<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03816488</url>
  </required_header>
  <id_info>
    <org_study_id>5451</org_study_id>
    <nct_id>NCT03816488</nct_id>
  </id_info>
  <brief_title>Oral Peri-operative TIming of Metformin (or) Salsalate to Improve Non-cardiac Surgery Glucose Control</brief_title>
  <acronym>OPTIM(i)SING</acronym>
  <official_title>Oral Peri-operative TIming of Metformin (or) Salsalate to Improve Non-cardiac Surgery Glucose Control - A Placebo-Controlled Internal Feasibility Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>McMaster University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>McMaster University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypothesis: In surgical patients with type 2 diabetes, taking either metformin or salsalate&#xD;
      on the morning of surgery will reduce the incidence of hyperglycemia, inflammation and even&#xD;
      surgical site infections, without any obvious patient risk relative to patients given a&#xD;
      placebo control.&#xD;
&#xD;
      Anesthesia and surgery induce a number of metabolic disturbances, particularly among patients&#xD;
      with type 2 diabetes (T2D). This includes altered glucose metabolism and hyperglycemia, which&#xD;
      is associated with significant morbidity and mortality, including an increase in surgical&#xD;
      site infections (SSI). Although insulin protocols can reduce blood glucose levels in&#xD;
      hyperglycemic surgical patients, leading to reduced SSI, this has caused severe hypoglycemia&#xD;
      in a number of patients. Instead, the use of simple and effective interventions, such as&#xD;
      continuing metformin on the day of surgery, could represent an important step toward reducing&#xD;
      the incidence of these morbid outcomes while improving glucose control. Alternatively,&#xD;
      salsalate, a non-acetylated dimer of salicylic acid, has also emerged as a novel&#xD;
      glucose-lowering medication that also possesses important anti-pyretic and anti-inflammatory&#xD;
      properties and could prove equally effective.These refinements may also reduce SSI and&#xD;
      inflammation. If the proposed pilot trial, to continue metformin, or take salsalate,&#xD;
      peri-operatively, is as safe and easy as the investigators anticipate it will allow for the&#xD;
      planning of a future definitive randomized clinical trial. The aims of this pilot trial are&#xD;
      to assess the feasibility of safely continuing metformin, or taking salsalate on the day of&#xD;
      surgery, with the goal of reducing the incidence of hyperglycemic events. This includes&#xD;
      assessing our ability to recruit patients, adhere to the proposed study protocol, assess&#xD;
      workload,and measure the desired outcomes, all of which are crucial for the planning of a&#xD;
      subsequent clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This internal pilot study (n=36) is designed as a 3-arm, parallel, placebo-controlled trial&#xD;
      with block randomization. All parties will be blinded.&#xD;
&#xD;
      Patient Recruitment: Patients with T2D on metformin presenting to the Hamilton Health&#xD;
      Sciences (HHS) preoperative clinic for elective surgery requiring general anesthetic will be&#xD;
      screened for eligibility.&#xD;
&#xD;
      Sample Size: 36 patients over the 1-year study. This sample size will allow for 3 groups of&#xD;
      12, which permits block randomization and precise confidence interval (CI) calculations.&#xD;
&#xD;
      Randomization and Allocation: Patients will be randomized on the day of their pre-operative&#xD;
      assessment by our department statistician using a computer-generated table, with an&#xD;
      allocation ratio of 1:1:1 in random permuted blocks of 3 or 6. Only the pharmacist and&#xD;
      statistician will know the allocation sequence. Concealed medications (over-encapsulated)&#xD;
      will be provided to the RC upon confirming the allotment with a unique identification number&#xD;
      (UIN), recorded on the patient-specific case record form (CRF).&#xD;
&#xD;
      Application of Intervention: Our intervention involves self-administered metformin (patient's&#xD;
      usual dose) vs. salsalate (1.5g) vs. placebo with sips of water 2h prior to surgery. Baseline&#xD;
      data (age, height, weight, ASA score, mean arterial BP, and baseline glucose) will be&#xD;
      collected by the RC in the pre-operative assessment area, and flash glucose sensors&#xD;
      (FreeStyle Libre, Abbot) will be placed on the upper arm as per manufacturer's instructions&#xD;
      and readings collected by the RC. Study data will be securely stored in the anesthesia&#xD;
      research office, McMaster University. Standard monitors will be used in the operating room,&#xD;
      with any additional monitoring left to the anesthesiologist's discretion. Although most&#xD;
      anesthetics appear to modify glucose metabolism, general anesthesia will be provided in their&#xD;
      preferred manner (including dexamethasone administration for post-operative nausea and&#xD;
      vomiting prophylaxis) to improve generalizability. Details of the type of drugs, fluids and&#xD;
      blood loss will be recorded. Following surgery, patients will be brought to the PACU for&#xD;
      routine monitoring (30-60 min), and additional blood samples will be drawn. Subsequent&#xD;
      samples will be collected on the evening of surgery (6-12h) and POD1. Any episodes of hyper-&#xD;
      or hypoglycemia will be managed routinely at the treating physician's discretion and details&#xD;
      recorded.&#xD;
&#xD;
      Measurements of Inflammation: Blood and urine samples will be collected on the morning of&#xD;
      surgery, upon admission to PACU, and will coincide with other tests to minimize needle&#xD;
      sticks. Blood samples will be processed at the HHS Core Research Laboratory and divided into&#xD;
      3 serum and 2 EDTA aliquots, barcoded and stored in liquid nitrogen. Urine samples will be&#xD;
      divided into 2 barcoded aliquots and stored in liquid nitrogen. This will allow for future&#xD;
      analysis and characterization of biochemical pathways related to the surgical stress&#xD;
      response. These future analyses will include measurement of insulin and proinsulin since&#xD;
      salsalate may modify their endogenous metabolism. Similarly, the investigators eventually&#xD;
      plan to measure various inflammatory markers implicated in the development of acute&#xD;
      stress-induced insulin resistance (i.e. IL-6, TNFα, and hsCRP), which could provide insight&#xD;
      into potential beneficial effects of salsalate or metformin.&#xD;
&#xD;
      Feasibility Outcomes: The primary feasibility outcomes include calculating the recruitment&#xD;
      rate (both the percentage of individuals who were approached in the pre-operative clinic that&#xD;
      enrolled in the study, and the total number of individuals that were recruited each month&#xD;
      (Table 1, supplemental document). The ability to follow study protocol will be reported as&#xD;
      the percentage of individuals who were able to complete the study protocol as a fraction of&#xD;
      the total number of individuals recruited for i) drug administration and blinding, ii) blood&#xD;
      sampling at specified times, and iii) reliability of CGM by comparison with laboratory&#xD;
      glucose values. Workload will be calculated per patient, and safety profile assessed by&#xD;
      recording adverse events. Together, this may identify pitfalls requiring modification prior&#xD;
      to a full RCT.&#xD;
&#xD;
      Statistical Analysis and Feasibility: Reporting and analysis will conform to the CONSORT&#xD;
      pilot and feasibility trials guidelines (www.consort-statement.org). Data will be collected&#xD;
      using an encrypted online tool (RedCap, Research Electronic Data Capture) hosted at McMaster.&#xD;
      To be feasible and continue onto a subsequent RCT the investigators will need to recruit at&#xD;
      least 3 patients per month. Additionally, the investigators seek an adherence rate of 88.9%&#xD;
      (32/36) to receive study drug, collect more than 90.3% (130/144) of pre-specified blood&#xD;
      samples, and ensure 83.3% (30/36) patients have been followed up within 6 weeks of their&#xD;
      procedure to document any complications (e.g. SSI). If targets prove difficult, then our&#xD;
      protocol will be reevaluated for possible amendments that will not compromise final outcomes.&#xD;
      Given this is a pilot, CIs will be calculated for outcomes of interest: rates of&#xD;
      hyperglycemia, SSI, and degree of inflammation.&#xD;
&#xD;
      Trial Management: This pilot trial will be conducted at HHS. The trial will enlist support&#xD;
      and collaboration from surgeons and fellow anesthesiologists. Study data will be securely&#xD;
      stored at the anesthesia research office, McMaster University. An RC will be employed for&#xD;
      patient recruitment and data collection. The CRFs for study patients will be randomly&#xD;
      cross-checked for completeness and accuracy. All reports of incorrect randomizations,&#xD;
      protocol violations or incomplete data will be noted.&#xD;
&#xD;
      Risk Assessment: This trial does not entail any higher risk to the patient than the present&#xD;
      standard of care. It is pragmatic, and uses clinically acceptable doses with a safe profile.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Unable to source salsalate.&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 1, 2023</start_date>
  <completion_date type="Anticipated">December 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Parallel, placebo-controlled trial with block randomization</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Patients will be randomized on the day of their pre-operative assessment by our department statistician using a computer-generated table, with an allocation ratio of 1:1:1 in random permuted blocks of 3 or 6. Only the pharmacist and statistician will know the allocation sequence. Concealed medications (over-encapsulated) will be provided to the RC upon confirming the allotment with a unique identification number (UIN), recorded on the patient-specific case record form (CRF).</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility: recruitment rate (percentage)</measure>
    <time_frame>One year</time_frame>
    <description>Percentage (%) of individuals who were approached in the pre-operative clinic that enrolled in the study</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Participants with hyperglycemia</measure>
    <time_frame>One year</time_frame>
    <description>Detect change in hyperglycemic events (glucose &gt;11mmol/L) at the 4 blood sampling time points for each participant</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility: recruitment rate (total number per month)</measure>
    <time_frame>One year</time_frame>
    <description>Number (n) of individuals recruited each month</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood glucose levels (glycemic control)</measure>
    <time_frame>One year</time_frame>
    <description>Evaluation of glycemic control by calculating mean blood glucose levels obtained at 4 time points</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with inflammation</measure>
    <time_frame>One year</time_frame>
    <description>Measured using validated biomarkers (IL-6, tumor necrosis factor, high-sensitivity C reactive protein), and surgical site infections recorded within 6 weeks of surgery</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Hyperglycemia</condition>
  <condition>Perioperative/Postoperative Complications</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Self-administered metformin (patient's usual dose) taken 2 hours prior to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Salsalate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Self-administered salsalate taken 2 hours prior to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Self-administered placebo taken 2 hours prior to surgery</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Metformin (usual dose) administered 2 h before surgery</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Salsalate</intervention_name>
    <description>Salsalate 1.5 g administered 2 h before surgery</description>
    <arm_group_label>Salsalate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Elective surgical patients requiring a general anesthetic at HHS requiring at least an&#xD;
             overnight admission;&#xD;
&#xD;
          -  Using metformin regularly for control of T2D;&#xD;
&#xD;
          -  American Society of Anesthesiologists (ASA) physical classification I, II and III;&#xD;
&#xD;
          -  Less than 1000 mL of blood loss is expected.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Procedures for which non-steroidal anti-inflammatory drugs are contraindicated;&#xD;
&#xD;
          -  Diagnosis of renal failure (estimated glomerular filtration rate &lt;60 mL/min/1.73m2);&#xD;
&#xD;
          -  Liver failure;&#xD;
&#xD;
          -  Previous episodes of congestive heart failure;&#xD;
&#xD;
          -  Severe hypoglycemia in the past year;&#xD;
&#xD;
          -  Conditions masking hypoglycemia (e.g. autonomic neuropathy);&#xD;
&#xD;
          -  Low random blood glucose during pre-screening (≤4.0 mmol/L);&#xD;
&#xD;
          -  Received contrast within 48h prior to, or during, surgery.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <reference>
    <citation>Palermo NE, Gianchandani RY, McDonnell ME, Alexanian SM. Stress Hyperglycemia During Surgery and Anesthesia: Pathogenesis and Clinical Implications. Curr Diab Rep. 2016 Mar;16(3):33. doi: 10.1007/s11892-016-0721-y.</citation>
    <PMID>26957107</PMID>
  </reference>
  <reference>
    <citation>Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe C, Hudson M, Mendoza J, Johnson R, Lin E, Umpierrez GE. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010 Aug;33(8):1783-8. doi: 10.2337/dc10-0304. Epub 2010 Apr 30.</citation>
    <PMID>20435798</PMID>
  </reference>
  <reference>
    <citation>Membership of the Working Party; Barker P, Creasey PE, Dhatariya K, Levy N, Lipp A, Nathanson MH, Penfold N, Watson B, Woodcock T. Peri-operative management of the surgical patient with diabetes 2015: Association of Anaesthetists of Great Britain and Ireland. Anaesthesia. 2015 Dec;70(12):1427-40. doi: 10.1111/anae.13233. Epub 2015 Sep 29. Erratum In: Anaesthesia. 2019 Jun;74(6):810.</citation>
    <PMID>26417892</PMID>
  </reference>
  <reference>
    <citation>Smith BK, Ford RJ, Desjardins EM, Green AE, Hughes MC, Houde VP, Day EA, Marcinko K, Crane JD, Mottillo EP, Perry CG, Kemp BE, Tarnopolsky MA, Steinberg GR. Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-beta1. Diabetes. 2016 Nov;65(11):3352-3361. doi: 10.2337/db16-0564. Epub 2016 Aug 23.</citation>
    <PMID>27554471</PMID>
  </reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>January 12, 2023</last_update_submitted>
  <last_update_submitted_qc>January 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metformin</keyword>
  <keyword>Salsalate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Hyperglycemia</mesh_term>
    <mesh_term>Postoperative Complications</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Salicylsalicylic acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03816488
org study id: 5451
nct id: NCT03816488
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Hypothesis: In surgical patients with type 2 diabetes, taking either metformin or salsalate
      on the morning of surgery will reduce the incidence of hyperglycemia, inflammation and even
      surgical site infections, without any obvious patient risk relative to patients given a
      placebo control.

      Anesthesia and surgery induce a number of metabolic disturbances, particularly among patients
      with type 2 diabetes (T2D). This includes altered glucose metabolism and hyperglycemia, which
      is associated with significant morbidity and mortality, including an increase in surgical
      site infections (SSI). Although insulin protocols can reduce blood glucose levels in
      hyperglycemic surgical patients, leading to reduced SSI, this has caused severe hypoglycemia
      in a number of patients. Instead, the use of simple and effective interventions, such as
      continuing metformin on the day of surgery, could represent an important step toward reducing
      the incidence of these morbid outcomes while improving glucose control. Alternatively,
      salsalate, a non-acetylated dimer of salicylic acid, has also emerged as a novel
      glucose-lowering medication that also possesses important anti-pyretic and anti-inflammatory
      properties and could prove equally effective.These refinements may also reduce SSI and
      inflammation. If the proposed pilot trial, to continue metformin, or take salsalate,
      peri-operatively, is as safe and easy as the investigators anticipate it will allow for the
      planning of a future definitive randomized clinical trial. The aims of this pilot trial are
      to assess the feasibility of safely continuing metformin, or taking salsalate on the day of
      surgery, with the goal of reducing the incidence of hyperglycemic events. This includes
      assessing our ability to recruit patients, adhere to the proposed study protocol, assess
      workload,and measure the desired outcomes, all of which are crucial for the planning of a
      subsequent clinical trial.
This internal pilot study (n=36) is designed as a 3-arm, parallel, placebo-controlled trial
      with block randomization. All parties will be blinded.

      Patient Recruitment: Patients with T2D on metformin presenting to the Hamilton Health
      Sciences (HHS) preoperative clinic for elective surgery requiring general anesthetic will be
      screened for eligibility.

      Sample Size: 36 patients over the 1-year study. This sample size will allow for 3 groups of
      12, which permits block randomization and precise confidence interval (CI) calculations.

      Randomization and Allocation: Patients will be randomized on the day of their pre-operative
      assessment by our department statistician using a computer-generated table, with an
      allocation ratio of 1:1:1 in random permuted blocks of 3 or 6. Only the pharmacist and
      statistician will know the allocation sequence. Concealed medications (over-encapsulated)
      will be provided to the RC upon confirming the allotment with a unique identification number
      (UIN), recorded on the patient-specific case record form (CRF).

      Application of Intervention: Our intervention involves self-administered metformin (patient's
      usual dose) vs. salsalate (1.5g) vs. placebo with sips of water 2h prior to surgery. Baseline
      data (age, height, weight, ASA score, mean arterial BP, and baseline glucose) will be
      collected by the RC in the pre-operative assessment area, and flash glucose sensors
      (FreeStyle Libre, Abbot) will be placed on the upper arm as per manufacturer's instructions
      and readings collected by the RC. Study data will be securely stored in the anesthesia
      research office, McMaster University. Standard monitors will be used in the operating room,
      with any additional monitoring left to the anesthesiologist's discretion. Although most
      anesthetics appear to modify glucose metabolism, general anesthesia will be provided in their
      preferred manner (including dexamethasone administration for post-operative nausea and
      vomiting prophylaxis) to improve generalizability. Details of the type of drugs, fluids and
      blood loss will be recorded. Following surgery, patients will be brought to the PACU for
      routine monitoring (30-60 min), and additional blood samples will be drawn. Subsequent
      samples will be collected on the evening of surgery (6-12h) and POD1. Any episodes of hyper-
      or hypoglycemia will be managed routinely at the treating physician's discretion and details
      recorded.

      Measurements of Inflammation: Blood and urine samples will be collected on the morning of
      surgery, upon admission to PACU, and will coincide with other tests to minimize needle
      sticks. Blood samples will be processed at the HHS Core Research Laboratory and divided into
      3 serum and 2 EDTA aliquots, barcoded and stored in liquid nitrogen. Urine samples will be
      divided into 2 barcoded aliquots and stored in liquid nitrogen. This will allow for future
      analysis and characterization of biochemical pathways related to the surgical stress
      response. These future analyses will include measurement of insulin and proinsulin since
      salsalate may modify their endogenous metabolism. Similarly, the investigators eventually
      plan to measure various inflammatory markers implicated in the development of acute
      stress-induced insulin resistance (i.e. IL-6, TNFα, and hsCRP), which could provide insight
      into potential beneficial effects of salsalate or metformin.

      Feasibility Outcomes: The primary feasibility outcomes include calculating the recruitment
      rate (both the percentage of individuals who were approached in the pre-operative clinic that
      enrolled in the study, and the total number of individuals that were recruited each month
      (Table 1, supplemental document). The ability to follow study protocol will be reported as
      the percentage of individuals who were able to complete the study protocol as a fraction of
      the total number of individuals recruited for i) drug administration and blinding, ii) blood
      sampling at specified times, and iii) reliability of CGM by comparison with laboratory
      glucose values. Workload will be calculated per patient, and safety profile assessed by
      recording adverse events. Together, this may identify pitfalls requiring modification prior
      to a full RCT.

      Statistical Analysis and Feasibility: Reporting and analysis will conform to the CONSORT
      pilot and feasibility trials guidelines (www.consort-statement.org). Data will be collected
      using an encrypted online tool (RedCap, Research Electronic Data Capture) hosted at McMaster.
      To be feasible and continue onto a subsequent RCT the investigators will need to recruit at
      least 3 patients per month. Additionally, the investigators seek an adherence rate of 88.9%
      (32/36) to receive study drug, collect more than 90.3% (130/144) of pre-specified blood
      samples, and ensure 83.3% (30/36) patients have been followed up within 6 weeks of their
      procedure to document any complications (e.g. SSI). If targets prove difficult, then our
      protocol will be reevaluated for possible amendments that will not compromise final outcomes.
      Given this is a pilot, CIs will be calculated for outcomes of interest: rates of
      hyperglycemia, SSI, and degree of inflammation.

      Trial Management: This pilot trial will be conducted at HHS. The trial will enlist support
      and collaboration from surgeons and fellow anesthesiologists. Study data will be securely
      stored at the anesthesia research office, McMaster University. An RC will be employed for
      patient recruitment and data collection. The CRFs for study patients will be randomly
      cross-checked for completeness and accuracy. All reports of incorrect randomizations,
      protocol violations or incomplete data will be noted.

      Risk Assessment: This trial does not entail any higher risk to the patient than the present
      standard of care. It is pragmatic, and uses clinically acceptable doses with a safe profile.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Parallel, placebo-controlled trial with block randomization
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Patients will be randomized on the day of their pre-operative assessment by our department statistician using a computer-generated table, with an allocation ratio of 1:1:1 in random permuted blocks of 3 or 6. Only the pharmacist and statistician will know the allocation sequence. Concealed medications (over-encapsulated) will be provided to the RC upon confirming the allotment with a unique identification number (UIN), recorded on the patient-specific case record form (CRF).
measure: Feasibility: recruitment rate (percentage)
time frame: One year
description: Percentage (%) of individuals who were approached in the pre-operative clinic that enrolled in the study
measure: Participants with hyperglycemia
time frame: One year
description: Detect change in hyperglycemic events (glucose >11mmol/L) at the 4 blood sampling time points for each participant
measure: Feasibility: recruitment rate (total number per month)
time frame: One year
description: Number (n) of individuals recruited each month
measure: Blood glucose levels (glycemic control)
time frame: One year
description: Evaluation of glycemic control by calculating mean blood glucose levels obtained at 4 time points
measure: Number of participants with inflammation
time frame: One year
description: Measured using validated biomarkers (IL-6, tumor necrosis factor, high-sensitivity C reactive protein), and surgical site infections recorded within 6 weeks of surgery
arm group label: Metformin
arm group type: Experimental
description: Self-administered metformin (patient's usual dose) taken 2 hours prior to surgery
arm group label: Salsalate
arm group type: Experimental
description: Self-administered salsalate taken 2 hours prior to surgery
arm group label: Placebo
arm group type: No Intervention
description: Self-administered placebo taken 2 hours prior to surgery
intervention type: Drug
intervention name: Metformin
description: Metformin (usual dose) administered 2 h before surgery
arm group label: Metformin
intervention type: Drug
intervention name: Salsalate
description: Salsalate 1.5 g administered 2 h before surgery
arm group label: Salsalate
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
citation: Palermo NE, Gianchandani RY, McDonnell ME, Alexanian SM. Stress Hyperglycemia During Surgery and Anesthesia: Pathogenesis and Clinical Implications. Curr Diab Rep. 2016 Mar;16(3):33. doi: 10.1007/s11892-016-0721-y.
PMID: 26957107
citation: Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe C, Hudson M, Mendoza J, Johnson R, Lin E, Umpierrez GE. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010 Aug;33(8):1783-8. doi: 10.2337/dc10-0304. Epub 2010 Apr 30.
PMID: 20435798
citation: Membership of the Working Party; Barker P, Creasey PE, Dhatariya K, Levy N, Lipp A, Nathanson MH, Penfold N, Watson B, Woodcock T. Peri-operative management of the surgical patient with diabetes 2015: Association of Anaesthetists of Great Britain and Ireland. Anaesthesia. 2015 Dec;70(12):1427-40. doi: 10.1111/anae.13233. Epub 2015 Sep 29. Erratum In: Anaesthesia. 2019 Jun;74(6):810.
PMID: 26417892
citation: Smith BK, Ford RJ, Desjardins EM, Green AE, Hughes MC, Houde VP, Day EA, Marcinko K, Crane JD, Mottillo EP, Perry CG, Kemp BE, Tarnopolsky MA, Steinberg GR. Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-beta1. Diabetes. 2016 Nov;65(11):3352-3361. doi: 10.2337/db16-0564. Epub 2016 Aug 23.
PMID: 27554471
responsible party type: Sponsor
mesh term: Diabetes Mellitus, Type 2
mesh term: Hyperglycemia
mesh term: Postoperative Complications
mesh term: Metformin
mesh term: Salicylsalicylic acid
sharing ipd: No