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

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)

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Tirzepatide; Drug: Oral antihyperglycemic medication (OAM)

• Study Type: Interventional
• Enrollment (Actual): 443
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 819 0006
    • Futata Tetsuhiro Clinic
  • Kumamoto, Japan, 860 0863
    • Morinaga Ueno Clinic
  • Kumamoto, Japan, 862-0976
    • Jinnouchi Hospital
  • Oita, Japan, 870-0039
    • Abe Diabetes Clinic
  • Osaka, Japan, 536 0001
    • Saiseikai Noe Hospital
  • Osaka, Japan, 538 0044
    • Kitada Clinic
  • Osaka, Japan, 553-0003
    • Kansai Denryoku Hospital
  • Shizuoka, Japan, 420-8630
    • Shizuoka City Shizuoka Hospital
  • Shizuoka, Japan, 424-0855
    • Suruga Clinic
  • Chiba
    • Chiba-shi, Chiba, Japan, 260 0804
      • Akaicho Clinic
    • Kashiwa, Chiba, Japan, 277-0825
      • Kashiwa hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-0001
      • Yuri Ono Clinic
    • Sapporo, Hokkaido, Japan, 060-0062
      • Manda Hospital
    • Sapporo, Hokkaido, Japan, 064-8570
      • Miyanomori Hospital
  • Hyogo
    • Amagasaki, Hyogo, Japan, 661-0002
      • Ikeda Hospital
  • Ibaraki
    • Mito, Ibaraki, Japan, 310 0826
      • Nakamoto Naika Clinic
    • Naka, Ibaraki, Japan, 311-0113
      • Naka Memorial Clinic
    • Tsuchiura, Ibaraki, Japan, 300-0835
      • Ohishi Naika Clinic
  • Kanagawa
    • Kamakura, Kanagawa, Japan, 247-0056
      • Takai Naika Clinic
    • Yamato, Kanagawa, Japan, 242-0004
      • Tsuruma Kaneshiro Diabetes Clinic
    • Yokohama, Kanagawa, Japan, 232-0064
      • Yokohama Minoru Clinic
    • Yokohama, Kanagawa, Japan, 235-0045
      • H.E.C. Science Clinic
  • Osaka
    • Takatsuki, Osaka, Japan, 569-1096
      • Takatsuki Red Cross Hospital
  • Shiga
    • Otsu, Shiga, Japan, 520-0804
      • Otsu City Hospital
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0433
      • Wakakusa Clinic
  • Tokyo
    • Adachi-ku, Tokyo, Japan, 123 0845
      • Seiwa Clinic
    • Chiyoda, Tokyo, Japan, 102-0082
      • HDC Atlas Clinic
    • Chuo-ku, Tokyo, Japan, 103 0002
      • Asahi Life Foundation Adult Disease Research Center
    • Chuo-ku, Tokyo, Japan, 103-0025
      • Nihonbashi Sakura Clinic
    • Chuo-ku, Tokyo, Japan, 103-0027
      • Tokyo-Eki Center-building Clinic
    • Chuo-ku, Tokyo, Japan, 103-0028
      • Tokyo Center Clinic
    • Chuo-ku, Tokyo, Japan, 104-0031
      • Tokyo Clinical Trial Centre Fukuwa Clinic
    • Mitaka, Tokyo, Japan, 181 0013
      • Kanno Naika
    • Shinjuku-Ku, Tokyo, Japan, 169-0073
      • Shinjuku Research Park Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: LY3298176; Drug: Oral antihyperglycemic medication (OAM); Oral antihyperglycemic medication (OAM): Sulfonylurea, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, glinide, or sodium-glucose cotransporter type 2 inhibitor.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Sep;10(9):634-644. doi: 10.1016/S2213-8587(22)00187-5. Epub 2022 Jul 30.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2019
• Primary Completion (Actual): January 26, 2021
• Study Completion (Actual): February 16, 2021

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): February 14, 2022
• Last Update Submitted That Met QC Criteria: January 21, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Hypoglycemic Agents; Tirzepatide
• Other Study ID Numbers: 17078; I8F-JE-GPGP (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing 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.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• 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