Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT)

• ClinicalTrials.gov Identifier: NCT03574597
• Recruitment Status: Completed
• First Posted: July 2, 2018
• Last Update Posted: April 2, 2024
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: June 21, 2018
• First Posted Date: July 2, 2018
• Last Update Posted Date: April 2, 2024
• Actual Study Start Date: October 24, 2018
• Actual Primary Completion Date: June 21, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 21, 2018)

Time to first occurrence of a composite endpoint consisting of: cardiovascular (CV) death, non-fatal myocardial infarction, or non-fatal stroke [ Time Frame: 0-59 months ]

Measured in months

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 8, 2019)

• Time to CV death [ Time Frame: 0-59 months ]
  Measured in months
• Time to all-cause death [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of an expanded composite CV endpoint consisting of: CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation or unstable angina requiring hospitalisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a composite heart failure endpoint consisting of: heart failure hospitalisation, urgent heartfailure visit or CV death [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a composite endpoint consisting of: all-cause death, non-fatal myocardial infarction, or non-fatal stroke [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of non-fatal myocardial infarction [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of non-fatal stroke [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of coronary revascularisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of unstable angina requiring hospitalisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of heart failure hospitalisation or urgent heart failure visit [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of HbA1c greater than or equal to 48 mmol/mol (6.5%) [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a 5-component composite nephropathy endpoint [ Time Frame: 0-59 months ]
  Measured in months. A 5-component composite nephropathy endpoint consists of: onset of persistent macroalbuminuria (UACR above 300 mg/g), persistent 50% reduction in estimated Glomerular Filtration Rate (eGFR) compared with baseline (randomisation), onset of persistent eGFR less than 15 ml/min/1.73m^2, initiation of chronic renal replacement therapy (dialysis or transplantation) or renal death.
• Time to HbA1c greater than or equal to 39 mmol/mol (5.7%) for subjects with a screening HbA1c less than 39 mmol/mol (5.7%) [ Time Frame: 0-59 months ]
  Measured in months
• Subjects with HbA1c less than 39 mmol/mol (5.7%) at each visit where HbA1c is assessed for subjects with a screening HbA1c greater than or equal to 39 mmol/mol (5.7%) [ Time Frame: 0-59 months ]
  Proportion of subjects
• Change in systolic blood pressure [ Time Frame: Week 0, year 2 ]
  Measured in mm Hg
• Change in diastolic blood pressure [ Time Frame: Week 0, year 2 ]
  Measured in mm Hg
• Change in pulse [ Time Frame: Week 0, year 2 ]
  Measured in beats per minute
• Change in High sensitivity C-Reactive Protein (hsCRP) [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in total cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in high density lipoprotein (HDL) cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in low density lipoprotein (LDL) cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in triglycerides [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in body weight [ Time Frame: Week 0, year 2 ]
  Measured in %
• Change in waist circumference [ Time Frame: Week 0, year 2 ]
  Measured in cm
• Change in EuroQol five dimensions five level (EQ-5D-5L) questionnaire [ Time Frame: Week 0, year 2 ]
  The EQ-5D-5L questionnaire will be used to estimate the impact on subjects' health-related quality of life and provides a description of subjects' problems by dimensions (descriptive system), a score for overall self-rated health (visual analogue scale [VAS]) as well as an index score (EQ-5D-5L index). EQ-5D index score range: 0 to 1 and EQ-5D-VAS: range 0 to 100. A higher score indicates better self reported health status.
• Change in total score weight related sign and symptom measure [ Time Frame: Week 0, year 2 ]
  The weight related sign and symptom measure assesses the presence and bother associated with weight-related symptoms using a self-rated VAS. It is a tool to assess the multifaceted aspects of obesity on symptom experience in subjects with overweight or obesity.
• Change in haemoglobin A1c (HbA1c) [ Time Frame: Screening (up to 3 weeks before randomisation at week 0), week 104 ]
  Measured in %
• Change in HbA1c [ Time Frame: Screening (up to 3 weeks before randomisation at week 0), week 104 ]
  Measured in mmol/mol

Original Secondary Outcome Measures (submitted: June 21, 2018)

• Time to CV death [ Time Frame: 0-59 months ]
  Measured in months
• Time to all-cause death [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of an expanded composite CV endpoint consisting of: CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation or unstable angina requiring hospitalisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a composite heart failure endpoint consisting of: heart failure hospitalisation, urgent heartfailure visit or CV death [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a composite endpoint consisting of: all-cause death, non-fatal myocardial infarction, or non-fatal stroke [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of non-fatal myocardial infarction [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of non-fatal stroke [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of coronary revascularisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of unstable angina requiring hospitalisation [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of heart failure hospitalisation or urgent heart failure visit [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of HbA1c greater than or equal to 48 mmol/mol (6.5%) [ Time Frame: 0-59 months ]
  Measured in months
• Time to first occurrence of a 5-component composite nephropathy endpoint [ Time Frame: 0-59 months ]
  Measured in months. A 5-component composite nephropathy endpoint consists of: onset of persistent macroalbuminuria, persistent 50% reduction in estimated Glomerular Filtration Rate (eGFR) compared with baseline (randomisation), onset of persistent eGFR less than 15 ml/min/1.73m^2, initiation of chronic renal replacement therapy (dialysis or transplantation) or renal death.
• Time to HbA1c greater than or equal to 39 mmol/mol (5.7%) for subjects with a screening HbA1c less than 39 mmol/mol (5.7%) [ Time Frame: 0-59 months ]
  Measured in months
• Subjects with HbA1c less than 39 mmol/mol (5.7%) at each visit where HbA1c is assessed for subjects with a screening HbA1c greater than or equal to 39 mmol/mol (5.7%) [ Time Frame: 0-59 months ]
  Proportion of subjects
• Change in systolic blood pressure [ Time Frame: Week 0, year 2 ]
  Measured in mm Hg
• Change in diastolic blood pressure [ Time Frame: Week 0, year 2 ]
  Measured in mm Hg
• Change in pulse [ Time Frame: Week 0, year 2 ]
  Measured in beats per minute
• Change in High sensitivity C-Reactive Protein (hsCRP) [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in total cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in high density lipoprotein (HDL) cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in low density lipoprotein (LDL) cholesterol [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in triglycerides [ Time Frame: Week 0, year 2 ]
  Measured in mg/dL
• Change in body weight [ Time Frame: Week 0, year 2 ]
  Measured in %
• Change in waist circumference [ Time Frame: Week 0, year 2 ]
  Measured in cm
• Change in EuroQol five dimensions five level (EQ-5D-5L) questionnaire [ Time Frame: Week 0, year 2 ]
  The EQ-5D-5L questionnaire will be used to estimate the impact on subjects' health-related quality of life and provides a description of subjects' problems by dimensions (descriptive system), a score for overall self-rated health (visual analogue scale [VAS]) as well as an index score (EQ-5D-5L index). EQ-5D index score range: 0 to 1 and EQ-5D-VAS: range 0 to 100. A higher score indicates better self reported health status.
• Change in total score weight related sign and symptom measure [ Time Frame: Week 0, year 2 ]
  The weight related sign and symptom measure assesses the presence and bother associated with weight-related symptoms using a self-rated VAS. It is a tool to assess the multifaceted aspects of obesity on symptom experience in subjects with overweight or obesity.
• Change in haemoglobin A1c (HbA1c) [ Time Frame: Screening (up to 3 weeks before randomisation at week 0), week 104 ]
  Measured in %
• Change in HbA1c [ Time Frame: Screening (up to 3 weeks before randomisation at week 0), week 104 ]
  Measured in mmol/mol

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

Descriptive Information

• Brief Title: Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity
• Official Title: SELECT - Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity
• Brief Summary: The researchers are doing the study to see if semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. The participant will either get semaglutide (active medicine) or placebo ("dummy" medicine). Which treatment the participants get is decided by chance. The participant's chance of getting semaglutide or placebo is the same. The participant will get the study medicine in a pen. The participants will need to use the pen to inject the study medicine in a skinfold once a week. The study will last for about 2.5 to 5 years. Participants will have up to 25 clinic visits with the study doctor.
• 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

• Overweight
• Obesity

Intervention

• Drug: Semaglutide
  Semaglutide will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Subjects will start semaglutide treatment at 0.24 mg; dose will gradually be increased every 4 weeks up to 2.4 mg.
• Drug: Placebo (semaglutide)
  Placebo will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Participants will receive placebo at an equivalent dose to semaglutide.

Study Arms

• Experimental: Semaglutide
  Participants will receive semaglutide as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months.
  Intervention: Drug: Semaglutide
• Placebo Comparator: Placebo (semaglutide)
  Participants will receive placebo (semaglutide) as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months.
  Intervention: Drug: Placebo (semaglutide)

Publications *

• Ryan DH, Lingvay I, Colhoun HM, Deanfield J, Emerson SS, Kahn SE, Kushner RF, Marso S, Plutzky J, Brown-Frandsen K, Gronning MOL, Hovingh GK, Holst AG, Ravn H, Lincoff AM. Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design. Am Heart J. 2020 Nov;229:61-69. doi: 10.1016/j.ahj.2020.07.008. Epub 2020 Jul 17.
• Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.
• Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornoe CW, Ryan DH; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232. doi: 10.1056/NEJMoa2307563. Epub 2023 Nov 11.
• Leite AR, Angelico-Goncalves A, Vasques-Novoa F, Borges-Canha M, Leite-Moreira A, Neves JS, Ferreira JP. Effect of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese adults without diabetes: A meta-analysis of placebo-controlled randomized trials. Diabetes Obes Metab. 2022 Aug;24(8):1676-1680. doi: 10.1111/dom.14707. Epub 2022 May 3.
• Mares AC, Chatterjee S, Mukherjee D. Semaglutide for weight loss and cardiometabolic risk reduction in overweight/obesity. Curr Opin Cardiol. 2022 Jul 1;37(4):350-355. doi: 10.1097/HCO.0000000000000955. Epub 2022 Feb 16.
• Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 27, 2023): 17609
• Original Estimated Enrollment (submitted: June 21, 2018): 17500
• Actual Study Completion Date: June 29, 2023
• Actual Primary Completion Date: June 21, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
• Male or female, age greater than or equal to 45 years at the time of signing informed consent
• Body mass index (BMI) greater than or equal to 27 kg/m^2
• Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease

Exclusion Criteria:

Cardiovascular-related:

• Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
• Presently classified as being in New York Heart Association (NYHA) Class IV heart failure

Glycaemia-related:

• HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening
• History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)
• Treatment with glucose-lowering agents within 90 days before screening
• Treatment with any glucagon-like-peptide-1 receptor agonist (GLP-1 RA) within 90 days before screening

General safety:

• History or presence of chronic pancreatitis
• Presence of acute pancreatitis within the past 180 days prior to the day of screening
• Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
• End stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis
• Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
• Severe psychiatric disorder which in the investigator's opinion could compromise compliance with the protocol
• Known or suspected hypersensitivity to trial products or related products
• Previous participation in this trial. Participation is defined as randomisation
• Receipt of any investigational medicinal product within 30 days before screening
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method
• Any disorder, unwillingness or inability, which in the investigator's opinion, might jeopardise the participant's safety or compliance with the protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 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: Algeria, Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Croatia, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Latvia, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03574597
• Other Study ID Numbers: EX9536-4388; 2017-003380-35 ( Registry Identifier: European Medicines Agency (EudraCT) ); U1111-1200-5564 ( Other Identifier: World Health Organization (WHO) )
• 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: http://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.2834); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: March 2024