Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Optimizing Surgical Outcomes at UPMC
Phase: PHASE3
Conditions: Aging
Sponsor: Matthew Neal MD

 
 
 
 
 
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 

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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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