A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes on Metformin With or Without Sulfonylurea (SURPASS-AP-Combo)

• ClinicalTrials.gov Identifier: NCT04093752
• Recruitment Status: Completed
• First Posted: September 18, 2019
• Results First Posted: January 6, 2023
• Last Update Posted: January 6, 2023
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: September 17, 2019
• First Posted Date: September 18, 2019
• Results First Submitted Date: October 27, 2022
• Results First Posted Date: January 6, 2023
• Last Update Posted Date: January 6, 2023
• Actual Study Start Date: December 9, 2019
• Actual Primary Completion Date: November 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2022)

Mean 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 covariates Baseline + Country + Baseline Oral Antihyperglycemic Medication (OAM) Use (Metformin (Met), Met plus Sulfonylurea (SU)) + Treatment + Time + Treatment*Time (Type III sum of squares).

Original Primary Outcome Measures (submitted: September 17, 2019)

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

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

Current Secondary Outcome Measures (submitted: October 27, 2022)

• Mean 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. LS mean was determined by MMRM model with covariates Baseline + Country + Baseline OAM Use (Met, Met plus SU) + Treatment + Time + Treatment*Time (Type III sum of squares).
• Mean Change From Baseline in Body Weight [ Time Frame: Baseline, Week 40 ]
  LS mean was determined by MMRM model with Baseline + Country + Baseline OAM Use (Met, Met plus SU) + Baseline HbA1c Group (<= 8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares) as covariates.
• Percentage of Participants Achieving an HbA1c Target Value of <7.0% [ Time Frame: Week 40 ]
  HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing.
• Percentage of Participants Achieving an HbA1c Target Value of <5.7% [ Time Frame: Week 40 ]
  HbA1c is the glycosylated fraction of hemoglobin A. Imputed data includes observed value and imputed value if endpoint measure is missing.
• Mean Change From Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 40 ]
  Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. LS mean was determined by MMRM model with Baseline + Country + Baseline OAM Use (Met, Met plus SU) + Baseline HbA1c Group (<= 8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares) as covariates.
• Mean Change in Daily Glucose Average From Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 40 ]
  The SMBG data was collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Post-meal, Midday Premeal, Midday 2-hour Post-meal, Evening Premeal, Evening 2-hour Post-meal and Bedtime. LS mean was determined by MMRM model with Baseline + Country + Baseline OAM Use (Met, Met plus SU) + Baseline HbA1c Group (<= 8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares) as covariates.
• Percentage of Participants Who Achieved Weight Loss ≥5% [ Time Frame: Week 40 ]
  Imputed data includes observed value and imputed value if endpoint measure is missing.
• Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Treatment Satisfaction 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 treatment satisfaction score 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 model for endpoint measures with Baseline + Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline OAM Use (Met, Met plus SU) + Treatment (Type III sum of squares) as covariates.
• Rate of Hypoglycemia With Blood Glucose < 54 mg/dL or Severe Hypoglycemia [ Time Frame: Baseline through end of safety follow-up (Up To Week 44) ]
  The hypoglycemia events were defined by participant reported events with blood glucose < 54 mg/dL [<3.0 Millimole per Liter (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 post-baseline hypoglycemia was estimated by negative binomial model: Number of episodes = Country + Baseline OAM Use (Met, Met plus SU) + Baseline HbA1c Group (<= 8.5%, >8.5%) + Treatment, with log (exposure in days/365.25) as an offset variable.

Original Secondary Outcome Measures (submitted: September 17, 2019)

• Mean Change from Baseline in HbA1c (5 mg) [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in HbA1c (5 mg)
• Mean Change from Baseline in Body Weight [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in Body Weight
• Mean Change from Baseline in HbA1c [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in HbA1c
• Percentage of Participants Achieving an HbA1c Target Value of <7.0% [ Time Frame: Week 40 ]
  Percentage of Participants Achieving an HbA1c Target Value of <7.0%
• Mean Change from Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in Fasting Serum Glucose
• Mean Change from Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 40 ]
  Mean Change from Baseline in 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 Patient-Reported Outcomes as Measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) [ Time Frame: Baseline, Week 40 ]
  Change from Baseline in Patient-Reported Outcomes 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) in Participants With Type 2 Diabetes on Metformin With or Without Sulfonylurea (SURPASS-AP-Combo)
• Official Title: A Randomized, Phase 3, Open-label Trial Comparing the Effect of Tirzepatide Once Weekly Versus Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes on Metformin With or Without a Sulfonylurea
• Brief Summary: The main reason for this study is to compare the study drug tirzepatide to insulin glargine in participants with type 2 diabetes on metformin with or without a sulfonylurea.
• 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: Insulin Glargine
  Administered SC

Study Arms

• Experimental: 5 mg Tirzepatide
  Participants received 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once weekly (QW).
  Intervention: Drug: Tirzepatide
• Experimental: 10 mg Tirzepatide
  Participants received 10 mg tirzepatide administered SC QW.
  Intervention: Drug: Tirzepatide
• Experimental: 15 mg Tirzepatide
  Participants received 15 mg tirzepatide administered SC QW.
  Intervention: Drug: Tirzepatide
• Active Comparator: Insulin Glargine
  Participants received insulin glargine administered once daily (QD) SC. The starting dose of insulin glargine was 6 Insulin Units (IU)/day at bedtime, titrated to a fasting blood glucose (FBG) between 72-100 milligrams per Deciliter (mg/dL), following a treat-to-target (TTT) algorithm.
  Intervention: Drug: Insulin Glargine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 10, 2021): 917
• Original Estimated Enrollment (submitted: September 17, 2019): 956
• Actual Study Completion Date: November 24, 2021
• Actual Primary Completion Date: November 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Type 2 diabetes mellitus
• Treated with stable metformin with or without a sulfonylurea (metformin ≥1000 milligrams/day; sulfonylurea should be at least half the maximum dose) for at least 2 months
• Are insulin-naive (except for the use of insulin for treatment of gestational diabetes or short-term use [≤14 consecutive days] for acute conditions)
• HbA1c ≥7.5% to ≤11.0% at screening
• Stable weight (±5%) ≥3 months, and agree to not initiate a diet and/or exercise program during the study with the intent of reducing body weight other than the lifestyle and dietary measures for diabetes treatment
• Body mass Index (BMI) ≥23 kilograms per meter squared

Exclusion Criteria:

• Type 1 diabetes mellitus
• Have history of chronic or acute pancreatitis
• Have history of proliferative diabetic retinopathy; or diabetic maculopathy; or non-proliferative diabetic retinopathy that requires acute treatment
• Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months
• Have a history of ketoacidosis or hyperosmolar state/coma
• Have a known clinically significant gastric emptying abnormality, have undergone or plan to have during the course of the study, or chronically take drugs that directly affect GI motility
• Have acute myocardial infarction (MI), stroke or hospitalization due to congestive heart failure (CHF) within 2 months
• Have family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2)
• Have been treated with prescription drugs that promote weight loss or similar other body weight loss medications including over the counter (OTC) within 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: Australia, China, India, Korea, Republic of

Administrative Information

• NCT Number: NCT04093752
• Other Study ID Numbers: 17210; I8F-MC-GPHO ( Other Identifier: Eli Lilly and Company )
• 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
• Product Manufactured in and Exported from the U.S.: Yes

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: http://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: December 2022