Effects of Sodium-glucose Co-transporter-2( SGLT-2 ) Inhibition on Sympathetic Nervous System Activity in Humans (EMPA-SNS)

• ClinicalTrials.gov Identifier: NCT03912909
• Recruitment Status: Recruiting
• First Posted: April 11, 2019
• Last Update Posted: September 29, 2022
• Sponsor: Royal Perth Hospital
• Information provided by (Responsible Party): Dr Markus Schlaich, Royal Perth Hospital

Tracking Information

• First Submitted Date: October 23, 2018
• First Posted Date: April 11, 2019
• Last Update Posted Date: September 29, 2022
• Actual Study Start Date: August 1, 2018
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 10, 2019)

• Reduction in cardiac sympathetic nerve activity [ Time Frame: 18 weeks ]
  Cardiac sympathetic nerve activity assessed by cardiac noradrenaline spillover
• Reduction in renal sympathetic nerve activity [ Time Frame: 18 weeks ]
  Renal sympathetic nerve activity assessed by renal noradrenaline spillover
• Reduction in muscle sympathetic nerve activity [ Time Frame: 18 weeks ]
  Muscle sympathetic nerve activity assessed by microneurography

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 11, 2019)

• Reduction in ambulatory BP (blood pressure) [ Time Frame: 18 weeks ]
  Blood Pressure assessed by ambulatory blood pressure monitoring
• Reduction in central Blood Pressure [ Time Frame: 18 weeks ]
  central Blood Pressure assessed by Sphygmocor XCEL
• Change in urinary sodium excretion [ Time Frame: 18 weeks ]
  Urinary sodium excretion assessed in a 24 hour urine sample
• Change in glycemic control [ Time Frame: 18 weeks ]
  Glycemic control as assessed by an oral glucose tolerance test

Original Secondary Outcome Measures (submitted: April 10, 2019)

• Reduction in ambulatory BP [ Time Frame: 18 weeks ]
  BP assessed by ambulatory blood pressure monitoring
• Reduction in central BP [ Time Frame: 18 weeks ]
  central BP assessed by Sphygmocor XCEL
• Change in urinary sodium excretion [ Time Frame: 18 weeks ]
  Urinary sodium excretion assessed in a 24 hour urine sample
• Change in glycemic control [ Time Frame: 18 weeks ]
  Glycemic control as assessed by an oral glucose tolerance test

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Sodium-glucose Co-transporter-2( SGLT-2 ) Inhibition on Sympathetic Nervous System Activity in Humans
• Official Title: Effects of SGLT-2 Inhibition on Sympathetic Nervous System Activity in Humans
• Brief Summary: This study is designed to investigate whether the sodium-glucose co-transporter-2 (SGLT-2) inhibitor Empagliflozin reduces sympathetic nervous system (SNS) activity in humans.

Detailed Description

This is a randomised, double-blind, placebo controlled, cross-over study. Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment.

Comprehensive testing will occur after each 4 week treatment phase and will include assessment of muscle sympathetic nerve activity, cardiac and renal noradrenaline spillover to assess organ specific SNS activity.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Other

Condition

• Metabolic Syndrome
• Type 2 Diabetes Mellitus
• Obesity

Intervention

• Drug: Empagliflozin Oral Tablet [Jardiance]
  Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases
• Drug: Placebo Oral Tablet
  Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases

Study Arms

• Active Comparator: Phase 1
  Empagliflozin 10mg daily or placebo
  Interventions:

  • Drug: Empagliflozin Oral Tablet [Jardiance]
  • Drug: Placebo Oral Tablet
• Placebo Comparator: Phase2
  Empagliflozin 10mg daily or placebo
  Interventions:

  • Drug: Empagliflozin Oral Tablet [Jardiance]
  • Drug: Placebo Oral Tablet

Publications *

• 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.
• Hall JE, Jones DW, Kuo JJ, da Silva A, Tallam LS, Liu J. Impact of the obesity epidemic on hypertension and renal disease. Curr Hypertens Rep. 2003 Oct;5(5):386-92. doi: 10.1007/s11906-003-0084-z.
• Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E. Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension. 2006 Nov;48(5):787-96. doi: 10.1161/01.HYP.0000242642.42177.49. Epub 2006 Sep 25. No abstract available.
• Straznicky NE, Grima MT, Sari CI, Karapanagiotidis S, Wong C, Eikelis N, Richards KL, Lee G, Nestel PJ, Dixon JB, Lambert GW, Schlaich MP, Lambert EA. The relation of glucose metabolism to left ventricular mass and function and sympathetic nervous system activity in obese subjects with metabolic syndrome. J Clin Endocrinol Metab. 2013 Feb;98(2):E227-37. doi: 10.1210/jc.2012-3277. Epub 2012 Dec 27.
• Straznicky NE, Lambert EA, Grima MT, Eikelis N, Richards K, Nestel PJ, Dawood T, Masuo K, Sari CI, Dixon JB, Esler MD, Paul E, Schlaich MP, Lambert GW. The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia. Obesity (Silver Spring). 2014 Mar;22(3):652-62. doi: 10.1002/oby.20614. Epub 2013 Dec 6.
• Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003 Aug 5;108(5):560-5. doi: 10.1161/01.CIR.0000081775.72651.B6. Epub 2003 Jul 7.
• Ziegler D, Weise F, Langen KJ, Piolot R, Boy C, Hubinger A, Muller-Gartner HW, Gries FA. Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I]metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients. Diabetologia. 1998 Apr;41(4):443-51. doi: 10.1007/s001250050928.
• Sverrisdottir YB, Jansson LM, Hagg U, Gan LM. Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals. PLoS One. 2010 Feb 17;5(2):e9257. doi: 10.1371/journal.pone.0009257.
• Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, Sobotka PA, Krum H, Esler M, Bohm M. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011 May 10;123(18):1940-6. doi: 10.1161/CIRCULATIONAHA.110.991869. Epub 2011 Apr 25.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 10, 2019): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2024
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age: 25 -65 years
• (Body Mass Index) BMI≥30kg/m2
• Currently weight stable (+/- 3% in previous 6-12 months and not on any specific exercise or dietary program)
• Metabolic syndrome (defined as having: obesity (BMI ≥30kg/m2 ) plus any two of the following four factors: Elevated triglycerides (Triglyceride≥ 1.7mmol/L), Reduced HDL (High - density lipoprotein) cholesterol (<1.0mmol/L in males, <1.3mmol/L in females), Elevated clinic systolic (Blood Pressure) BP ≥130 or diastolic BP ≥85mmHg, Fasting glucose ≥5.6mmol/L or type 2 diabetes.
• office BP for screening purposes ≤160/90mmHg
• drug naïve for at least 6 weeks prior to baseline assessment

Exclusion Criteria:

• Grade 2-3 hypertension (systolic office BP >160, diastolic office BP >100 mmHg)
• Secondary causes of hypertension
• CKD (Chronic kidney disease) stage 4-5 {(estimated glomerular filtration) eGFR<30ml/min}
• Heart failure NYHA (New York Heart Association) class II-IV
• Recent CV (cardiovascular) event (acute myocardial infarction, acute coronary syndrome, stroke or transient ischaemic attack within the previous six months)
• unstable psychiatric condition
• medication such as corticosteroids, several antidepressants and antipsychotics
• Female participants of childbearing potential must have a negative pregnancy test prior to treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Anu Joyson, MSN; +61 8 92240390; anu.joyson@uwa.edu.au

• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT03912909
• Other Study ID Numbers: REG 16-157
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual Participant Data will not be shared to maintain anonymity and confidentiality of the participants

• Current Responsible Party: Dr Markus Schlaich, Royal Perth Hospital
• Original Responsible Party: Markus Schlaich, Royal Perth Hospital, Dobney Chair Clinical Research
• Current Study Sponsor: Royal Perth Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Markus Schlaich, MD,FAHA,FESC; Royal Perth Hospital

• PRS Account: Royal Perth Hospital
• Verification Date: September 2022