Efficacy and Safety of Semaglutide Once-weekly Versus Placebo as add-on to Basal Insulin Alone or Basal Insulin in Combination With Metformin in Subjects With Type 2 Diabetes (SUSTAIN™ 5)

This trial is conducted in Asia, Europe and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of semaglutide once weekly versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in subjects with type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: semaglutide; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 397
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45219
    • Novo Nordisk Investigational Site
  • Falkensee, Germany, 14612
    • Novo Nordisk Investigational Site
  • Friedrichsthal, Germany, 66299
    • Novo Nordisk Investigational Site
  • Hamburg, Germany, 22607
    • Novo Nordisk Investigational Site
  • Hamburg, Germany, 21073
    • Novo Nordisk Investigational Site
  • Hamburg, Germany, 22587
    • Novo Nordisk Investigational Site
  • Hohenmölsen, Germany, 06679
    • Novo Nordisk Investigational Site
  • Münster, Germany, 48145
    • Novo Nordisk Investigational Site
  • Rehlingen-Siersburg, Germany, 66780
    • Novo Nordisk Investigational Site
  • Saint Ingbert-Oberwürzbach, Germany, 66386
    • Novo Nordisk Investigational Site
  • Stuttgart, Germany, 70378
    • Novo Nordisk Investigational Site
  • Sulzbach-Rosenberg, Germany, 92237
    • Novo Nordisk Investigational Site
• Japan
  • Ibaraki, Japan, 311-0113
    • Novo Nordisk Investigational Site
  • Kashiwara-shi, Osaka, Japan, 582-0005
    • Novo Nordisk Investigational Site
  • Kumamoto-shi, Kumamoto, Japan, 860-0811
    • Novo Nordisk Investigational Site
  • Miyazaki, Japan, 880-0034
    • Novo Nordisk Investigational Site
  • Osaka, Japan, 569-1045
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 103-0027
    • Novo Nordisk Investigational Site
• Puerto Rico
  • Manati, Puerto Rico, 00674
    • Novo Nordisk Investigational Site
• Serbia
  • Belgrade, Serbia, 11000
    • Novo Nordisk Investigational Site
  • Kragujevac, Serbia, 34000
    • Novo Nordisk Investigational Site
  • Novi Sad, Serbia, 21000
    • Novo Nordisk Investigational Site
• Slovakia
  • Bratislava, Slovakia, 833 05
    • Novo Nordisk Investigational Site
  • Kosice, Slovakia, 040 01
    • Novo Nordisk Investigational Site
  • Levice, Slovakia, 93401
    • Novo Nordisk Investigational Site
  • Lucenec, Slovakia, 984 01
    • Novo Nordisk Investigational Site
  • Presov, Slovakia, 080 01
    • Novo Nordisk Investigational Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Novo Nordisk Investigational Site
  • California
    • Anaheim, California, United States, 92801
      • Novo Nordisk Investigational Site
    • Fresno, California, United States, 93720
      • Novo Nordisk Investigational Site
    • Lomita, California, United States, 90717
      • Novo Nordisk Investigational Site
    • Los Angeles, California, United States, 90057-3550
      • Novo Nordisk Investigational Site
    • Northridge, California, United States, 91325
      • Novo Nordisk Investigational Site
    • Poway, California, United States, 92064
      • Novo Nordisk Investigational Site
    • Riverside, California, United States, 92506
      • Novo Nordisk Investigational Site
    • Roseville, California, United States, 95661
      • Novo Nordisk Investigational Site
    • San Ramon, California, United States, 94583
      • Novo Nordisk Investigational Site
    • Van Nuys, California, United States, 91405
      • Novo Nordisk Investigational Site
    • Walnut Creek, California, United States, 94598
      • Novo Nordisk Investigational Site
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Novo Nordisk Investigational Site
  • Florida
    • Bradenton, Florida, United States, 34201
      • Novo Nordisk Investigational Site
    • Fleming Island, Florida, United States, 32003
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32204
      • Novo Nordisk Investigational Site
    • Port Charlotte, Florida, United States, 33952
      • Novo Nordisk Investigational Site
    • Spring Hill, Florida, United States, 34609
      • Novo Nordisk Investigational Site
    • Tampa, Florida, United States, 33634
      • Novo Nordisk Investigational Site
  • Georgia
    • Roswell, Georgia, United States, 30076
      • Novo Nordisk Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Novo Nordisk Investigational Site
    • Chicago, Illinois, United States, 60611
      • Novo Nordisk Investigational Site
    • Gillespie, Illinois, United States, 62033
      • Novo Nordisk Investigational Site
    • Skokie, Illinois, United States, 60077
      • Novo Nordisk Investigational Site
  • Indiana
    • Avon, Indiana, United States, 46123
      • Novo Nordisk Investigational Site
    • Greenfield, Indiana, United States, 46140
      • Novo Nordisk Investigational Site
    • Indianapolis, Indiana, United States, 46254
      • Novo Nordisk Investigational Site
    • Muncie, Indiana, United States, 47304
      • Novo Nordisk Investigational Site
  • Iowa
    • Council Bluffs, Iowa, United States, 51501
      • Novo Nordisk Investigational Site
  • Kansas
    • Overland Park, Kansas, United States, 66209
      • Novo Nordisk Investigational Site
    • Topeka, Kansas, United States, 66606
      • Novo Nordisk Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Novo Nordisk Investigational Site
    • Paducah, Kentucky, United States, 42003
      • Novo Nordisk Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70002
      • Novo Nordisk Investigational Site
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Novo Nordisk Investigational Site
  • Massachusetts
    • Waltham, Massachusetts, United States, 02453
      • Novo Nordisk Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Novo Nordisk Investigational Site
    • Flint, Michigan, United States, 48532
      • Novo Nordisk Investigational Site
    • Kalamazoo, Michigan, United States, 49009
      • Novo Nordisk Investigational Site
  • Mississippi
    • Jackson, Mississippi, United States, 39209
      • Novo Nordisk Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89103
      • Novo Nordisk Investigational Site
    • Las Vegas, Nevada, United States, 89128
      • Novo Nordisk Investigational Site
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Novo Nordisk Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Novo Nordisk Investigational Site
  • New York
    • West Seneca, New York, United States, 14224
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Novo Nordisk Investigational Site
    • Cincinnati, Ohio, United States, 45255
      • Novo Nordisk Investigational Site
    • Cincinnati, Ohio, United States, 45246
      • Novo Nordisk Investigational Site
    • Dayton, Ohio, United States, 45439
      • Novo Nordisk Investigational Site
    • Kettering, Ohio, United States, 45429
      • Novo Nordisk Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73162-4704
      • Novo Nordisk Investigational Site
    • Yukon, Oklahoma, United States, 73099
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Levittown, Pennsylvania, United States, 19056-2404
      • Novo Nordisk Investigational Site
    • Philadelphia, Pennsylvania, United States, 19114
      • Novo Nordisk Investigational Site
  • Tennessee
    • Athens, Tennessee, United States, 37303
      • Novo Nordisk Investigational Site
    • Bristol, Tennessee, United States, 37620-7352
      • Novo Nordisk Investigational Site
    • Chattanooga, Tennessee, United States, 37411
      • Novo Nordisk Investigational Site
    • Kingsport, Tennessee, United States, 37660
      • Novo Nordisk Investigational Site
  • Texas
    • Amarillo, Texas, United States, 79106
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75390-9302
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75251
      • Novo Nordisk Investigational Site
    • Fort Worth, Texas, United States, 76132
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77008
      • Novo Nordisk Investigational Site
    • Hurst, Texas, United States, 76054
      • Novo Nordisk Investigational Site
    • Katy, Texas, United States, 77450
      • Novo Nordisk Investigational Site
    • Mesquite, Texas, United States, 75149
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78224
      • Novo Nordisk Investigational Site
    • Sugar Land, Texas, United States, 77478
      • Novo Nordisk Investigational Site
    • Sugar Land, Texas, United States, 77479
      • Novo Nordisk Investigational Site
  • Utah
    • Bountiful, Utah, United States, 84010
      • Novo Nordisk Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Novo Nordisk Investigational Site
  • Wisconsin
    • Kenosha, Wisconsin, United States, 53144
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: - Male or female, age at least 18 years at the time of signing inform consent. For Japan: Male or female, age at least 20 years at the time of signing informed consent - Subjects diagnosed with T2DM (type 2 diabetes mellitus) and on stable diabetes treatment (plus/minus 20 percent change in total daily dose) with basal insulin (minimum of 0.25 IU/kg/day and/or 20 IU/day of: insulin glargine, insulin detemir, insulin degludec and/or NPH insulin) alone or in combination with metformin (minimum of 1500 mg/day or maximal tolerable dose) for 90 days prior to screening - HbA1c (glycosylated haemoglobin) 7.0 - 10.0 percent (53 - 86 mmol/mol) both inclusive Exclusion Criteria: - Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method throughout the trial including the 5 weeks follow-up period (adequate contraceptive measures as required by local regulation or practice). Germany: Only highly effective methods of birth control are accepted (ie one that results in less than 1% per year failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence or vasectomised partner. Japan: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives - Treatment with any glucose lowering agents other than stated in the inclusion criteria in a period of 90 days before screening. An exception is short-term treatment (7 days or less in total) with bolus insulin in connection with intercurrent illness - Experienced more than 3 episodes of severe hypoglycaemia within 6 months prior to screening, and/or hypoglycaemia unawareness - History of pancreatitis (acute or chronic) - Screening calcitonin value above or equal to 50 ng/L (pg/mL) - Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome 2 (MEN 2) - Severe renal impairment defined as eGFR (estimated glomerular filtration rate) below 30 mL/min/1.73 m^2 per Modification of Diet in Renal Disease (MDRD) formula (4 variable version) - Acute coronary or cerebrovascular event within 90 days before randomisation - Heart failure, New York Heart Association (NYHA) Class IV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide 0.5 mg/Week	Drug: semaglutide; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Experimental: Semaglutide 1.0 mg/Week	Drug: semaglutide; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Placebo Comparator: Semaglutide Placebo 0.5 mg/Week	Drug: placebo; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Placebo Comparator: Semaglutide Placebo 1.0 mg/Week	Drug: placebo; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c (Glycosylated Haemoglobin)	Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.	Week 0, week 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight	Estimated mean change from baseline in body weight at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.	Week 0, week 30
Change in Fasting Plasma Glucose (FPG)	Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.	week 0, week 30
Change in Insulin Dose	Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.	week 0, week 30
Change in Systolic and Diastolic Blood Pressure	Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.	week 0, week 30
Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ)	The DTSQs questionnaire was used to assess subjects' treatment satisfaction and contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening [<= 8.0% or > 8.0%] and use of metformin [yes or no]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.	week 0, week 30
HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target	Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.	After 30 weeks treatment
HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target	Percentage of participants with HbA1c below or equal to 6.5% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.	After 30 weeks treatment

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020 Sep 30;19(1):156. doi: 10.1186/s12933-020-01106-4.
• Rodbard HW, Bellary S, Hramiak I, Seino Y, Silver R, Damgaard LH, Nayak G, Zacho J, Aroda VR. GREATER COMBINED REDUCTIONS IN HbA1C >/=1.0% AND WEIGHT >/=5.0% WITH SEMAGLUTIDE VERSUS COMPARATORS IN TYPE 2 DIABETES. Endocr Pract. 2019 Jun;25(6):589-597. doi: 10.4158/EP-2018-0444. Epub 2019 Mar 13.
• Warren M, Chaykin L, Trachtenbarg D, Nayak G, Wijayasinghe N, Cariou B. Semaglutide as a therapeutic option for elderly patients with type 2 diabetes: Pooled analysis of the SUSTAIN 1-5 trials. Diabetes Obes Metab. 2018 Sep;20(9):2291-2297. doi: 10.1111/dom.13331. Epub 2018 Jun 7.
• Ahren B, Atkin SL, Charpentier G, Warren ML, Wilding JPH, Birch S, Holst AG, Leiter LA. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. Diabetes Obes Metab. 2018 Sep;20(9):2210-2219. doi: 10.1111/dom.13353. Epub 2018 Jun 12.
• DeVries JH, Desouza C, Bellary S, Unger J, Hansen OKH, Zacho J, Woo V. Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme. Diabetes Obes Metab. 2018 Oct;20(10):2426-2434. doi: 10.1111/dom.13396. Epub 2018 Jul 9.
• Aroda VR, Ahmann A, Cariou B, Chow F, Davies MJ, Jodar E, Mehta R, Woo V, Lingvay I. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials. Diabetes Metab. 2019 Oct;45(5):409-418. doi: 10.1016/j.diabet.2018.12.001. Epub 2019 Jan 4.
• DeSouza C, Cariou B, Garg S, Lausvig N, Navarria A, Fonseca V. Efficacy and Safety of Semaglutide for Type 2 Diabetes by Race and Ethnicity: A Post Hoc Analysis of the SUSTAIN Trials. J Clin Endocrinol Metab. 2020 Feb 1;105(2):dgz072. doi: 10.1210/clinem/dgz072.
• Jendle J, Birkenfeld AL, Polonsky WH, Silver R, Uusinarkaus K, Hansen T, Hakan-Bloch J, Tadayon S, Davies MJ. Improved treatment satisfaction in patients with type 2 diabetes treated with once-weekly semaglutide in the SUSTAIN trials. Diabetes Obes Metab. 2019 Oct;21(10):2315-2326. doi: 10.1111/dom.13816. Epub 2019 Jul 12.
• Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, Vilsboll T. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020 Mar;22(3):442-451. doi: 10.1111/dom.13955. Epub 2020 Feb 5.
• Rodbard H, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, Araki E, Chu P-L, Wijayasinghe N, Norwood P. Efficacy and safety of semaglutide once-weekly vs placebo as add-on to basal insulin alone or in combination with metformin in subjects with type 2 diabetes (SUSTAIN 5). Diabetologia. 2016; 59: S364-5.
• Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, Araki E, Chu PL, Wijayasinghe N, Norwood P. Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2291-2301. doi: 10.1210/jc.2018-00070.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): November 21, 2015
• Study Completion (Actual): November 21, 2015

Study Registration Dates

• First Submitted: November 28, 2014
• First Submitted That Met QC Criteria: November 28, 2014
• First Posted (Estimate): December 2, 2014

Study Record Updates

• Last Update Posted (Actual): June 11, 2019
• Last Update Submitted That Met QC Criteria: May 28, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: NN9535-3627; 2013-004502-26 (EudraCT Number); U1111-1149-3738 (Other Identifier: WHO); JapicCTI-142729 (Other Identifier: JAPIC)