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A Long-term Safety Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03861039
Recruitment Status : Completed
First Posted : March 4, 2019
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 this study is to determine the long-term safety of the study drug tirzepatide in combination with oral antihyperglycemic medications in participants with type 2 diabetes.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Tirzepatide Drug: Oral antihyperglycemic medication (OAM) Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 443 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Long-Term Safety Study of Tirzepatide in Combination With Monotherapy of Oral Antihyperglycemic Medications in Patients With Type 2 Diabetes Mellitus (SURPASS J-combo)
Actual Study Start Date : March 30, 2019
Actual Primary Completion Date : January 26, 2021
Actual Study Completion Date : February 16, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Medicines
Drug Information available for: Tirzepatide

Arms and Interventions
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Arm Intervention/treatment
Experimental: 5 mg Tirzepatide
5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. Participant received the following pre-treatment oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.
 Drug: Tirzepatide
Administered SC
Other Name: LY3298176

Drug: Oral antihyperglycemic medication (OAM)
Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.
Experimental: 10 mg Tirzepatide
10 mg tirzepatide administered SC once a week. Participant received the following pre-treatment oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.
 Drug: Tirzepatide
Administered SC
Other Name: LY3298176

Drug: Oral antihyperglycemic medication (OAM)
Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.
Experimental: 15 mg Tirzepatide
15 mg tirzepatide administered SC once a week. Participant received the following pre-treatment oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.
 Drug: Tirzepatide
Administered SC
Other Name: LY3298176

Drug: Oral antihyperglycemic medication (OAM)
Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration [ Time Frame: Baseline through Week 52 ]

    An SAE is any AE from this study that results in one of the following outcomes:

    • Death
    • Initial or prolonged inpatient hospitalization
    • A life-threatening experience (that is, immediate risk of dying)
    • Persistent or significant disability/incapacity
    • Congenital anomaly/birth defect.
    • Important medical events that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the patient or may require.

    A summary of all SAE's, regardless of causality, is located in the Reported Adverse Events section.



Secondary Outcome Measures :
  1. Change From Baseline in Hemoglobin A1c (HbA1c) [ 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 + oral antihyperglycemic medication (OAM) Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).

  2. Percentage of Participants Who Achieve HbA1c <7% [ Time Frame: Week 52 ]
    Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

  3. Change From Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 52 ]
    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 for post-baseline measures: Variable = Baseline + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).

  4. 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 analysis of covariance (ANCOVA) model for endpoint measures: Variable = Baseline + OAM Group 1 + Treatment (Type III sum of squares).

  5. Change From Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
    LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).

  6. Percentage of Participants Who Achieve Weight Loss of ≥5% From Baseline [ Time Frame: Week 52 ]
    Percentage of Participants who Achieve Weight Loss of ≥5% from Baseline

  7. Change From Baseline in Fasting Insulin [ Time Frame: Baseline, Week 52 ]
    LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).

  8. Change From Baseline in Fasting C-Peptide [ Time Frame: Baseline, Week 52 ]
    LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).

  9. Change From Baseline in Homeostasis Model Assessment B (HOMA-2B) (Insulin) [ Time Frame: Baseline, Week 52 ]

    The HOMA2 is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) and to estimate insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. The change from baseline for fasting insulin concentrations are presented as insulin secretion (HOMA2-%B) and insulin sensitivity (HOMA2-%S).

    LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).


  10. Change From Baseline in HOMA-2S (Insulin) [ Time Frame: Baseline, Week 52 ]

    The HOMA2 is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) and to estimate insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. The change from baseline for fasting insulin concentrations are presented as insulin secretion (HOMA2-%B) and insulin sensitivity (HOMA2-%S).

    LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + OAM Group 1 + Treatment + Time + Treatment*Time (Type III sum of squares).


  11. Number of Participants With Hypoglycemia Incidence and Rate With Blood Glucose <54 mg/dL or Severe Hypoglycemia, Exclude Hypoglycemic Events Occurring After Initiation of a New Antihyperglycemic Therapy [ Time Frame: Baseline through Week 56 ]
    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.

  12. Number of Participants With Anti-Tirzepatide Antibodies [ Time Frame: Baseline through Week 52 ]
    Number of Participants with Anti-Tirzepatide Antibodies


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participant must:

  • Have been diagnosed with type 2 diabetes mellitus based on the World Health Organization classification before the screening visit.
  • Have HbA1c ≥7.0% to <11.0%, as determined by the central laboratory at screening.
  • Have been taking sulfonylureas, biguanides, thiazolidinedione, alpha-glucosidase inhibitor, glinides, or sodium-glucose cotransporter type 2 inhibitor monotherapy for at least 3 months before screening and have been on the following dose for at least 8 weeks before screening.
  • Have body mass index (BMI) of ≥23 kilograms per meter squared at screening.
  • Be of stable weight (±5%) during 3 months preceding screening; and agree to not initiate an intensive 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.

Exclusion Criteria:

Participant 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 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): NCT03861039


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] January 17, 2019
Statistical Analysis Plan  [PDF] February 17, 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: NCT03861039    
Other Study ID Numbers: 17078
I8F-JE-GPGP ( Other Identifier: Eli Lilly and Company )
First Posted: March 4, 2019    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
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Tirzepatide
 Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists