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

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: Tirzepatide
Drug: Oral antihyperglycemic medication (OAM)

Registration Number: NCT03861039

Lead Sponsor: Eli Lilly and Company

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 443

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
10 mg Tirzepatide	Oral antihyperglycemic medication (OAM)	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.
15 mg Tirzepatide	Oral antihyperglycemic medication (OAM)	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.
5 mg Tirzepatide	Oral antihyperglycemic medication (OAM)	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.
5 mg Tirzepatide	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.
10 mg Tirzepatide	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.
15 mg Tirzepatide	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration	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

Name	Time	Method
Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values	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).
Change From Baseline in Body Weight	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).
Change From Baseline in Hemoglobin A1c (HbA1c)	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).
Percentage of Participants Who Achieve HbA1c <7%	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.
Change From Baseline in Fasting Serum Glucose	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).
Percentage of Participants Who Achieve Weight Loss of ≥5% From Baseline	Week 52	Percentage of Participants who Achieve Weight Loss of ≥5% from Baseline
Change From Baseline in Fasting Insulin	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).
Change From Baseline in Fasting C-Peptide	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).
Change From Baseline in Homeostasis Model Assessment B (HOMA-2B) (Insulin)	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).
Change From Baseline in HOMA-2S (Insulin)	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).
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	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.
Number of Participants With Anti-Tirzepatide Antibodies	Baseline through Week 52	Number of Participants with Anti-Tirzepatide Antibodies

Trial Locations

Locations (34): Yuri Ono Clinic
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Sapporo, Hokkaido, Japan
Miyanomori Hospital
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Sapporo, Hokkaido, Japan
Ikeda Hospital
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Amagasaki, Hyogo, Japan
Nakamoto Naika Clinic
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Mito, Ibaraki, Japan
Manda Hospital
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Sapporo, Hokkaido, Japan
Naka Memorial Clinic
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Naka, Ibaraki, Japan
Tsuruma Kaneshiro Diabetes Clinic
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Yamato, Kanagawa, Japan
H.E.C. Science Clinic
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Yokohama, Kanagawa, Japan
Asahi Life Foundation Adult Disease Research Center
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Chuo-ku, Tokyo, Japan
Ohishi Naika Clinic
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Tsuchiura, Ibaraki, Japan
Takatsuki Red Cross Hospital
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Takatsuki, Osaka, Japan
Wakakusa Clinic
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Shimotsuke, Tochigi, Japan
Seiwa Clinic
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Adachi-ku, Tokyo, Japan
Nihonbashi Sakura Clinic
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Chuo-ku, Tokyo, Japan
Tokyo Center Clinic
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Chuo-ku, Tokyo, Japan
Kanno Naika
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Mitaka, Tokyo, Japan
Morinaga Ueno Clinic
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Kumamoto, Japan
Jinnouchi Hospital
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Kumamoto, Japan
Abe Diabetes Clinic
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Oita, Japan
Saiseikai Noe Hospital
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Osaka, Japan
Kansai Denryoku Hospital
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Osaka, Japan
Shizuoka City Shizuoka Hospital
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Shizuoka, Japan
Akaicho Clinic
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Chiba-shi, Chiba, Japan
Kashiwa hospital
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Kashiwa, Chiba, Japan
Tokyo-Eki Center-building Clinic
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Chuo-ku, Tokyo, Japan
Yokohama Minoru Clinic
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Yokohama, Kanagawa, Japan
Takai Naika Clinic
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Kamakura, Kanagawa, Japan
HDC Atlas Clinic
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Chiyoda, Tokyo, Japan
Tokyo Clinical Trial Centre Fukuwa Clinic
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Chuo-ku, Tokyo, Japan
Shinjuku Research Park Clinic
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Shinjuku-Ku, Tokyo, Japan
Otsu City Hospital
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Otsu, Shiga, Japan
Futata Tetsuhiro Clinic
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Fukuoka, Japan
Kitada Clinic
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Osaka, Japan
Suruga Clinic
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Shizuoka, Japan