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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Oral antihyperglycemic medication (OAM)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg Tirzepatide<br>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<br>* Administered SC<br>* Other names: LY3298176;Drug: Oral antihyperglycemic medication (OAM)<br>* Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.<br>|
| Experimental: 10 mg Tirzepatide<br>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<br>* Administered SC<br>* Other names: LY3298176;Drug: Oral antihyperglycemic medication (OAM)<br>* Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.<br>|
| Experimental: 15 mg Tirzepatide<br>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<br>* Administered SC<br>* Other names: LY3298176;Drug: Oral antihyperglycemic medication (OAM)<br>* Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | 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. | Baseline through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) | 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). | Baseline, Week 52 | 
| Percentage of Participants Who Achieve HbA1c <7% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. | Week 52 | 
| Change From Baseline in Fasting Serum Glucose | 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). | Baseline, Week 52 | 
| Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | 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). | Baseline, Week 52 | 
| Change From Baseline in Body Weight | 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). | Baseline, Week 52 | 
| Percentage of Participants Who Achieve Weight Loss of ≥5% From Baseline | Percentage of Participants who Achieve Weight Loss of ≥5% from Baseline | Week 52 | 
| Change From Baseline in Fasting Insulin | 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). | Baseline, Week 52 | 
| Change From Baseline in Fasting C-Peptide | 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). | Baseline, Week 52 | 
| Change From Baseline in Homeostasis Model Assessment B (HOMA-2B) (Insulin) | 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). | Baseline, Week 52 | 
| Change From Baseline in HOMA-2S (Insulin) | 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). | Baseline, Week 52 | 
| 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 | 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. | Baseline through Week 56 | 
| Number of Participants With Anti-Tirzepatide Antibodies | Number of Participants with Anti-Tirzepatide Antibodies | Baseline through Week 52 |