A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)

• ClinicalTrials.gov Identifier: NCT03987919
• Recruitment Status: Completed
• First Posted: June 17, 2019
• Results First Posted: February 14, 2022
• Last Update Posted: February 14, 2022
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: June 14, 2019
• First Posted Date: June 17, 2019
• Results First Submitted Date: January 21, 2022
• Results First Posted Date: February 14, 2022
• Last Update Posted Date: February 14, 2022
• Actual Study Start Date: July 30, 2019
• Actual Primary Completion Date: January 28, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 21, 2022)

Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) [ Time Frame: Baseline, Week 40 ]

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).

Original Primary Outcome Measures (submitted: June 14, 2019)

Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) [ Time Frame: Baseline, Week 40 ]

Change from Baseline in HbA1c (10 mg and 15 mg)

Current Secondary Outcome Measures (submitted: January 21, 2022)

• Change From Baseline in HbA1c (5 mg) [ Time Frame: Baseline, Week 40 ]
  HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).
• Change From Baseline in Body Weight [ Time Frame: Baseline, Week 40 ]
  Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares).
• Percentage of Participants Achieving an HbA1c Target Value of <7% [ Time Frame: Week 40 ]
  Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
• Change From Baseline in Fasting Serum Glucose (FSG) [ Time Frame: Baseline, Week 40 ]
  Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares).
• Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 40 ]
  The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares).
• Percentage of Participants Who Achieved Weight Loss ≥5% [ Time Frame: Week 40 ]
  Percentage of Participants who Achieved Weight Loss ≥5%.
• Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score [ Time Frame: Baseline, Week 40 ]
  DTSQc, an 8-item questionnaire, assesses relative change in treatment satisfaction perceived frequency of hyperglycemia, and perceived frequency of hypoglycemia from baseline to week 40 or early termination. The questionnaire consists of 8 items, 6 of which (1 and 4 through 8) assess treatment satisfaction. Each item is rated on a 7-point Likert scale. The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 to 18 where the higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment. The hyperglycemia and hypoglycemia scores range from -3 to 3 where negative scores indicate fewer problems with blood glucose levels and positive scores indicate more problems than before. LS Mean was determined by ANCOVA with Baseline DTSQs + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment (Type III sum of squares).
• Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia [ Time Frame: Baseline through Safety Follow-Up (Up to Week 44) ]
  The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL) (<3.0 mmol/L] or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment.
• Percentage of Participants Achieving an HbA1c Target Value of <5.7% [ Time Frame: Week 40 ]
  Percentage of Participants Achieving an HbA1c Target Value of <5.7%.

Original Secondary Outcome Measures (submitted: June 14, 2019)

• Change from Baseline in HbA1c (5 mg) [ Time Frame: Baseline, Week 40 ]
  Change from Baseline in HbA1c
• Change from Baseline in Body Weight [ Time Frame: Baseline, Week 40 ]
  Change from Baseline in Body Weight
• Percentage of Participants Achieving an HbA1c Target Value of <7% [ Time Frame: Week 40 ]
  Percentage of Participants Achieving an HbA1c Target Value of <7%
• Change from Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 40 ]
  Change from Baseline in Fasting Serum Glucose
• Mean Change from Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in Daily Average 7-Point SMBG Values
• Percentage of Participants who Achieved Weight Loss ≥5% [ Time Frame: Week 40 ]
  Percentage of Participants who Achieved Weight Loss ≥5%
• Change from Baseline in Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) [ Time Frame: Baseline, Week 40 ]
  Change from Baseline in Diabetes Treatment Satisfaction as Measured by the DTSQ
• Rate of Documented Symptomatic Hypoglycemic Episodes [ Time Frame: Baseline through Week 40 ]
  Rate of Documented Symptomatic Hypoglycemic Episodes

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

Descriptive Information

• Brief Title: A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes
• Official Title: A Phase 3, Randomized, Open-Label Trial Comparing Efficacy and Safety of Tirzepatide Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Patients With Type 2 Diabetes
• Brief Summary: The reason for this study is to compare the effect of the study drug tirzepatide to semaglutide on blood sugar levels in participants with type 2 diabetes. The study will last approximately 47 weeks and may include about 12 visits.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Type 2 Diabetes

Intervention

• Drug: Tirzepatide
  Administered SC
  Other Name: LY3298176
• Drug: Semaglutide
  Administered SC

Study Arms

• Experimental: 5 mg Tirzepatide
  5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.
  Intervention: Drug: Tirzepatide
• Experimental: 10 mg Tirzepatide
  10 mg tirzepatide administered SC once a week.
  Intervention: Drug: Tirzepatide
• Experimental: 15 mg Tirzepatide
  15 mg tirzepatide administered SC once a week.
  Intervention: Drug: Tirzepatide
• Active Comparator: 1 mg Semaglutide
  1 mg semaglutide administered SC once a week.
  Intervention: Drug: Semaglutide

Publications *

• Ten Doesschate T, van der Vaart TW, Debisarun PA, Taks E, Moorlag SJCFM, Paternotte N, Boersma WG, Kuiper VP, Roukens AHE, Rijnders BJA, Voss A, Veerman KM, Kerckhoffs APM, Oever JT, van Crevel R, van Nieuwkoop C, Lalmohamed A, van de Wijgert JHHM, Netea MG, Bonten MJM, van Werkhoven CH. Bacillus Calmette-Guerin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial. Clin Microbiol Infect. 2022 Sep;28(9):1278-1285. doi: 10.1016/j.cmi.2022.04.009. Epub 2022 Apr 28.
• Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24.
• Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, Liu B, Cui X, Brown K; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021 Aug 5;385(6):503-515. doi: 10.1056/NEJMoa2107519. Epub 2021 Jun 25.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 16, 2021): 1879
• Original Estimated Enrollment (submitted: June 14, 2019): 1872
• Actual Study Completion Date: February 15, 2021
• Actual Primary Completion Date: January 28, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have been diagnosed with type 2 diabetes mellitus (T2DM)
• Have HbA1c between ≥7.0% and ≤10.5%
• Be on stable treatment with unchanged dose of metformin >1500 mg/day for at least 3 months prior to screening
• Be of stable weight (±5%) for at least 3 months before screening
• Have a body mass index (BMI) ≥25 kilograms per meter squared (kg/m²) at screening

Exclusion Criteria:

• Have type 1 diabetes mellitus
• Have had chronic or acute pancreatitis any time prior to study entry
• Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment
• Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss
• Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is ≤3.0 the ULN for the reference range
• Have an estimated glomerular filtration rate <45 milliliters/minute/1.73 m² (or lower than the country specific threshold for using the protocol required dose of metformin per local label)
• Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months
• Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2
• Have been taking any other diabetes medicines other than metformin during the last 3 months
• Have been taking weight loss drugs, including over-the-counter medications during the last 3 months

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, Brazil, Canada, Israel, Mexico, Puerto Rico, United Kingdom, United States

Administrative Information

• NCT Number: NCT03987919
• Other Study ID Numbers: 17001; I8F-MC-GPGL ( Other Identifier: Eli Lilly and Company ); 2018-004422-29 ( EudraCT Number )
• Has Data Monitoring Committee: No

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: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: July 2021