A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW)

• ClinicalTrials.gov Identifier: NCT03819153
• Recruitment Status: Active, not recruiting
• First Posted: January 28, 2019
• Last Update Posted: May 17, 2023
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: January 18, 2019
• First Posted Date: January 28, 2019
• Last Update Posted Date: May 17, 2023
• Actual Study Start Date: June 17, 2019
• Estimated Primary Completion Date: August 19, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 25, 2019)

Time to first occurrence of a composite primary outcome event defined as persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease [ Time Frame: Week 0 to month 61 ]

Measured in month(s). End Stage Renal Disease (ESRD) is defined as the following individual components: Persistent estimated glomerular filtration rate (eGFR) less than 15 mL/min/1.73m^2 or, Chronic dialysis treatment or receiving a kidney transplantation.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 25, 2019)

• Annual rate of change in eGFR (chronic kidney disease - epidemiology collaboration (CKD-EPI)) (total eGFR slope) [ Time Frame: Week 0 to month 61 ]
  Measured in (mL/min/1.73 m^2)/year.
• Time to first occurrence of a composite cardiovascular major adverse cardiovascular event (MACE) endpoint consisting of: Non-fatal myocardial infarction, non-fatal stroke, and cardiovascular (CV) death [ Time Frame: Week 0 to month 61 ]
  Measured in month(s).
• Time to occurrence of all-cause death [ Time Frame: Week 0 to month 61 ]
  Measured in month(s).
• Time to occurrence of each of the individual components of the primary composite endpoint and of the confirmatory secondary MACE endpoint [ Time Frame: Week 0 to month 61 ]
  Measured in month(s).
• Time to first occurrence of major adverse limb events (MALE), a composite endpoint consisting of: Acute limb ischemia hospitalisation and chronic limb ischemia hospitalisation [ Time Frame: Week 0 to month 61 ]
  Measured in month(s).
• Annual rate of change in eGFR (CKD-EPI) (chronic eGFR slope) [ Time Frame: Week 12 to month 61 ]
  Measured in (mL/min/1.73 m^2)/year.
• Change in eGFR (CKD-EPI) [ Time Frame: Week 0, Week 12 ]
  Measured in mL/min/1.73 m^2.
• Change in eGFR (cystatin C CKD-EPI) [ Time Frame: Week 0, Year 3 ]
  Measured in mL/min/1.73 m^2.
• Relative change in urinary albumin-to-creatinine ratio (UACR) [ Time Frame: Week 0, Year 3 ]
  Measured in percentage.
• Change in body weight [ Time Frame: Week 0, Year 3 ]
  Measured in kilogram.
• Change in glycosylated haemoglobin (HbA1c) [ Time Frame: Week 0, Year 3 ]
  Measured in percentage point.
• Change in systolic blood pressure [ Time Frame: Week 0, Year 3 ]
  Measured in mmHg.
• Change in diastolic blood pressure [ Time Frame: Week 0, Year 3 ]
  Measured in mmHg.
• Number of severe hypoglycaemic episodes [ Time Frame: Week 0 to month 61 ]
  Number of events.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease
• Official Title: Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease
• Brief Summary: The researchers are doing this study to see if semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will get semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when there is enough information collected to show clear result of the study. The total time participants will be in this study is about 3 to 5 years, but it could be longer.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Sponsor staff involved in the clinical trial is masked according to company standard procedures

Primary Purpose: Treatment

• Condition: Diabetes Mellitus, Type 2

Intervention

• Drug: Semaglutide
  Participants are to inject semaglutide with a needle in the stomach, thigh or upper arm. Participants will use a pen to inject semaglutide under their skin. Participants will inject semaglutide 1 time a week on the same day of the week. Participants' dose of semaglutide will be changed over time. Participants start by taking a smaller amount (0.25 mg). After 4 weeks the dose will be increased to 0.5 mg. It will be increased more (to 1 mg) at 8 weeks. Participants will then stay on the same dose for the rest of the study.
• Drug: Placebo (semaglutide)
  Participants are to inject placebo (semaglutide) with a needle in the stomach, thigh or upper arm. Participants will use a pen to inject placebo (semaglutide) under their skin. Participants will inject placebo (semaglutide) 1 time a week on the same day of the week. Participants' dose of placebo (semaglutide) will be changed over time. Participants start by taking a smaller amount (0.25 mg). After 4 weeks the dose will be increased to 0.5 mg. It will be increased more (to 1 mg) at 8 weeks. Participants will then stay on the same dose for the rest of the study.

Study Arms

• Experimental: Semaglutide
  Participants are to receive semglutide for up to 5 years or more (event driven). The trial is event driven with a pre-defined minimum number of renal endpoint events for the primary endpoint.
  Intervention: Drug: Semaglutide
• Placebo Comparator: Placebo
  Participants are to receive placebo (semglutide) for up to 5 years or more (event driven). The trial is event driven with a pre-defined minimum number of renal endpoint events for the primary endpoint.
  Intervention: Drug: Placebo (semaglutide)

Publications *

• Rossing P, Baeres FMM, Bakris G, Bosch-Traberg H, Gislum M, Gough SCL, Idorn T, Lawson J, Mahaffey KW, Mann JFE, Mersebach H, Perkovic V, Tuttle K, Pratley R. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant. 2023 Jan 18:gfad009. doi: 10.1093/ndt/gfad009. Online ahead of print.
• Cohen S, Sternlicht H, Bakris GL. Mineralocorticoid Receptor Antagonists in the Treatment of Diabetic Kidney Disease: Their Application in the Era of SGLT2 Inhibitors and GLP-1 Receptor Agonists. Curr Diab Rep. 2022 May;22(5):213-218. doi: 10.1007/s11892-022-01461-4. Epub 2022 Apr 20.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 6, 2020): 3508
• Original Estimated Enrollment (submitted: January 25, 2019): 3120
• Estimated Study Completion Date: August 19, 2024
• Estimated Primary Completion Date: August 19, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female, age above or equal to 18 years at the time of signing informed consent. Japan: Male or female, age above or equal to 20 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus
• HbA1c less than or equal to 10% (less than or equal to 86 mmol/mol)

• Renal impairment defined either by:

  1. serum creatinine-based eGFR greater than or equal to 50 and less than or equal to 75 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 300 and less than 5000 mg/g or
  2. serum creatinine-based eGFR greater than or equal to 25 and less than 50 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 100 and less than 5000 mg/g
• Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment is contraindicated or not tolerated. Treatment dose must be stable for at least 4 weeks prior to the date of the laboratory assessments used for determination of the inclusion criteria for renal impairment and kept stable until screening

Exclusion Criteria:

• Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations
• Use of any glucagon-like peptide-1 (GLP-1) receptor agonist within 30 days prior to screening
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 60 days prior to the day of screening
• Presently classified as being in New York Heart Association (NYHA) Class IV heart failure
• Planned coronary, carotid or peripheral artery revascularisation
• Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Poland, Russian Federation, Slovakia, South Africa, Spain, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03819153
• Other Study ID Numbers: NN9535-4321; U1111-1217-6259 ( Other Identifier: World Health Organization (WHO) ); 2018-002878-50 ( Registry Identifier: European Medicines Agency (EudraCT) ); JapicCTI-194843 ( Registry Identifier: JAPIC (Japan) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
• URL: https://www.novonordisk-trials.com

• Current Responsible Party: Novo Nordisk A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Novo Nordisk A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Transparency (dept. 1452); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: May 2023