A Study of Tirzepatide (LY3298176) Compared to Dulaglutide in Participants With Type 2 Diabetes (SURPASS J-mono)

A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients With Type 2 Diabetes Mellitus

The reason for this study is to see if the study drug tirzepatide (LY3298176) is effective and safe compared to dulaglutide in participants with type 2 diabetes in Japan.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Tirzepatide; Drug: Dulaglutide

• Study Type: Interventional
• Enrollment (Actual): 636
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 810-0006
    • Futata Tetsuhiro Clinic
  • Hiroshima, Japan, 732-0057
    • JR Hiroshima Hospital
  • Kumamoto, Japan, 861-8039
    • Yoshimura Clinic
  • Kyoto, Japan, 6008898
    • Keiseikai Kajiyama Clinic
  • Oita, Japan, 870-0039
    • Abe Clinic
  • Okayama, Japan, 701-1192
    • Okayama Medical Center
  • Osaka, Japan, 538-0044
    • Kitada Clinic
  • Osaka, Japan, 530-0001
    • AMC Nishiumeda Clinic
  • Osaka, Japan, 559-0011
    • Nanko Clinic
  • Shizuoka, Japan, 424-0855
    • Suruga Clinic
  • Yokohama, Japan, 232-0064
    • Yokohama Minoru Clinic
  • Chiba
    • Chiba Mihama-ku, Chiba, Japan, 261-0004
      • Medical corporation THY Tokuyama Clinic
    • Chiba-shi, Chiba, Japan, 260 0804
      • Akaicho Clinic
  • Hiroshima
    • Kure, Hiroshima, Japan, 737-0023
      • National Hospital Organization Kure Medical Center
  • Hokkaido
    • Chitose, Hokkaido, Japan, 066-0032
      • Hasegawa Medical Clinic
    • Sapporo, Hokkaido, Japan, 060-0001
      • Yuri Ono Clinic
  • Hyogo
    • Nishinomiya, Hyogo, Japan, 662-0971
      • Watanabe Naika Clinic
    • Nishinomiya, Hyogo, Japan, 663-8113
      • Hayashi Clinic
  • Ibaraki
    • Naka, Ibaraki, Japan, 311-0113
      • Naka Memorial Clinic
  • Kanagawa
    • Chigasaki-sh, Kanagawa, Japan, 253-0044
      • Hayashi Diabetes Internal Medicine Clinic
    • Ebina, Kanagawa, Japan, 243-0432
      • Matoba Diabetes Clinic
    • Kamakura, Kanagawa, Japan, 247-0056
      • Takai Naika Clinic
    • Kawasaki, Kanagawa, Japan, 211-8510
      • Kanto Rosai Hospital
    • Yokohama, Kanagawa, Japan, 235-0045
      • H.E.C. Science Clinic
  • Osaka
    • Suita-shi, Osaka, Japan, 565-0853
      • Medical Corporation Heishinkai OCROM Clinic
    • Takatsuki, Osaka, Japan, 569-1096
      • Takatsuki Red Cross Hospital
    • Toyonaka, Osaka, Japan, 560-0082
      • Senrichuo Ekimae Clinic
  • Saitama
    • Kawagoe, Saitama, Japan, 350 0581
      • Asano Clinic
    • Kawaguchi, Saitama, Japan, 332-8558
      • Kawaguchi General 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
    • Chiyodaku, Tokyo, Japan, 101 0041
      • Meiwa Hospital
    • 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, 104-0031
      • Fukuwa Clinic
    • Chuo-ku, Tokyo, Japan, 103-0028
      • Medical Corporation Chiseikai Tokyo Center Clinic
    • Chuo-ku, Tokyo, Japan, 104 0031
      • Tokyo Asbo Clinic
    • Minato-ku, Tokyo, Japan, 108-0075
      • IHL Shinagawa East One Medical Clinic
    • Ootaku, Tokyo, Japan, 143-0015
      • Sato Medical Clinic
    • Shinjuku, Tokyo, Japan, 169-0073
      • Shinjuku Research Park Clinic
    • Shinjuku-ku, Tokyo, Japan, 160 0008
      • Medical Corporation Heishinkai ToCROM Clinic
    • Shinjuku-ku, Tokyo, Japan, 160 0022
      • Tomonaga Clinic
    • Suginami, Tokyo, Japan, 166-0003
      • Shinei Clinic
    • Toshima-ku, Tokyo, Japan, 171-0021
      • Ikebukuro Metropolitan 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 meeting the following criteria, as determined by the central laboratory at screening and baseline:

  • for participants who are oral antihyperglycemic medication (OAM)-naïve at screening, ≥7.0% to ≤10.0% at both screening and baseline.
  • for participants who have been taking OAM monotherapy at screening, ≥6.5% to ≤9.0% at screening, and ≥7.0% to ≤10.0% at baseline.
• 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: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5 mg Tirzepatide; Participants received 5 milligram (mg) tirzepatide administered subcutaneously (SC) once weekly for 52 weeks.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 10 mg Tirzepatide; Participants received 10 mg tirzepatide administered SC once weekly for 52 weeks.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 15 mg Tirzepatide; Participants received 15 mg tirzepatide administered SC once weekly for 52 weeks.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Active Comparator: 0.75 mg Dulaglutide; Participants received 0.75 mg dulaglutide administered SC once weekly for 52 weeks.	Drug: Dulaglutide; Administered SC; Other Names: LY2189265

What is the study measuring?

Primary 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 + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HbA1c of <7.0%	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 + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Change From Baseline in 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 with Baseline + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment (Type III sum of squares) as variables.	Baseline, Week 52
Change From Baseline in Body Weight	Change from baseline in body weight. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline HbA1c Group (<=8.5%, >8.5%) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline	Percentage of participants who achieve weight loss ≥5% from baseline.	Week 52
Change From Baseline in Fasting Insulin	Fasting Insulin is a test used to measure the amount of insulin in the body. LS mean was determined by MMRM model for post-baseline measures with log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.	Baseline, Week 52
Change From Baseline in Fasting C-Peptide	Fasting C-peptide is a test used to measure the amount of C-peptide in the body. A high level of C-peptide can mean that body is making too much insulin. LS mean was determined by MMRM model for post-baseline measures: log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin)	HOMA-2B is an estimated steady state beta cell function based on updated HOMA2 model. The HOMA2 model estimates steady state pancreatic beta cell function (%B) as a percentage of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement/Baseline) = log(Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Change From Baseline in HOMA-2S (Insluin)	HOMA2-S is an estimated insulin sensitivity based on updated HOMA2 model. The HOMA2 model is a computer model that estimates insulin sensitivity (%S) as percentages of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia	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. The rate of postbaseline hypoglycemia was estimated by negative binomial model for post-baseline comparisons between treatment and control group: number of episodes = baseline hypoglycemia incidence + baseline BMI Group (<25 or >=25 kg/m^2) + washout of antidiabetic medication + baseline hemoglobin A1C (%) + treatment, with log (exposure in days/365.25) as an offset variable.	Baseline through Week 52
Number of Participants With Anti-Tirzepatide Antibodies	Number of participants with anti-tirzepatide antibodies. A participant is treatment emergent (TE) anti-drug antibody (ADA) evaluable if there is at least one non-missing test result for tirzepatide ADA for each of the baseline period and the postbaseline period. All percentages are relative to the total number of TE ADA evaluable participants in each treatment group. A TE ADA evaluable participant is considered to be TE ADA+ if the participant has at least one postbaseline titer that is a 4-fold or greater increase in titer from baseline measurement.	Baseline through Week 52

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Sep;10(9):623-633. doi: 10.1016/S2213-8587(22)00188-7. Epub 2022 Jul 30.
• Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2019
• Primary Completion (Actual): March 10, 2021
• Study Completion (Actual): March 31, 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): April 14, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 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; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Dulaglutide; Tirzepatide
• Other Study ID Numbers: 17077; I8F-JE-GPGO (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