xml: <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/NCT05979038</url>
    </required_header>
    <id_info>
      <org_study_id>FMASU MD146/2023</org_study_id>
      <nct_id>NCT05979038</nct_id>
    </id_info>
    <brief_title>Clinical Evaluation of the Effect of Metformin in Sepsis</brief_title>
    <official_title>Evaluation of the Effect of Metformin on the Clinical Outcome of ICU Patients With Sepsis</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>German University in Cairo</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>German University in Cairo</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>
        Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host&#xD;
        response to infection. It is considered a condition that arises when the body's response to&#xD;
        an infection injures its own tissues and organs. The pathogenesis of sepsis is very&#xD;
        complicated as it involves imbalance in inflammatory response, immune dysfunction,&#xD;
        mitochondrial damage, coagulopathy, neuroendocrine immune network abnormalities, endoplasmic&#xD;
        reticulum stress, autophagy, and other pathophysiological processes, and leads to organ&#xD;
        dysfunction. Inflammatory Imbalance represents the most critical basis of sepsis&#xD;
        pathogenesis. Sepsis is associated with many biochemical abnormalities that is correlated&#xD;
        with patients' prognosis and risk of mortality including increased levels of lactate,&#xD;
        procalcitonin and inflammatory cytokines as TNF alpha.&#xD;
  &#xD;
        Metformin is an oral anti-diabetic drug from the class of biguanides. It is the first line&#xD;
        treatment of diabetes type 2. It is widely used as it has good safety profile, low side&#xD;
        effect and cheap cost. Metformin has been reported to have an anti-inflammatory and&#xD;
        anti-microbial effect.&#xD;
  &#xD;
        Some studies have shown that metformin has a beneficial effect in sepsis patients. Our study&#xD;
        will be the first prospective controlled randomized trial to assess the clinical outcome of&#xD;
        metformin in patients with sepsis.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host&#xD;
        response to infection. It is considered a life-threatening condition that arises when the&#xD;
        body's response to an infection injures its own tissues and organs (Singer et al., 2016a).&#xD;
        Organ dysfunction can be defined as an increase in the Sequential (sepsis related) Organ&#xD;
        Failure Assessment (SOFA) score more than two points consequent to the infection. A SOFA&#xD;
        score more than two points indicates that an overall mortality risk of approximately 10% in&#xD;
        hospital population with suspected infection.(Singer et al., 2016b). Septic shock is defined&#xD;
        as subset of sepsis in which circulatory, cellular, and metabolic abnormalities are&#xD;
        associated with a greater risk of mortality than sepsis alone. Patients with septic shock can&#xD;
        be identified with a clinical construct of sepsis with persisting hypotension requiring&#xD;
        vasopressors to maintain MAP (mean arterial pressure) more than or equal 65mmHg and having a&#xD;
        serum lactate level &gt;2 mmol/L (18mg/dL) despite adequate volume resuscitation (Seymour et&#xD;
        al., 2016).&#xD;
  &#xD;
        Sepsis and septic shock are major healthcare problems, affecting millions of people around&#xD;
        the world each year with a mortality rate between one in three and one in six of those it&#xD;
        affects (Evans et al., 2021). According to a meta-analysis conducted in 2020, it was found&#xD;
        that the incidence of sepsis was 189 hospital-treated sepsis cases per 100,000 person-years&#xD;
        with a 26.7% mortality rate. In ICU patients, the incidence was 58 per 100,000 person-years&#xD;
        with a mortality rate of 41.9% prior to hospital discharge (Fleischmann-Struzek et al.,&#xD;
        2020).&#xD;
  &#xD;
        The pathogenesis of sepsis is very complicated as it involves imbalance in inflammatory&#xD;
        response, immune dysfunction, mitochondrial damage, coagulopathy, neuroendocrine immune&#xD;
        network abnormalities, endoplasmic reticulum stress, autophagy, and other pathophysiological&#xD;
        processes, and leads to organ dysfunction. Inflammatory Imbalance represents the most&#xD;
        critical basis of sepsis pathogenesis. The host's initial acute response to invasive&#xD;
        pathogens causes macrophages to engulf the pathogens and produce a range of pro-inflammatory&#xD;
        cytokines, and this can trigger cytokine storms and activate the innate immune system. The&#xD;
        activation of the innate immune system is mediated by pattern-recognition receptors (PRRs),&#xD;
        which initiate a series of activation in immune cells by detecting damage-associated&#xD;
        molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), and thus&#xD;
        upregulate the expression of inflammation related genes. In the immune response to sepsis,&#xD;
        both exogenous factors derived from the pathogen (e.g., lipopolysaccharide (LPS)) and&#xD;
        endogenous factors released by injured cells (e.g., high-mobility group box-1 (HMGB-1)&#xD;
        protein) can interact with various PRRs, such as Toll-like receptors (TLRs), which leads to&#xD;
        the activation of several pathways including p38 mitogen-activated protein kinase (MAPK), and&#xD;
        nuclear factor-κB (NF-κB) signaling pathways. These events are followed by the production of&#xD;
        inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α),&#xD;
        interferon (IFN) regulatory factor 7 (IRF7), and adaptor protein 1 (AP-1) (Huang, Cai and Su,&#xD;
        2019).&#xD;
  &#xD;
        Moreover, studies have also shown that in early stages of sepsis, exaggerated endothelial&#xD;
        activation, vascular leakage, disturbance of blood flow, as well as other derangements cause&#xD;
        the loss of vascular integrity, which contributes significantly to sepsis-associated organ&#xD;
        failure. Therapies interfering endothelial activation are potential to attenuate&#xD;
        sepsis-induced organ dysfunction (Tian et al., 2019) Sepsis is associated with many&#xD;
        biochemical abnormalities that is correlated with patients' prognosis and risk of mortality&#xD;
        including increased levels of lactate, procalcitonin and inflammatory cytokines as TNF&#xD;
        alpha.(Cho and Choi, 2014) Despite great efforts was done to understand the pathogenesis of&#xD;
        sepsis and investigate therapeutic strategies, the management of sepsis remains a clinical&#xD;
        challenge (Tian et al., 2019). Till current date the pathogenesis of sepsis is not completely&#xD;
        clear but most of the studies suggested that the release of inflammatory factors by patient's&#xD;
        innate immune cell plays an important role in the disease progression (Liang et al., 2019).&#xD;
        Recently several studies revealed the anti-inflammatory effect of some drugs in sepsis. One&#xD;
        of the drugs that showed anti-inflammatory effect in these studies is metformin (Han et al.,&#xD;
        2018).&#xD;
  &#xD;
        Metformin is an oral anti-diabetic drug from the class of biguanides. It is the first line&#xD;
        treatment of diabetes type 2. It is widely used as it has good safety profile, low side&#xD;
        effect and cheap cost (Malik et al., 2018). Studies have shown that metformin modulates&#xD;
        cellular metabolism by two inter-related mechanisms. It transiently inhibits mitochondrial&#xD;
        complex I of the electron transport chain, decreasing the production of mitochondrial&#xD;
        reactive oxygen species and complex I inhibition also leads to an increase of the adenosine&#xD;
        monophosphate/adenosine triphosphate (ATP) ratio (a critical signal of energy imbalance),&#xD;
        which activates the AMPK. AMPK is a ubiquitous, critical cellular energy sensor with&#xD;
        pleiotropic effects on cell metabolism, which can protect the cell by shutting down ATP&#xD;
        consuming processes, promoting fatty acid oxidation and controlling the turn-over cycle of&#xD;
        injured mitochondria. Metformin and AMPK activation improve endothelial function, reducing&#xD;
        capillary leak and inducible nitric oxide synthase and increasing endothelial nitric oxide&#xD;
        synthase activity potentially improving vascular tone and microvascular function (Gómez et&#xD;
        al., 2022) Metformin has been reported to have an anti-inflammatory effect. In a prospective&#xD;
        study to investigate the anti-inflammatory effect of AMPK activation in vivo, metformin and&#xD;
        AICAR was administered respectively to mice prior to LPS injection. LPS injection&#xD;
        significantly increased the level of VCAM1 in the arterioles, peritubular capillaries, post&#xD;
        capillary venules, and glomerulus in the kidneys as well as in the arterioles, alveolar&#xD;
        capillaries, and venules in the lungs. Metformin and AICAR administration effectively reduced&#xD;
        VCAM1 expression in the microvascular beds both in the kidneys and lungs. Furthermore,&#xD;
        LPS-induced increase of the serum levels of pro-inflammatory cytokines TNF⍺ and IL-6 were&#xD;
        both significantly decreased by metformin and AICAR (Tian et al., 2019). In a trial of&#xD;
        patients receiving glucocorticoid treatment for various chronic inflammatory diseases, 12&#xD;
        weeks of treatment with metformin 2550 mg/day resulted in lower serum levels of&#xD;
        high-sensitive CRP as compared to placebo. Furthermore, carbohydrate-challenged TNF-α levels&#xD;
        increased significantly in the placebo-treated group but not in the metformin-treated group&#xD;
        (Pernicova et al., 2020) In addition, metformin showed some antibacterial activity. A&#xD;
        retrospective study conducted in 2022 has shown that at the cellular level, metformin&#xD;
        modulates cell metabolism through transient inhibition of complex I of mitochondrial electron&#xD;
        transport chain and activates AMPK that protects energy balance in the cell (Gómez et al.,&#xD;
        2022). It enhances neutrophil chemotaxis and phagocytosis and bacterial clearance (Bai and&#xD;
        Chen, 2021).&#xD;
  &#xD;
        Some studies have shown that metformin has a beneficial effect in sepsis patients. In two&#xD;
        retrospective studies of septic shock patients receiving metformin, it showed an improvement&#xD;
        in inflammatory response and oxidative stress induced by sepsis which resulted in improved&#xD;
        mortality at different doses of metformin (Gras et al., 2006; Doenyas-Barak et al., 2015) .&#xD;
        In a systematic review and meta-analysis done by Liang et al for published observational&#xD;
        cohort data to determine the association between preadmission metformin use and mortality in&#xD;
        septic adult patients with diabetes mellitus, it was concluded that preadmission metformin&#xD;
        users had lower mortality than non-users and this analysis suggested that the effect of&#xD;
        metformin is related to its anti-inflammatory effect (Liang et al., 2019).&#xD;
  &#xD;
        Metformin has not significant adverse effects; however, it may cause gastrointestinal upset&#xD;
        that can be overcome by titration of the dose and administration with meals (Nasri and&#xD;
        Rafieian-Kopaei, 2014) and a rare but serious condition called lactic acidosis with the&#xD;
        following symptoms: dizziness, severe drowsiness, muscle pain, tiredness, chills, blue/cold&#xD;
        skin, fast/difficult breathing, slow/irregular heartbeat, stomach pain with diarrhea, nausea&#xD;
        or vomiting. Lactic acidosis usually occurs due to drug overdose or in some contraindicated&#xD;
        conditions (Scheen and Paquot, 2013). Rare incidence of lactic acidosis has been reported&#xD;
        with the use of metformin especially in patients with renal impairment, hence, metformin is&#xD;
        contraindicated in those with creatinine clearance less than 45ml/min. In sepsis, previous&#xD;
        study reported that patients hospitalized for suspected sepsis who were on metformin had&#xD;
        slightly higher prevalence of hyperlactatemia than non- metformin users though non-metformin&#xD;
        users were found to have a higher 28-days mortality risk than metformin users (Green et al.,&#xD;
        2012). In another study, conducted to compare the prognosis of extremely elevated plasma&#xD;
        lactate levels and septic shock between metformin users and non-users it was found that the&#xD;
        rate of in hospital mortality was lower for those who were actively treated with metformin&#xD;
        than those who were not. the prognosis of metformin users were better despite higher lactate&#xD;
        levels (Doenyas-Barak et al., 2015). One last study was done to evaluate the impact of&#xD;
        metformin use on lactate kinetics in septic patients and showed that lactate levels in&#xD;
        metformin users were initially elevated in the early phase in severe sepsis and septic shock.&#xD;
        However, there was no significant difference in lactate levels, lactate clearance and&#xD;
        normalization over the initial 24 hours period based on metformin use (Park et al., 2017)&#xD;
  &#xD;
        To the best of our knowledge our study will be the first prospective controlled randomized&#xD;
        trial to assess the clinical outcome of metformin in patients with sepsis.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">September 10, 2023</start_date>
    <completion_date type="Anticipated">July 10, 2024</completion_date>
    <primary_completion_date type="Anticipated">June 15, 2024</primary_completion_date>
    <phase>Phase 3</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>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>28 days mortality</measure>
      <time_frame>28 days</time_frame>
      <description>Patients mortality rate and time from ICU admission till death due to any cause will be assessed within 28 days even after discharge from the ICU.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>2.Total ICU lengths of stay:</measure>
      <time_frame>28 days</time_frame>
      <description>The number of days that the patient will stay in the ICU will be calculated.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>3.Arterial blood gases (ABG):</measure>
      <time_frame>28 days</time_frame>
      <description>ABG will be measured daily for every patient throughout his/her stay in the ICU. The total number of days that ABG are abnormal will be calculated for every patients in order to get the number of abnormal readings and check after how long ABG returned to normal</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>4- Serum TNF alpha:</measure>
      <time_frame>28 days</time_frame>
      <description>Blood samples will be withdrawn at baseline and day ten of ICU admission from every patient included in the study to measure TNF alpha. Samples will be stored in -80C and will be assessed using ELISA technique.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>5- Total Leucocytic Count (TLC):</measure>
      <time_frame>28 days</time_frame>
      <description>Blood samples will be withdrawn daily from every patient included in the study to measure TLC. The total number of days that TLC is high will be calculated for every patients in order to get the number of abnormal readings and check after how long TLC returned to normal ( 4000 to 11,000/microliters).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>6- Sequential organ Failure assessment Scores (SOFA):</measure>
      <time_frame>28 days</time_frame>
      <description>SOFA score will be calculated daily for every patient to assess organ failure and recovery. Sequential Organ Failure Assessment score (SOFA) is a scoring system used to evaluate organ failure. The score is based on six different scores: respiratory, cardiovascular, hepatic, coagulation, renal and neurological system. It calculates the degree of organ failure by assigning a point of 0 (normal) to 4 (failure) for each organ. Score ranges from 0 (best) to 24 (worst) points. For calculating SOFA score the below table 1 will be used:(Singer et al., 2016a)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>7- APACHE II Score:</measure>
      <time_frame>28 days</time_frame>
      <description>APACH II score will be calculated daily for every patient to assess disease severity. The score can help in the assessment of patients to determine the level &amp; degree of diagnostic &amp; therapeutic intervention. Score ranges from minimum 0 and maximum 71; increasing score is associated with an increasing risk of hospital death. For calculating APACHE score, below table will be used (Akavipat, 2019)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>8-GCS Score:</measure>
      <time_frame>28 days</time_frame>
      <description>Glasgow Coma scale (GCS) will be calculated daily to assess patient's consciousness. It is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye response (E), best verbal response (V), and best motor response (M). A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury (Teasdale and Jennett, 1974).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>9-28 days Readmission:</measure>
      <time_frame>28 days</time_frame>
      <description>The number of patients who were discharged from the ICU and returned again within 28 days will be calculated</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>10-Blood Pressure</measure>
      <time_frame>28 days</time_frame>
      <description>All patients included in the study will be monitored 24 hours a day (24/24) by putting them on a vital signs monitor in order to follow up their blood pressure. The total number of abnormal blood pressure measurements will be calculated for every patient. Mean arterial blood pressure will also be calculated (target is 65 mm Hg) and the total number of days patient will need a vasopressor will be calculated and doses of vasopressor will be documented.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>11-Mechanical Ventilation:</measure>
      <time_frame>28 days</time_frame>
      <description>Number of patients who will need mechanical ventilation will be calculated. In addition, ventilation free days will be assessed for every patient.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>12-Serum Lactate levels:</measure>
      <time_frame>28 days</time_frame>
      <description>Blood samples will be withdrawn every other day from every patient included in the study to measure serum lactate levels. The lactate cutoffs determining an elevated level ranged from 1.6-2.5 mmol/L (Evans et al., 2021). Patients with elevated serum lactate levels will be closely monitored. The number of days that serum lactate levels are high will be calculated for every patient throughout the study</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>GIT Disturbances:</measure>
      <time_frame>28 days</time_frame>
      <description>Patient will be interviewed for the incidence of nausea, vomiting or diarrhea. If patient cannot reply (low conscious level), nurses will be asked. The total number of days that patient will suffer any of the GIT disturbances will be calculated and documented.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">110</enrollment>
    <condition>Sepsis</condition>
    <arm_group>
      <arm_group_label>Metformin arm</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>In this arm patients will administrate metformin 500 mg three times a day together with the standard care of sepsis.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control Arm</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>In this arm patients will receive the standard care of sepsis only</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Metformin</intervention_name>
      <description>Patients in the intervention arm will take metformin 500mg three times a day</description>
      <arm_group_label>Metformin arm</arm_group_label>
      <other_name>Glucophage</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age more than 18 years old.&#xD;
  &#xD;
            -  A diagnosis of sepsis according to the latest Sepsis-3 definition&#xD;
  &#xD;
            -  Estimated GFR &gt;45 ml/min&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  • Immunosuppressed or end stage cancer.&#xD;
  &#xD;
                 -  Septic Shock.&#xD;
  &#xD;
                 -  Pregnancy and breast feeding.&#xD;
  &#xD;
                 -  Patients on metformin, Sodium glucose cotransporters or Gliptins.&#xD;
  &#xD;
                 -  End stage hepatic disease.&#xD;
  &#xD;
                 -  Contraindications to metformin (chronic respiratory failure, chronic cardiac&#xD;
                    failure, chronic kidney or liver disease, myocardial infarction within the last&#xD;
                    month).&#xD;
  &#xD;
                 -  Patients with hypersensitivity to metformin.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Mai M.T Ghannoum, Assistant Lecturer</last_name>
      <phone>002-01221054807</phone>
      <email>mai.tarek@guc.edu.eg</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Mohamed H. Solayman, Lecturer</last_name>
      <phone>002-01005882550</phone>
      <email>mohamed.solayman@guc.edu.eg</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Al Demerdash University Hospital</name>
        <address>
          <city>Cairo</city>
          <country>Egypt</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Mai M.T Ghannoum, Ass. Lecturer</last_name>
        <phone>01221054807</phone>
        <phone_ext>002</phone_ext>
        <email>mai.tarek@guc.edu.eg</email>
      </contact>
      <contact_backup>
        <last_name>Mai Shawki, Ass. Prof</last_name>
        <phone>01001701461</phone>
        <phone_ext>002</phone_ext>
        <email>mannus.ahmed@yahoo.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Egypt</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 30, 2023</study_first_submitted>
    <study_first_submitted_qc>July 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 7, 2023</study_first_posted>
    <last_update_submitted>September 11, 2023</last_update_submitted>
    <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>German University in Cairo</investigator_affiliation>
      <investigator_full_name>Mai Tarek Ghannoum</investigator_full_name>
      <investigator_title>Assistant Lecturer of Clinical Pharmacy</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sepsis</mesh_term>
      <mesh_term>Toxemia</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Metformin</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05979038
  org study id: FMASU MD146/2023
  nct id: NCT05979038
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host
        response to infection. It is considered a condition that arises when the body's response to
        an infection injures its own tissues and organs. The pathogenesis of sepsis is very
        complicated as it involves imbalance in inflammatory response, immune dysfunction,
        mitochondrial damage, coagulopathy, neuroendocrine immune network abnormalities, endoplasmic
        reticulum stress, autophagy, and other pathophysiological processes, and leads to organ
        dysfunction. Inflammatory Imbalance represents the most critical basis of sepsis
        pathogenesis. Sepsis is associated with many biochemical abnormalities that is correlated
        with patients' prognosis and risk of mortality including increased levels of lactate,
        procalcitonin and inflammatory cytokines as TNF alpha.
  
        Metformin is an oral anti-diabetic drug from the class of biguanides. It is the first line
        treatment of diabetes type 2. It is widely used as it has good safety profile, low side
        effect and cheap cost. Metformin has been reported to have an anti-inflammatory and
        anti-microbial effect.
  
        Some studies have shown that metformin has a beneficial effect in sepsis patients. Our study
        will be the first prospective controlled randomized trial to assess the clinical outcome of
        metformin in patients with sepsis.
  Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host
        response to infection. It is considered a life-threatening condition that arises when the
        body's response to an infection injures its own tissues and organs (Singer et al., 2016a).
        Organ dysfunction can be defined as an increase in the Sequential (sepsis related) Organ
        Failure Assessment (SOFA) score more than two points consequent to the infection. A SOFA
        score more than two points indicates that an overall mortality risk of approximately 10% in
        hospital population with suspected infection.(Singer et al., 2016b). Septic shock is defined
        as subset of sepsis in which circulatory, cellular, and metabolic abnormalities are
        associated with a greater risk of mortality than sepsis alone. Patients with septic shock can
        be identified with a clinical construct of sepsis with persisting hypotension requiring
        vasopressors to maintain MAP (mean arterial pressure) more than or equal 65mmHg and having a
        serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation (Seymour et
        al., 2016).
  
        Sepsis and septic shock are major healthcare problems, affecting millions of people around
        the world each year with a mortality rate between one in three and one in six of those it
        affects (Evans et al., 2021). According to a meta-analysis conducted in 2020, it was found
        that the incidence of sepsis was 189 hospital-treated sepsis cases per 100,000 person-years
        with a 26.7% mortality rate. In ICU patients, the incidence was 58 per 100,000 person-years
        with a mortality rate of 41.9% prior to hospital discharge (Fleischmann-Struzek et al.,
        2020).
  
        The pathogenesis of sepsis is very complicated as it involves imbalance in inflammatory
        response, immune dysfunction, mitochondrial damage, coagulopathy, neuroendocrine immune
        network abnormalities, endoplasmic reticulum stress, autophagy, and other pathophysiological
        processes, and leads to organ dysfunction. Inflammatory Imbalance represents the most
        critical basis of sepsis pathogenesis. The host's initial acute response to invasive
        pathogens causes macrophages to engulf the pathogens and produce a range of pro-inflammatory
        cytokines, and this can trigger cytokine storms and activate the innate immune system. The
        activation of the innate immune system is mediated by pattern-recognition receptors (PRRs),
        which initiate a series of activation in immune cells by detecting damage-associated
        molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), and thus
        upregulate the expression of inflammation related genes. In the immune response to sepsis,
        both exogenous factors derived from the pathogen (e.g., lipopolysaccharide (LPS)) and
        endogenous factors released by injured cells (e.g., high-mobility group box-1 (HMGB-1)
        protein) can interact with various PRRs, such as Toll-like receptors (TLRs), which leads to
        the activation of several pathways including p38 mitogen-activated protein kinase (MAPK), and
        nuclear factor-κB (NF-κB) signaling pathways. These events are followed by the production of
        inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α),
        interferon (IFN) regulatory factor 7 (IRF7), and adaptor protein 1 (AP-1) (Huang, Cai and Su,
        2019).
  
        Moreover, studies have also shown that in early stages of sepsis, exaggerated endothelial
        activation, vascular leakage, disturbance of blood flow, as well as other derangements cause
        the loss of vascular integrity, which contributes significantly to sepsis-associated organ
        failure. Therapies interfering endothelial activation are potential to attenuate
        sepsis-induced organ dysfunction (Tian et al., 2019) Sepsis is associated with many
        biochemical abnormalities that is correlated with patients' prognosis and risk of mortality
        including increased levels of lactate, procalcitonin and inflammatory cytokines as TNF
        alpha.(Cho and Choi, 2014) Despite great efforts was done to understand the pathogenesis of
        sepsis and investigate therapeutic strategies, the management of sepsis remains a clinical
        challenge (Tian et al., 2019). Till current date the pathogenesis of sepsis is not completely
        clear but most of the studies suggested that the release of inflammatory factors by patient's
        innate immune cell plays an important role in the disease progression (Liang et al., 2019).
        Recently several studies revealed the anti-inflammatory effect of some drugs in sepsis. One
        of the drugs that showed anti-inflammatory effect in these studies is metformin (Han et al.,
        2018).
  
        Metformin is an oral anti-diabetic drug from the class of biguanides. It is the first line
        treatment of diabetes type 2. It is widely used as it has good safety profile, low side
        effect and cheap cost (Malik et al., 2018). Studies have shown that metformin modulates
        cellular metabolism by two inter-related mechanisms. It transiently inhibits mitochondrial
        complex I of the electron transport chain, decreasing the production of mitochondrial
        reactive oxygen species and complex I inhibition also leads to an increase of the adenosine
        monophosphate/adenosine triphosphate (ATP) ratio (a critical signal of energy imbalance),
        which activates the AMPK. AMPK is a ubiquitous, critical cellular energy sensor with
        pleiotropic effects on cell metabolism, which can protect the cell by shutting down ATP
        consuming processes, promoting fatty acid oxidation and controlling the turn-over cycle of
        injured mitochondria. Metformin and AMPK activation improve endothelial function, reducing
        capillary leak and inducible nitric oxide synthase and increasing endothelial nitric oxide
        synthase activity potentially improving vascular tone and microvascular function (Gómez et
        al., 2022) Metformin has been reported to have an anti-inflammatory effect. In a prospective
        study to investigate the anti-inflammatory effect of AMPK activation in vivo, metformin and
        AICAR was administered respectively to mice prior to LPS injection. LPS injection
        significantly increased the level of VCAM1 in the arterioles, peritubular capillaries, post
        capillary venules, and glomerulus in the kidneys as well as in the arterioles, alveolar
        capillaries, and venules in the lungs. Metformin and AICAR administration effectively reduced
        VCAM1 expression in the microvascular beds both in the kidneys and lungs. Furthermore,
        LPS-induced increase of the serum levels of pro-inflammatory cytokines TNF⍺ and IL-6 were
        both significantly decreased by metformin and AICAR (Tian et al., 2019). In a trial of
        patients receiving glucocorticoid treatment for various chronic inflammatory diseases, 12
        weeks of treatment with metformin 2550 mg/day resulted in lower serum levels of
        high-sensitive CRP as compared to placebo. Furthermore, carbohydrate-challenged TNF-α levels
        increased significantly in the placebo-treated group but not in the metformin-treated group
        (Pernicova et al., 2020) In addition, metformin showed some antibacterial activity. A
        retrospective study conducted in 2022 has shown that at the cellular level, metformin
        modulates cell metabolism through transient inhibition of complex I of mitochondrial electron
        transport chain and activates AMPK that protects energy balance in the cell (Gómez et al.,
        2022). It enhances neutrophil chemotaxis and phagocytosis and bacterial clearance (Bai and
        Chen, 2021).
  
        Some studies have shown that metformin has a beneficial effect in sepsis patients. In two
        retrospective studies of septic shock patients receiving metformin, it showed an improvement
        in inflammatory response and oxidative stress induced by sepsis which resulted in improved
        mortality at different doses of metformin (Gras et al., 2006; Doenyas-Barak et al., 2015) .
        In a systematic review and meta-analysis done by Liang et al for published observational
        cohort data to determine the association between preadmission metformin use and mortality in
        septic adult patients with diabetes mellitus, it was concluded that preadmission metformin
        users had lower mortality than non-users and this analysis suggested that the effect of
        metformin is related to its anti-inflammatory effect (Liang et al., 2019).
  
        Metformin has not significant adverse effects; however, it may cause gastrointestinal upset
        that can be overcome by titration of the dose and administration with meals (Nasri and
        Rafieian-Kopaei, 2014) and a rare but serious condition called lactic acidosis with the
        following symptoms: dizziness, severe drowsiness, muscle pain, tiredness, chills, blue/cold
        skin, fast/difficult breathing, slow/irregular heartbeat, stomach pain with diarrhea, nausea
        or vomiting. Lactic acidosis usually occurs due to drug overdose or in some contraindicated
        conditions (Scheen and Paquot, 2013). Rare incidence of lactic acidosis has been reported
        with the use of metformin especially in patients with renal impairment, hence, metformin is
        contraindicated in those with creatinine clearance less than 45ml/min. In sepsis, previous
        study reported that patients hospitalized for suspected sepsis who were on metformin had
        slightly higher prevalence of hyperlactatemia than non- metformin users though non-metformin
        users were found to have a higher 28-days mortality risk than metformin users (Green et al.,
        2012). In another study, conducted to compare the prognosis of extremely elevated plasma
        lactate levels and septic shock between metformin users and non-users it was found that the
        rate of in hospital mortality was lower for those who were actively treated with metformin
        than those who were not. the prognosis of metformin users were better despite higher lactate
        levels (Doenyas-Barak et al., 2015). One last study was done to evaluate the impact of
        metformin use on lactate kinetics in septic patients and showed that lactate levels in
        metformin users were initially elevated in the early phase in severe sepsis and septic shock.
        However, there was no significant difference in lactate levels, lactate clearance and
        normalization over the initial 24 hours period based on metformin use (Park et al., 2017)
  
        To the best of our knowledge our study will be the first prospective controlled randomized
        trial to assess the clinical outcome of metformin in patients with sepsis.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: 28 days mortality
  time frame: 28 days
  description: Patients mortality rate and time from ICU admission till death due to any cause will be assessed within 28 days even after discharge from the ICU.
  measure: 2.Total ICU lengths of stay:
  time frame: 28 days
  description: The number of days that the patient will stay in the ICU will be calculated.
  measure: 3.Arterial blood gases (ABG):
  time frame: 28 days
  description: ABG will be measured daily for every patient throughout his/her stay in the ICU. The total number of days that ABG are abnormal will be calculated for every patients in order to get the number of abnormal readings and check after how long ABG returned to normal
  measure: 4- Serum TNF alpha:
  time frame: 28 days
  description: Blood samples will be withdrawn at baseline and day ten of ICU admission from every patient included in the study to measure TNF alpha. Samples will be stored in -80C and will be assessed using ELISA technique.
  measure: 5- Total Leucocytic Count (TLC):
  time frame: 28 days
  description: Blood samples will be withdrawn daily from every patient included in the study to measure TLC. The total number of days that TLC is high will be calculated for every patients in order to get the number of abnormal readings and check after how long TLC returned to normal ( 4000 to 11,000/microliters).
  measure: 6- Sequential organ Failure assessment Scores (SOFA):
  time frame: 28 days
  description: SOFA score will be calculated daily for every patient to assess organ failure and recovery. Sequential Organ Failure Assessment score (SOFA) is a scoring system used to evaluate organ failure. The score is based on six different scores: respiratory, cardiovascular, hepatic, coagulation, renal and neurological system. It calculates the degree of organ failure by assigning a point of 0 (normal) to 4 (failure) for each organ. Score ranges from 0 (best) to 24 (worst) points. For calculating SOFA score the below table 1 will be used:(Singer et al., 2016a)
  measure: 7- APACHE II Score:
  time frame: 28 days
  description: APACH II score will be calculated daily for every patient to assess disease severity. The score can help in the assessment of patients to determine the level & degree of diagnostic & therapeutic intervention. Score ranges from minimum 0 and maximum 71; increasing score is associated with an increasing risk of hospital death. For calculating APACHE score, below table will be used (Akavipat, 2019)
  measure: 8-GCS Score:
  time frame: 28 days
  description: Glasgow Coma scale (GCS) will be calculated daily to assess patient's consciousness. It is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye response (E), best verbal response (V), and best motor response (M). A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury (Teasdale and Jennett, 1974).
  measure: 9-28 days Readmission:
  time frame: 28 days
  description: The number of patients who were discharged from the ICU and returned again within 28 days will be calculated
  measure: 10-Blood Pressure
  time frame: 28 days
  description: All patients included in the study will be monitored 24 hours a day (24/24) by putting them on a vital signs monitor in order to follow up their blood pressure. The total number of abnormal blood pressure measurements will be calculated for every patient. Mean arterial blood pressure will also be calculated (target is 65 mm Hg) and the total number of days patient will need a vasopressor will be calculated and doses of vasopressor will be documented.
  measure: 11-Mechanical Ventilation:
  time frame: 28 days
  description: Number of patients who will need mechanical ventilation will be calculated. In addition, ventilation free days will be assessed for every patient.
  measure: 12-Serum Lactate levels:
  time frame: 28 days
  description: Blood samples will be withdrawn every other day from every patient included in the study to measure serum lactate levels. The lactate cutoffs determining an elevated level ranged from 1.6-2.5 mmol/L (Evans et al., 2021). Patients with elevated serum lactate levels will be closely monitored. The number of days that serum lactate levels are high will be calculated for every patient throughout the study
  measure: GIT Disturbances:
  time frame: 28 days
  description: Patient will be interviewed for the incidence of nausea, vomiting or diarrhea. If patient cannot reply (low conscious level), nurses will be asked. The total number of days that patient will suffer any of the GIT disturbances will be calculated and documented.
  arm group label: Metformin arm
  arm group type: Experimental
  description: In this arm patients will administrate metformin 500 mg three times a day together with the standard care of sepsis.
  arm group label: Control Arm
  arm group type: No Intervention
  description: In this arm patients will receive the standard care of sepsis only
  intervention type: Drug
  intervention name: Metformin
  description: Patients in the intervention arm will take metformin 500mg three times a day
  arm group label: Metformin arm
  other name: Glucophage
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Mai M.T Ghannoum, Assistant Lecturer
  phone: 002-01221054807
  email: mai.tarek@guc.edu.eg
  last name: Mohamed H. Solayman, Lecturer
  phone: 002-01005882550
  email: mohamed.solayman@guc.edu.eg
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Egypt
  responsible party type: Principal Investigator
  investigator affiliation: German University in Cairo
  investigator full name: Mai Tarek Ghannoum
  investigator title: Assistant Lecturer of Clinical Pharmacy
  mesh term: Sepsis
  mesh term: Toxemia
  mesh term: Metformin
  sharing ipd: No