to non-diabetic patients in the perioperative period would reduce the age-accelerating 
physiologic stress as demonstrated through an increase in postoperative 90-day hospital free days (HFD) 
following an elective, major surgical intervention.13 
 
4. 
DESIGN CONSIDERATIONS 
 
SPRY investigates the effects of perioperative metformin on the primary outcome of 90-day HFD by 
pragmatically randomizing patients with different preoperative exposure durations to placebo or one of 
three doses of metformin. We planned to evaluate three preoperative exposure durations (short, 7-28 
days; intermediate, 29-90 days; and long, 90 days) as well as three doses of metformin extended release 
(ER; 500mg, 1000mg, and 1500mg) among patients undergoing 14 surgical types (i.e., surgical strata). 
The primary Bayesian model, prespecified prior to patient enrollment, is a Bayesian ordinal logistic 
regression to estimate the effect of dose and duration of metformin on the distribution of HFD under 
placebo adjusting for expected differences given the surgical type/strata. Due to early discontinuation of 
the trial, 14 planned surgical types were consolidated into 6 surgical categories and three perioperative 
exposure durations were consolidated into one category for the primary Bayesian model. 
 
In response to the COVID-19 pandemic, SPRY temporarily closed enrollment on 3/20/2020. On 
8/17/2020, SPRY continued to enroll through in-person clinic-based screening and enrollment but 


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expanded to also complete virtual patient screening and enrollment. As a result, two enrollment 
strategies were utilized – in-person and virtual enrollment. 
 
Prespecified adaptive randomization strategies for dose and duration dropping as well as thresholds for 
treatment efficacy, inferiority, futility, and equivalence were defined for interval analysis with 500 
patients enrolled and for every additional 500 patients up to 2,500 followed for 90 days. The complete 
description of the a priori statistical analysis plan was completed prior to patient enrollment and 
previously published.13 However, the trial was discontinued prior to the first interval analysis due to low 
enrollment in the setting of COVID-19 and poor tolerance of perioperative study drug. As such, no 
interim results triggered response adaptive randomization. As previously planned, trial termination 
would result in public disclosure and a declaration of results. 
 
5. 
UNBLINDING 
 
The original intent was for the timing of unblinding to be determined by completion of predetermined 
endpoints by all subjects enrolled. Unblinding at the time of completion of secondary endpoints was not 
considered due to the possibility of their occurrence very early in the trial. As SPRY has closed prior to 
enrolling the goal number of subjects, unblinding will not occur until the statistical analysis plan 
described in this document is finalized. 
 
6. 
INTERVENTIONS 
 
There is one active intervention and one control within this analysis plan: 
1- Metformin 
2- Placebo 
 
Preoperative duration of study drug was pragmatically chosen based upon the time interval between 
the time of enrollment and scheduled operating room date including: 
1- Short – 7-28 days 
2- Medium – 29-90 days 
3- Long – >90 days 
 
Preoperative duration is not considered in the primary model but was considered in planned sensitivity 
analyses. Patients were randomly assigned, √3:1:1:1 to placebo and the 3 doses of metformin: 


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1- Placebo 
2- Metformin 500mg ER 
3- Metformin 1000mg ER 
4- Metformin 1500mg ER 
 
The dosing of and route of administration of metformin guidance included to take an oral dose once 
daily and complete all dispensed medication from the provided pill bottle. 
 
7. 
DISEASE STATES 
 
The disease state under investigation includes the older (age >60) and/or medically frail (age<60 with >2 
Charlson Comorbidity Index) non-diabetic patients undergoing a major surgical intervention. Major 
surgical interventions analyzed include 6 surgical strata: 
 
1- Colon and Rectal Surgery, enrolling from the following clinics 
a. Colon and Rectal Surgery at UPMC Presbyterian University Hospital 
b. Center for Perioperative Care at UPMC Presbyterian Hospital 
c. Center for Perioperative Care at UPMC Shadyside Hospital 
d. Pitt+Me 
2- Genera and Oncological Surgery, enrolling from the following clinics 
a. General Surgery at UPMC Presbyterian University Hospital 
b. General Surgery at UPMC Saint Margaret’s Hospital 
c. Surgical Oncology at UPMC Presbyterian University Hospital, at Presbyterian 
d. Surgical Oncology at UPMC Presbyterian University Hospital, at Shadyside 
e. General Surgery at UPMC Passavant Hospital 
f. 
Center for Perioperative Care at UPMC Presbyterian Hospital 
g. Center for Perioperative Care at UPMC Shadyside Hospital 
h. Pitt+Me 
3- Orthopedic/Spine Surgery, enrolling from the following clinics 
a. Ortho/Spine Surgery at UPMC Presbyterian University Hospital 
b. Center for Perioperative Care at UPMC Presbyterian Hospital 
c. Center for Perioperative Care at UPMC Shadyside Hospital 
d. Pitt+Me 


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4- Neurosurgery, enrolling from the following clinics 
a. Center for Perioperative Care at UPMC Presbyterian Hospital 
b. Center for Perioperative Care at UPMC Shadyside Hospital 
c. Pitt+Me 
5- Vascular Surgery, enrolling from the following clinics 
a. UPMC East Hospital 
b. UPMC Mercy Hospital 
c. UPMC Saint Margaret’s Hospital 
d. Center for Perioperative Care at UPMC Presbyterian Hospital 
e. Center for Perioperative Care at UPMC Shadyside Hospital 
f. 
Pitt+Me 
6- Other, enrolling from the following clinics 
a. Center for Perioperative Care at UPMC Presbyterian Hospital 
b. Center for Perioperative Care at UPMC Shadyside Hospital 
c. Pitt+Me (on-line recruitment) 
 
8. 
ANALYSIS POPULATIONS 
 
All participants who were randomized and underwent a surgical intervention within 365 days of 
randomization will be considered in our analysis population. 
• 
SPRY intention to treat (ITT). This population consists of all patients enrolled and randomized to 
any treatment dose and duration. This population will only include those who underwent a 
surgical intervention at any time in the 365 days following randomization. All comparisons will 
be made based up the randomization table allocated treatment. 
• 
SPRY per protocol analysis (PPA): This population consists of all patients enrolled and 
randomized who also completed randomization table allocated treatment and underwent a 
surgical intervention within 365 days of enrollment. Adherence to the protocol is determined by 
those who confirmed compliance with study drug at their 90-day postoperative evaluation with 
the study team. Compliance is defined by the verbal confirmation of study drug completion at 
the 90-day follow up timepoint. 


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9. 
ENDPOINTS 
 
The following endpoints will be analyzed, displayed graphically, and summarized through descriptive 
statistics. Endpoints will be reported among the analysis populations as well as among the pre-specified 
subgroups. Categorical endpoints may be collapsed where appropriate in case of data sparseness. 
 
9.1. 
Primary Endpoint 
 
The primary endpoint for this domain is the REMAP primary outcome of hospital free days at 90 days 
after the index date (HFD-90). The index date for HFD-90 outcome is defined as the data of the elective 
surgical encounter. 
 
Hospital free days Score 
Score 
-1 
Patient died during surgery or within the 90 days following their 
surgical intervention 
0 
No days out of the hospital in the 90 days following the surgical 
intervention 
1-90 
One to 90 days out of the hospital and alive in the 90 days 
following the surgical intervention 
 
 
 
9.2. 
Secondary Endpoints 
 
Secondary domain-specific outcome measures include information about EHR based alerts reported 
during the index elective surgical admission, perioperative outcomes, and surgical outcomes. 
Specifically, they include: 
• 
Perioperative outcomes (enrollment to postoperative 90 days) 
o Gastrointestinal intolerance (dichotomous; present/absent) 
o SAE as defined in Core Protocol (mild, moderate, severe, life threatening/disabling; 
adjudicated as related, possibly related, unrelated) 


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• 
Surgical outcomes 
o Index admission 
▪ 
Postoperative intensive care unit (ICU) admission (dichotomous; any 
admission/none) 
▪ 
ICU length of stay (LOS; continuous, days) 
▪ 
Hospital LOS (continuous, days) 
▪ 
Discharge disposition (categorical; Home, SNF/LTAC, Death/Hospice) 
▪ 
In-hospital mortality (dichotomous; yes/no) 
o 30-day outcomes 
▪ 
Organ failure free days (i.e., vasopressor exposure, hemodialysis, or mechanical 
ventilation; continuous, days) 
▪ 
Surgical site infection, as defined by NSQIP and the CDC (categorical) 
▪ 
Surgical site occurrence, as defined by Ventral Hernia Working Group 
(categorical) 
o 90-day outcomes 
▪ 
Reoperation/reintervention, both incidence and total number (dichotomous, 
time to event; any/none and continuous, number) 
▪ 
Readmission (dichotomous, time to event; any/none, days) 
▪ 
Venous thromboembolic events including deep vein thrombosis and pulmonary 
embolus after surgery (dichotomous, time to event; any/none, days) 
▪ 
Mortality (dichotomous, time to event; yes/no, days) 
 
10. 
GRAPHICAL DATA SUMMARIES 
 
1. 
Overall cohort accrual, including number of subjects screened, number excluded for each 
inclusion/exclusion criteria, and number of subjects per preoperative enrollment category 
will be presented graphically as a flow/consort diagram. 
2. 
All ordinal endpoints will be plotted using stacked cumulative bar plots and cumulative 
probability plots. 
3. 
All time-to-event endpoints will be plotted using Kaplan-Meier plots. Positive clinical event 
outcomes will be plotted as the cumulative rate of event, and negative events will be plotted 
as the cumulative rate of event-free. 
4. 
All continuous endpoints will be plotted using histograms and boxplots. 


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5. 
All Bayesian logistic and frequentist logistic regression models will be plotted using forest plots. 
 
11. 
DESCRIPTIVE STATISTICS 
 
All demographics, baseline characteristics, and perioperative information will be summarized for all 
randomized participants, the ITT, and PPA analysis populations. Summaries will be presented by 
treatment group (metformin vs placebo), by treatment and dosage group, and by surgical strata. Data 
abstracted prospectively throughout the trial, data within trail reporting documentation, as well as data 
abstracted from the electronic health record will be recorded and included in the summaries. Baseline 
demographics and characteristics will include age at randomization, sex at birth, race, ethnicity, body 
mass index, frailty status as measured by the Risk Analysis Index, smoking status, Charlson Comorbidity 
Index, occurrence of comorbid conditions, preoperative medications, ASA class, surgical strata, and year 
of randomization. All analyses will be completed both in the ITT and PPA populations. 
 
Primary and supplemental tables will include the following populations: 
1- By primary treatment group (Metformin vs placebo) 
2- By primary treatment group, separated by dose 
3- By primary treatment group, separated by preoperative duration and dose 
4- By surgical strata 
 
All endpoints will be modeled following a standard convention based upon the frequency of the events. 
For interventions with <10 subjects, we will summarize outcomes with No. (%) without modeling due to 
the small sample size. All analysis will be completed both in the ITT and PPA populations. 
1- Ordinal endpoints will be summarized by the number and cumulative frequency of each 
outcome. The 25th, 50th, and 75th percentiles will be summarized. 
2- Dichotomous endpoints will be summarized by the proportion in each category. 
3- Composite endpoints will be summarized overall and for each component individually. 
4- Time-to-event outcomes will be summarized by the 2.5th, 10th, 25th, 50th, 75th, 90th, and 97.5th 
percentiles from the Kaplan-Meier estimates, as available. 
5- Continuous endpoints will be summarized by the mean, standard deviation or median, 
interquartile range (IQR) pending the distribution of the data. 


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12. 
TREATMENT DELIVERY 
 
Following randomization, study drug was either provided to the subjects in clinic or study drug was 
mailed directly to their home. Study drug compliance was monitored at the postoperative 90-day 
interaction with the study team. At this time, participants who discontinued their medications were 
determined not adherent and those who continued were adherent. In addition, if patients reported 
early termination or non-adherence to study drug, this was recorded by study coordinators and 
reported. 
 
13. 
ANALYTIC APPROACH 
 
Primary inferential analyses will be done using a Bayesian approach. Sensitivity analyses will be 
conducted using both Bayesian and Frequentist approaches, as described. Secondary endpoints will be 
analyzed using frequentist approaches. A summary of the analyses methods is provided below. For all 
frequentist models, statistical significance will be defined as a one-sided p-value of <0.025, and for all 
Bayesian models a one-sided posterior probability > 0.975. If stable inference cannot be made due to 
sparseness of data within strata/categories, data may be further collapsed as needed. 
 
13.1. Primary Analysis of Primary Endpoint 
 
Primary Analysis 
 
The primary analysis model is a Bayesian cumulative logistic model for the ordinal primary endpoint. 
The primary analysis is to be completed in both the ITT and PPA populations described above. 
 
In the primary analysis, observations will be pooled across pre-operative duration of study drug and will 
borrow across study drug dose. The primary endpoint for this model is HFD-90 and will be compared 
across the placebo and three levels of study drug dose. The general Bayesian cumulative logistic model 
is defined below: 
Throughout we assume for patient i, 𝑌𝑌𝑖𝑖 is the observed 90-day HFD, 𝑔𝑔(𝑖𝑖), is the surgical strata from 1:G, d(i) 
is the pre-op duration from 1:3 with 1 = short, 2 = intermediate, and 3=long, and t(i) is the 
intervention from 1:4 with 1 = placebo, 2 = 500mg, 3 = 1000mg, and 4 = 1500mg. 


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The general Bayesian ordinal logistic regression model is used to estimate the effect of dose and 
duration of metformin on the distribution of HFD-90 under placebo adjusting for expected differences 
given the surgical strata. The ordinal scale parameterization is a generalized version of the dichotomous 
parameterization where we model all cumulative probabilities of 90-day HFD being less than or equal to 
a cut point c, where c=–1,…, 89. Given each cut point c, we denote the 91 dichotomized versions of 90- 
day HFD for patient i as 𝑌𝑌𝑐𝑐,𝑖𝑖 where 𝑌𝑌𝑐𝑐,𝑖𝑖  = 1 if 90-day HFD is in [-1, c] and 𝑌𝑌𝑐𝑐,𝑖𝑖  = 0 if 90-day HFD is in 
[c+1,90] for c=-1,…, 89.  𝑌𝑌𝑐𝑐,𝑖𝑖 is then modeled throughout as: 
 
𝑌𝑌𝑐𝑐,𝑖𝑖~ 𝐵𝐵𝑒𝑒𝑟𝑟𝑛𝑛𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑖𝑖(𝜙𝜙𝑐𝑐,𝑖𝑖); 
 
𝑙𝑙𝑙𝑙𝑔𝑔𝑖𝑖𝑡𝑡(𝜙𝜙𝑐𝑐,𝑖𝑖) = 𝛾𝛾𝑐𝑐 + 𝜇𝜇𝑖𝑖; 
 
where 𝜇𝜇𝑖𝑖 is a patient-specific mean function and 𝛾𝛾𝑐𝑐 is common across all patients. To assure model 
stability, if there is an outcome in the ordinal scale that did not occur in the data, then that outcome will 
be combined with a neighboring outcome (the worse outcome). For example, if the outcome 11 never 
occurred, then a combined outcome of 10 & 11 will be modeled for the analysis. 
 
The subject-specific mean function is as follows: 
 
𝜇𝜇𝑖𝑖  = 𝛼𝛼𝑔𝑔(𝑖𝑖) + 𝜃𝜃𝑡𝑡(𝑖𝑖),𝑑𝑑(𝑖𝑖). 
 
Within this model we assume that the underlying distribution of HFD-90 is different within each 
stratum, g, and these differences across strata can be explained by a proportional log-odds ratio shift in 
the HFD-90 distribution, 𝛼𝛼𝑔𝑔. Stratum are defined in Section 7. Furthermore, we assume that the effects of 
each intervention within each pre-op duration are constant across strata and can be explained by a 
proportional log-odds ratio shift in the HFD-90 distribution 𝜃𝜃𝑡𝑡,𝑑𝑑 . Where a log-odds ratio 𝜃𝜃𝑡𝑡,𝑑𝑑 < 0 results 
in an increase in expected HFD-90. For identifiability we assume the effect of placebo across all 
durations is zero, 𝜃𝜃1,𝑑𝑑 = 0 𝑓𝑓𝑓𝑓𝑓𝑓 𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑 = 1: 3. As such, the values of the inverse logit of 𝛾𝛾𝑐𝑐 define the 
cumulative probabilities for each HFD-90 value under placebo, common across pre-op durations, and 
averaged across all strata. For all doses of metformin, we assume that the log-odds ratio of the effect of 
the dose is dependent on the pre-op duration and takes on the following form: 
 
𝜃𝜃𝑡𝑡(𝑖𝑖),𝑑𝑑(𝑖𝑖)  = 𝛽𝛽𝑡𝑡 + 𝜅𝜅𝑑𝑑    𝑓𝑓𝑜𝑜𝑜𝑜 𝑡𝑡 = 2,3,4 𝑎𝑎𝑎𝑎𝑑𝑑 𝑑𝑑 = 1,2,3. 


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ℎ=
Here, 𝛽𝛽𝑡𝑡 is the log-odds ratio due to the dose and 𝜅𝜅𝑑𝑑 is the log-odds ratio due to the duration. Under the 
primary analysis where we pool across all pre-op durations we assume 𝜅𝜅𝑑𝑑 = 0 for all pre-op 
durations, 𝑑𝑑 = 1: 3. 
 
The prior distribution of 𝛾𝛾𝑐𝑐 is specified on the probability scale: 
 
𝜋𝜋 ~ 𝐷𝐷𝑖𝑖𝑖𝑖𝑖𝑖𝑐𝑐ℎ𝑙𝑙𝑒𝑒𝑡𝑡(𝛼𝛼−1, ⋯ 𝛼𝛼90); 
 
𝑐𝑐 
𝛾𝛾𝑐𝑐  = 𝑙𝑙𝑙𝑙𝑔𝑔𝑖𝑖𝑖𝑖 ( ∑ 𝜋𝜋𝑖𝑖) ; 
𝑖𝑖=−1 
 
With hyper-parameters, 𝛼𝛼ℎ, specified based on the observed rates of HFD-90 across all strata in pre-trial 
data (discussed in Section 4) and providing 1 patient worth of information so that  ∑90 
𝛼𝛼ℎ  = 1. 
 
For the strata-specific log-odds ratios we place a normal prior distribution with mean 0 and standard 
deviation 2: 
 
𝛼𝛼𝑔𝑔~𝑁𝑁(0,22). 
 
Under the primary analysis, we assume a hierarchical distribution for the dose-effects centered around a 
common mean so there is borrowing of information across doses: 
 
𝛽𝛽𝑡𝑡~𝑁𝑁(𝜇𝜇𝛽𝛽, . 52) 𝑓𝑓𝑜𝑜𝑜𝑜 𝑡𝑡 = 2,3,4; 
 
𝜇𝜇𝛽𝛽~𝑁𝑁(0,1). 
 
 
 
Bayesian Sensitivity Analyses 
 
Sensitivity analyses will be conducted in both ITT and PPA populations to assess alternative definitions 
to degree of study drug exposure. Specifically, the Bayesian cumulative logistic regression with HFD-90 
outcome and analysis populations will be conducted for pooling across study drug dose and borrowing 
across pre-operative duration of study drug. The Bayesian ordinal logistic model will be the same as 
described above except with the following modifications to 𝜃𝜃𝑡𝑡,𝑑𝑑 


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𝜃𝜃𝑡𝑡(𝑖𝑖),𝑑𝑑(𝑖𝑖)  = 𝛽𝛽𝑡𝑡 + 𝜅𝜅𝑑𝑑    𝑓𝑓𝑜𝑜𝑜𝑜 𝑡𝑡 = 2,3,4 𝑎𝑎𝑎𝑎𝑑𝑑 𝑑𝑑 = 1,2,3. 


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Here, 𝛽𝛽𝑡𝑡 is the log-odds ratio due to the dose and 𝜅𝜅𝑑𝑑 is the log-odds ratio due to the duration. Under the 
sensitivity analysis where we pool across all active doses we assume 𝛽𝛽𝑡𝑡 = 0 for all active doses, 𝑡𝑡 = 2: 4. 
 
Under the sensitivity analysis, we assume a hierarchical distribution for the pre-op duration effects 
centered around a common mean so there is borrowing of information across pre-op durations: 
 
𝜅𝜅𝑑𝑑~𝑁𝑁(𝜇𝜇𝜅𝜅, . 52) 𝑓𝑓𝑜𝑜𝑜𝑜 𝑑𝑑 = 1,2,3; 
 
𝜇𝜇𝜅𝜅~𝑁𝑁(0,1). 
 
Frequentist Sensitivity Analyses 
 
In addition, sensitivity analyses will be conducted in which frequentist regression models are used in 
place of the Bayesian cumulative logistic regression and without borrowing across groups. For these 
analyses, we will assess HFD-90 by 4 definitions of treatment arms based on the intervention, on both 
the ITT and PPA populations: 
 
1. Treated (any duration and/or dose combined to a single group) vs. placebo 
2. Metformin 1500mg ER vs. Metformin 1000mg ER vs. Metformin 500mg ER vs. Placebo (each 
pooled across duration) 
3. Long Metformin (>90 days) vs. Medium Metformin (29-90 days) vs. Short Metformin (7-28 days) 
vs. Placebo (each pooled across the 3 doses of study drug) 
4. Placebo vs. 500mg and 7-28 day duration vs. all other treatment combinations 
For each of these definitions, we will apply two approaches: 
1. A frequentist proportional odds model for the cumulative odds of 90-day HFD being less than or 
equal to a cut point c, where c=–1,…, 89, as described in the primary Bayesian analysis above. 
The treatment effect will be estimated, adjusting for surgical strata and duration as covariates. 
2. A Mann-Whitney U test with ties for differences in HFD-90 by treatment arm. Test statistics and 
p-values will be presented. We will report death as a dichotomous outcome (vs. no death) and, 
among survivors, HFD-90 as a continuous outcome, as outlined in Section 11. 
 
In the logistic regression model, the model structure will be as follows: 


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𝑦𝑦𝑖𝑖  = 𝑙𝑙𝑙𝑙𝑔𝑔𝑖𝑖𝑡𝑡(𝛽𝛽0 + 𝛽𝛽𝑖𝑖 ∗ 𝑡𝑡𝑥𝑥 𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖 + 𝜀𝜀𝑖𝑖 ); 
 
Where: 
yi: Outcome (HFD-90 = 90 vs. ≠ 90) for subject i 
β0 = Coefficient for intercept (for odds of outcome for placebo (reference) group) 
βi = Coefficient(s) for treatment(s) vs. placebo 
εi = Residual Error for Subject I (i.e. Subject-level random/residual error) 
 
13.1.1. 
Proportional Odds Assumption 
 
The proportional odds assumption of the treatment effect from the cumulative logistic regression model 
can be viewed as an average of the individual ORs resulting from dichotomizing at each of the possible 
cut points of HFD-90. The proportional odds assumption is not required to obtain the average OR 
estimate; however, this estimate may be a poor summary of treatment effect in the presence of large 
deviations from proportionality. The degree to which the proportionality assumption is valid will be 
assessed through visual inspection of the cumulative probability curve across all HFD-90 values within 
each active treatment arm (when pooling pre-op duration) and within each pre-op duration (when pool 
active doses) will be compared to the cumulative probability curve under the placebo group. 
Additionally, we will evaluate the individual ORs under each dichotomization of HFD-90 compared to the 
overall average OR under the cumulative logistic regression model. 
 
13.2. 
Analytic Approach for Secondary Endpoints 
 
Primary Analysis 
 
The analysis of secondary endpoints will be conducted with Frequentist methods using unadjusted linear 
regression, logistic regression, and Cox models for continuous, dichotomous, and time-to-even 
secondary endpoints, respectively on both the ITT and PPA populations. Secondary endpoints are 
described in section 9.2 above. Treatment arms will be pooled across all durations and doses to form 
treated vs. placebo groups, with the placebo group used as the reference category in all analyses. There 
will be no adjustment for covariates, other than treatment arm. 
 
The model structures will mimic the approach used in the frequentist analysis of the primary endpoint 
above. Specifically: 


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Linear regression: 
 
𝑦𝑦𝑖𝑖  = 𝛽𝛽0 + 𝛽𝛽𝑖𝑖 ∗ 𝑡𝑡𝑥𝑥 𝑎𝑎𝑎𝑎𝑚𝑚𝑖𝑖 + 𝜀𝜀𝑖𝑖; 
 
Logistic regression: 
 
𝑦𝑦𝑖𝑖  = 𝑙𝑙𝑙𝑙𝑔𝑔𝑖𝑖𝑡𝑡(𝛽𝛽0 + 𝛽𝛽𝑖𝑖 ∗ 𝑡𝑡𝑥𝑥 𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖 + 𝜀𝜀𝑖𝑖 ); 
 
Cox Regression: 
 
ℎ(𝑡𝑡|𝑥𝑥𝑖𝑖) = ℎ0(𝑡𝑡) ∗ exp (𝛽𝛽𝑖𝑖 ∗ 𝑡𝑡𝑥𝑥 𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖); 
 
Where: 
yi or h(t|xi): Secondary outcome of interest for subject i 
β0 or h0(t) = Coefficient for intercept or baseline hazard estimate 
βi = Coefficient(s) for treatment(s) vs. placebo 
εi = Residual Error for Subject I (i.e. Subject-level random/residual error) 
 
Statistical significance will be defined as an unadjusted p<0.025. For all models, outputs will be reported 
using standard conventions and will include regression coefficients, standard deviations, confidence 
intervals, test statistics, and p-values, as relevant to each model. Model outputs will be reported both 
graphically and in tables, as described in sections 10 and 13.10. 
 
Sensitivity Analysis 
 
Secondary endpoints will be assessed for alternative definitions of treatment arm. Analyses will mirror 
the primary analysis of secondary endpoints, replacing the treatment arm with the following alternative 
definitions: 
 
1. Metformin 1500mg ER vs. Metformin 1000mg ER vs. Metformin 500mg ER vs. Placebo (each 
pooled across duration) (Primary Approach) 
2. Long Metformin (>90 days) vs. Medium Metformin (29-90 days) vs. Short Metformin (7-28 days) 
vs. Placebo (each pooled across the 3 doses of study drug) 
3. Placebo vs. 500mg and 7-28 day duration vs. all other treatment combinations 
 
Model structures will mirror the primary analysis of secondary endpoints and statistical significance 


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will again be defined as an unadjusted p<0.025. 


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13.2.1. 
Descriptive Statistics for Secondary Dichotomous Endpoints 
 
In addition to models described above, dichotomous, categorical, and time-to-event endpoints will be 
reported using descriptive statistics, including number and percent, overall and by strata, as described 
above in Section 11. Results will be stratified by the definition of treatment used in the primary analysis 
of secondary endpoints (i.e., treated vs. untreated) only. 
 
13.3. Subgroup Analyses 
 
For the primary outcome of HFD-90 only, subgroups will be evaluated using a frequentist cumulative 
logistic regression model, as in the primary analysis. These analyses will be conducted on both the ITT 
and PPA populations and will follow the same approach to pooling across duration and borrowing across 
dose as in the primary analysis. Analyses will be stratified by each of the following subgroups: 
1. Age >= overall median vs < overall median (hypothesis, more effective among those > median) 
2. Sex at birth (hypothesis: no difference) 
3. Frailty, comparing robust/normal vs. frail/very frail (hypothesis, more effective among frail and 
very frail). Note that subgroup of robust with normal and frail with very frail may be modified as 
necessary (e.g., to robust vs. normal/frail/very frail) if sample size for either group is <= 25). 
4. Surgical strata (hypothesis, no difference) 
o No operation 
o Spine 
o General surgery/surgical oncology 
o Colorectal Surgery 
o Other 
o Any strata with <= 25 subjects will be combined into the “Other” category, except the 
“No operation” group 
5. Surgical stress (hypothesis, more effective among higher stress procedures) 
o Same day surgery procedures 
o Procedures with subsequent hospital admission 


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13.4. Exploratory Analyses 
 
Exploratory analyses after unblinding will not be considered inferential. Any post hoc exploratory 
analyses will be clearly labeled as exploratory and will use the conventions below. 
1. 
Ordinal endpoints will be compared using a cumulative proportional odds model with 
summaries of the OR, 95% credible intervals, and Wilcoxon tests for robustness against a lack 
of proportional odds. 
2. 
Time-to-Event analyses will utilize a Cox proportional hazards model, summarizing the hazard 
ratios and 95% confidence intervals. 
3. 
Continuous endpoints will compare means with 95% confidence intervals based on two-sample 
t-test and/or Mann Whitney U test procedures. 
4. 
Dichotomous proportions will be compared using logistic regression summarizing the OR and 
95% confidence intervals. Differences between proportions will be summarized using 
observed differences and normal approximations for the 95% credible intervals. 
13.5. Missing Data Approach 
 
Missing data will be minimized by chart abstraction, as feasible, for missing covariates of all models. 
Missing data will be reported with number and proportion in summary statistics. For statistical model, 
where data was not captured, it will be assumed Missing at Random (MAR) and will be imputed as the 
median value among observed subjects, within strata of dose. 
13.6. Multiple Comparisons 
 
No adjustment for multiple comparisons will be made, as the primary analysis model is for a single 
endpoint and secondary endpoints are intended to provide a broad statistical context for results of the 
primary analysis model.