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出境医 / 临床实验 / Antidiuretic Function Before and During Treatment With SGLT2 Inhibitors (GliRACo1)

Antidiuretic Function Before and During Treatment With SGLT2 Inhibitors (GliRACo1)

Study Description
Brief Summary:
Subjects treated with Canagliflozin, Dapagliflozin and Empagliflozin obtained improvement on blood pressure values, body weight and cardiovascular mortality but pathophysiological explanations of these effects are not yet known.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Arterial Hypertension Body Weight Changes Drug: SGLT2 inhibitor Not Applicable

Detailed Description:

The pathophysiological explanations of the cardiovascular improvement of patients treated with SGLT2i are not yet known: osmotic diuresis and natriuresis, direct effects of weight reduction, increased in nitric oxide release, oxidative stress reduction, local renin-angiotensin-aldosterone system (RAAS) inhibition are the supposed mechanism. In the Literature the diuretic effect of SGLT2i therapy seems to be even stronger than thiazide or thiazide-like drugs. However, it is not defined the role of SGLT2i on antidiuretic function (RAAS, brain natriuretic peptide-BNP and antidiuretic hormone-ADH). Defining this relation could be important for:

  • knowing effect of SGLT2i on RAAS (drugs interferences are important particularly during case detection of primary aldosteronism);
  • discovering antidiuretic response to SGLT2i treatment and interactions between RAAS, BNP and ADH on the volume improvement induced by this new antidiabetic drugs.

In addition the aim of the study is to define effect of treatment on blood pressure and body composition.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Assessment of the Renin-angiotensin-aldosterone System (RAAS) and Antidiuretic Function in Patients With Type 2 Diabetes Before and During Treatment With Sodium-glucose Co-transporter 2 Inhibitors (SGLT2i): the GliRACo 1 Study
Actual Study Start Date : October 10, 2018
Actual Primary Completion Date : July 30, 2020
Estimated Study Completion Date : October 30, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Diabetic patients
30 diabetic patients candidate to treatment with SGLT2i in add-on to metformin.
 Drug: SGLT2 inhibitor
Start of the treatment with SGLT2i.
Other Name: Dapagliflozin, Empagliflozin, Canagliflozin
Outcome Measures
Primary Outcome Measures :
  1. Changes from baseline of antidiuretic function parameters (BNP) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for BNP (pg/mL).

  2. Changes from baseline of antidiuretic function parameters (BNP) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for BNP (pg/mL).

  3. Changes from baseline of antidiuretic function parameters (vasopressin) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for Copeptin (pmol/L).

  4. Changes from baseline of antidiuretic function parameters (vasopressin) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for Copeptin (pmol/L).

  5. Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for plasma osmolality (mOsm/Kg).

  6. Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary osmolality (mOsm/Kg).

  7. Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for plasma osmolality (mOsm/Kg).

  8. Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary osmolality (mOsm/Kg).

  9. Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for serum sodium (mmol/L).

  10. Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for serum sodium (mmol/L).

  11. Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary sodium (mmol/L).

  12. Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary sodium (mmol/L).

  13. Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for serum potassium (mmol/L).

  14. Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for serum potassium (mmol/L).

  15. Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary potassium (mmol/L).

  16. Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary potassium (mmol/L).

  17. Changes from baseline of renin-angiotensin-aldosterone system parameters (renin) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h).

  18. Changes from baseline of renin-angiotensin-aldosterone system parameters (renin) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h).

  19. Long term changes from baseline of renin-angiotensin-aldosterone system parameters aldosterone) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for aldosterone (pg/mL).

  20. Long term changes from baseline of renin-angiotensin-aldosterone system parameters [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h) and aldosterone (pg/mL)


Secondary Outcome Measures :
  1. Changes from baseline of blood pressure values (ABPM) [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Mean Systolic and Diastolic Blood Pressure (mmHg)

  2. Changes from baseline of body composition [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Variation of parameters of Bioelectrical Impedance Analysis (BIA)

  3. Changes in basal glicemic control [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Blood samples for basal glucose (mg/dL).

  4. Changes in long term glicemic control [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Blood samples for Glycated albumin (mmol/mol).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • diabetic patients;
  • clinical indication to SGLT2i therapy.

Exclusion Criteria:

  • signs and symptoms of poor glycemic control (polydipsia, polyuria and weight loss);
  • HbA1c >10% or 86 mmol/mol;
  • Body Mass Index (BMI) > 40 Kg/m2;
  • personal history of primary and secondary aldosteronism;
  • personal history of heart failure;
  • personal history of acute kidney injury;
  • personal history of chronic kidney disease;
  • personal history of liver cirrhosis;
  • personal history of protein-wasting syndrome;
  • personal history of renin secreting tumor;
  • personal history of diabetes insipidus;
  • personal history of syndrome of inappropriate antidiuresis (SIAD);
  • personal history of hypocortisolism and hypercortisolism;
  • therapy with Angiotensin Converting Enzyme inhibitors;
  • therapy with Angiotensin Receptor Blockers;
  • therapy with renin inhibitors;
  • therapy with beta-blockers;
  • therapy with alfa2-receptors agonists;
  • therapy with Calcium Channel Blockers;
  • therapy with diuretics;
  • therapy with mineralocorticoid receptor antagonists;
  • therapy with non steroidal and steroidal anti-inflammatory drugs.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Mauro M Maccario, MD 00390116709559 mauro.maccario@unito.it
Contact: Mirko M Parasiliti Caprino, MD, PhD 00390116335544 mirko.parasiliticaprino@unito.it

Locations
Layout table for location information
Italy
Mauro Maccario Recruiting
Torino, Piemonte, Italy, 10126
Contact: Mauro M Maccario, MD    00390116709559    mauro.maccario@unito.it   
Contact: Mirko M Parasiliti Caprino, MD, PhD    00390116335544    mirko.parasiliticaprino@unito.it   
Sub-Investigator: Nunzia N Prencipe, MD         
Sub-Investigator: Alessandro Maria A Berton, MD         
Sub-Investigator: Chiara C Lopez, MD         
Sub-Investigator: Chiara C Bona, MD         
Sub-Investigator: Andrea A Benso, MD, PhD         
Sub-Investigator: Silvia S Grottoli, MD         
Sub-Investigator: Ezio E Ghigo, MD         
Principal Investigator: Mauro M Maccario, MD         
Sub-Investigator: Mirko M Parasiliti Caprino, MD, PhD         
Sub-Investigator: Fabio F Broglio, MD, PhD         
Sponsors and Collaborators
University of Turin, Italy
Investigators
Layout table for investigator information
Principal Investigator: Mauro M Maccario, MD Endocrinology, Diabetology and Metabolism; University of Turin
Study Chair: Ezio E Ghigo, MD Endocrinology, Diabetology and Metabolism; University of Turin
Tracking Information
First Submitted Date  ICMJE April 7, 2019
First Posted Date  ICMJE April 17, 2019
Last Update Posted Date November 3, 2020
Actual Study Start Date  ICMJE October 10, 2018
Actual Primary Completion Date July 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2019)
  • Changes from baseline of antidiuretic function parameters (BNP) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for BNP (pg/mL).
  • Changes from baseline of antidiuretic function parameters (BNP) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for BNP (pg/mL).
  • Changes from baseline of antidiuretic function parameters (vasopressin) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for Copeptin (pmol/L).
  • Changes from baseline of antidiuretic function parameters (vasopressin) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for Copeptin (pmol/L).
  • Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for plasma osmolality (mOsm/Kg).
  • Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary osmolality (mOsm/Kg).
  • Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for plasma osmolality (mOsm/Kg).
  • Changes from baseline of antidiuretic function parameters (osmolality) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary osmolality (mOsm/Kg).
  • Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for serum sodium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for serum sodium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary sodium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (sodium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary sodium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for serum potassium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for serum potassium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Samples for urinary potassium (mmol/L).
  • Changes from baseline of antidiuretic function parameters (potassium balance) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Samples for urinary potassium (mmol/L).
  • Changes from baseline of renin-angiotensin-aldosterone system parameters (renin) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h).
  • Changes from baseline of renin-angiotensin-aldosterone system parameters (renin) [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h).
  • Long term changes from baseline of renin-angiotensin-aldosterone system parameters aldosterone) [ Time Frame: Before starting SGLT2i and 30 days the starting SGLT2i therapy ]
    Blood samples for aldosterone (pg/mL).
  • Long term changes from baseline of renin-angiotensin-aldosterone system parameters [ Time Frame: 90 days after starting SGLT2i therapy ]
    Blood samples for plasma renin activity (ng/mL/h) and aldosterone (pg/mL)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2019)
  • Changes from baseline of blood pressure values (ABPM) [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Mean Systolic and Diastolic Blood Pressure (mmHg)
  • Changes from baseline of body composition [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Variation of parameters of Bioelectrical Impedance Analysis (BIA)
  • Changes in basal glicemic control [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Blood samples for basal glucose (mg/dL).
  • Changes in long term glicemic control [ Time Frame: Before starting SGLT2i and 90 days after the starting ]
    Blood samples for Glycated albumin (mmol/mol).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Antidiuretic Function Before and During Treatment With SGLT2 Inhibitors
Official Title  ICMJE Assessment of the Renin-angiotensin-aldosterone System (RAAS) and Antidiuretic Function in Patients With Type 2 Diabetes Before and During Treatment With Sodium-glucose Co-transporter 2 Inhibitors (SGLT2i): the GliRACo 1 Study
Brief Summary Subjects treated with Canagliflozin, Dapagliflozin and Empagliflozin obtained improvement on blood pressure values, body weight and cardiovascular mortality but pathophysiological explanations of these effects are not yet known.
Detailed Description

The pathophysiological explanations of the cardiovascular improvement of patients treated with SGLT2i are not yet known: osmotic diuresis and natriuresis, direct effects of weight reduction, increased in nitric oxide release, oxidative stress reduction, local renin-angiotensin-aldosterone system (RAAS) inhibition are the supposed mechanism. In the Literature the diuretic effect of SGLT2i therapy seems to be even stronger than thiazide or thiazide-like drugs. However, it is not defined the role of SGLT2i on antidiuretic function (RAAS, brain natriuretic peptide-BNP and antidiuretic hormone-ADH). Defining this relation could be important for:

  • knowing effect of SGLT2i on RAAS (drugs interferences are important particularly during case detection of primary aldosteronism);
  • discovering antidiuretic response to SGLT2i treatment and interactions between RAAS, BNP and ADH on the volume improvement induced by this new antidiabetic drugs.

In addition the aim of the study is to define effect of treatment on blood pressure and body composition.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Diabetes Mellitus, Type 2
  • Arterial Hypertension
  • Body Weight Changes
Intervention  ICMJE Drug: SGLT2 inhibitor
Start of the treatment with SGLT2i.
Other Name: Dapagliflozin, Empagliflozin, Canagliflozin
Study Arms  ICMJE Experimental: Diabetic patients
30 diabetic patients candidate to treatment with SGLT2i in add-on to metformin.
Intervention: Drug: SGLT2 inhibitor
Publications *
  • Reed JW. Impact of sodium-glucose cotransporter 2 inhibitors on blood pressure. Vasc Health Risk Manag. 2016 Oct 27;12:393-405. eCollection 2016. Review.
  • Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
  • Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013 Sep;15(9):853-62. doi: 10.1111/dom.12127. Epub 2013 Jun 5.
  • Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, Ahn YB, Kim ES, Moon SD, Kim MJ, Ko SH. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes. PLoS One. 2016 Nov 1;11(11):e0165703. doi: 10.1371/journal.pone.0165703. eCollection 2016.
  • Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014 Feb 4;129(5):587-97. doi: 10.1161/CIRCULATIONAHA.113.005081. Epub 2013 Dec 13.
  • Boertien WE, Riphagen IJ, Drion I, Alkhalaf A, Bakker SJ, Groenier KH, Struck J, de Jong PE, Bilo HJ, Kleefstra N, Gansevoort RT. Copeptin, a surrogate marker for arginine vasopressin, is associated with declining glomerular filtration in patients with diabetes mellitus (ZODIAC-33). Diabetologia. 2013 Aug;56(8):1680-8. doi: 10.1007/s00125-013-2922-0. Epub 2013 Apr 28.
  • Nogueira-Silva L, Blanchard A, Curis E, Lorthioir A, Zhygalina V, Bergerot D, Baron S, Amar L, Bobrie G, Plouin PF, Ménard J, Azizi M. Deciphering the Role of Vasopressin in Primary Aldosteronism. J Clin Endocrinol Metab. 2015 Sep;100(9):3297-303. doi: 10.1210/JC.2015-2007. Epub 2015 Jul 10.
  • Pikkemaat M, Melander O, Bengtsson Boström K. Association between copeptin and declining glomerular filtration rate in people with newly diagnosed diabetes. The Skaraborg Diabetes Register. J Diabetes Complications. 2015 Nov-Dec;29(8):1062-5. doi: 10.1016/j.jdiacomp.2015.07.006. Epub 2015 Jul 9.
  • DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, Leslie BR, Boulton DW, Ching A, LaCreta FP, Griffen SC. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013 Oct;36(10):3169-76. doi: 10.2337/dc13-0387. Epub 2013 Jun 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 12, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 30, 2020
Actual Primary Completion Date July 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • diabetic patients;
  • clinical indication to SGLT2i therapy.

Exclusion Criteria:

  • signs and symptoms of poor glycemic control (polydipsia, polyuria and weight loss);
  • HbA1c >10% or 86 mmol/mol;
  • Body Mass Index (BMI) > 40 Kg/m2;
  • personal history of primary and secondary aldosteronism;
  • personal history of heart failure;
  • personal history of acute kidney injury;
  • personal history of chronic kidney disease;
  • personal history of liver cirrhosis;
  • personal history of protein-wasting syndrome;
  • personal history of renin secreting tumor;
  • personal history of diabetes insipidus;
  • personal history of syndrome of inappropriate antidiuresis (SIAD);
  • personal history of hypocortisolism and hypercortisolism;
  • therapy with Angiotensin Converting Enzyme inhibitors;
  • therapy with Angiotensin Receptor Blockers;
  • therapy with renin inhibitors;
  • therapy with beta-blockers;
  • therapy with alfa2-receptors agonists;
  • therapy with Calcium Channel Blockers;
  • therapy with diuretics;
  • therapy with mineralocorticoid receptor antagonists;
  • therapy with non steroidal and steroidal anti-inflammatory drugs.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mauro M Maccario, MD 00390116709559 mauro.maccario@unito.it
Contact: Mirko M Parasiliti Caprino, MD, PhD 00390116335544 mirko.parasiliticaprino@unito.it
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03917758
Other Study ID Numbers  ICMJE GliRACo 1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mauro Maccario, University of Turin, Italy
Study Sponsor  ICMJE University of Turin, Italy
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mauro M Maccario, MD Endocrinology, Diabetology and Metabolism; University of Turin
Study Chair: Ezio E Ghigo, MD Endocrinology, Diabetology and Metabolism; University of Turin
PRS Account University of Turin, Italy
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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