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A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

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ClinicalTrials.gov Identifier: NCT03730662
Recruitment Status : Completed
First Posted : November 5, 2018
Results First Posted : February 14, 2022
Last Update Posted : February 14, 2022
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
The purpose of the trial is to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in participants with type 2 diabetes and increased cardiovascular risk. The study will last about 108 weeks and may include up to 30 visits.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Tirzepatide Drug: Insulin Glargine Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2002 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)
Actual Study Start Date : November 20, 2018
Actual Primary Completion Date : January 22, 2021
Actual Study Completion Date : April 22, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 5 mg Tirzepatide
5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.
 Drug: Tirzepatide
Administered SC.
Other Name: LY3298176
Experimental: 10 mg Tirzepatide
10 mg tirzepatide administered SC once a week.
 Drug: Tirzepatide
Administered SC.
Other Name: LY3298176
Experimental: 15 mg Tirzepatide
15 mg tirzepatide administered SC once a week.
 Drug: Tirzepatide
Administered SC.
Other Name: LY3298176
Active Comparator: Insulin Glargine

Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets.

The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm.

 Drug: Insulin Glargine
Administered SC


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) [ Time Frame: Baseline, Week 52 ]
    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 for post-baseline measures: Variable = Baseline + Pooled Country + Baseline sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).


Secondary Outcome Measures :
  1. Change From Baseline in HbA1c (5 mg) [ Time Frame: Baseline, Week 52 ]
    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 for post-baseline measures: Variable = Baseline + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

  2. Change From Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
    LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

  3. Percentage of Participants With HbA1c of <7.0% [ Time Frame: Week 52 ]
    HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing.

  4. Change From Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 52 ]
    LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

  5. Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 52 ]
    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. LS mean was determined by mixed-model repeated measures (MMRM) model with variables Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

  6. Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide [ Time Frame: 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35 ]
    Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide

  7. Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia [ Time Frame: Baseline through Week 52 ]
    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. Post-baseline comparisons between treatment and control group was evaluated using negative binomial model with variables : Number of episodes = Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants must:

  • Have been diagnosed with type 2 diabetes mellitus (T2DM)
  • Have HbA1c between ≥7.5% and ≤10.5%
  • Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening
  • Have increased risk for cardiovascular (CV) events
  • Be of stable weight (± 5%)
  • Have a BMI ≥25 kilograms per meter squared (kg/m2) at screening

Exclusion Criteria

Participants must not:

  • 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 immediate or urgent 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 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, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months
  • Have been taking weight loss drugs, including over-the-counter medications during the last 3 months
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03730662


Locations
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Sponsors and Collaborators
Eli Lilly and Company
Investigators
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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
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] July 10, 2020
Statistical Analysis Plan  [PDF] February 15, 2021

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT03730662    
Other Study ID Numbers: 17072
I8F-MC-GPGM ( Other Identifier: Eli Lilly and Company )
2018-002618-11 ( EudraCT Number )
First Posted: November 5, 2018    Key Record Dates
Results First Posted: February 14, 2022
Last Update Posted: February 14, 2022
Last Verified: January 2022
Individual Participant Data (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
Statistical Analysis Plan (SAP)
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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eli Lilly and Company:
GIP
GLP-1
glucose metabolism disorders
 metabolic diseases
endocrine system diseases
cardiovascular risk
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Glargine
 Tirzepatide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists