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

• ClinicalTrials.gov Identifier: NCT03861052
• Recruitment Status: Completed
• First Posted: March 4, 2019
• Results First Posted: April 14, 2022
• Last Update Posted: April 14, 2022
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes	Drug: Tirzepatide; Drug: Dulaglutide	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 636 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients With Type 2 Diabetes Mellitus
• Actual Study Start Date: May 7, 2019
• Actual Primary Completion Date: March 10, 2021
• Actual Study Completion Date: March 31, 2021

Arms and Interventions

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 Name: LY3298176
Experimental: 10 mg Tirzepatide; Participants received 10 mg tirzepatide administered SC once weekly for 52 weeks.	Drug: Tirzepatide; Administered SC; Other Name: LY3298176
Experimental: 15 mg Tirzepatide; Participants received 15 mg tirzepatide administered SC once weekly for 52 weeks.	Drug: Tirzepatide; Administered SC; Other Name: 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 Name: LY2189265

Outcome Measures

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

Secondary Outcome Measures :

1. Percentage of Participants With HbA1c of <7.0% [ Time Frame: Week 52 ]
   HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
2. 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 + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
3. Change From Baseline in 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 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.
4. Change From Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
   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).
5. Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline [ Time Frame: Week 52 ]
   Percentage of participants who achieve weight loss ≥5% from baseline.
6. Change From Baseline in Fasting Insulin [ Time Frame: Baseline, Week 52 ]
   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.
7. Change From Baseline in Fasting C-Peptide [ Time Frame: Baseline, Week 52 ]
   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).
8. Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) [ Time Frame: Baseline, Week 52 ]
   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).
9. Change From Baseline in HOMA-2S (Insluin) [ Time Frame: Baseline, Week 52 ]
   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).
10. Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia [ Time Frame: Baseline through Week 52 ]
    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.
11. Number of Participants With Anti-Tirzepatide Antibodies [ Time Frame: Baseline through Week 52 ]
    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.

Eligibility Criteria

• 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 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.

Contacts and Locations

Locations

Japan

Medical corporation THY Tokuyama Clinic

Chiba Mihama-ku, Chiba, Japan, 261-0004

Akaicho Clinic

Chiba-shi, Chiba, Japan, 260 0804

National Hospital Organization Kure Medical Center

Kure, Hiroshima, Japan, 737-0023

Hasegawa Medical Clinic

Chitose, Hokkaido, Japan, 066-0032

Yuri Ono Clinic

Sapporo, Hokkaido, Japan, 060-0001

Watanabe Naika Clinic

Nishinomiya, Hyogo, Japan, 662-0971

Hayashi Clinic

Nishinomiya, Hyogo, Japan, 663-8113

Naka Memorial Clinic

Naka, Ibaraki, Japan, 311-0113

Hayashi Diabetes Internal Medicine Clinic

Chigasaki-sh, Kanagawa, Japan, 253-0044

Matoba Diabetes Clinic

Ebina, Kanagawa, Japan, 243-0432

Takai Naika Clinic

Kamakura, Kanagawa, Japan, 247-0056

Kanto Rosai Hospital

Kawasaki, Kanagawa, Japan, 211-8510

H.E.C. Science Clinic

Yokohama, Kanagawa, Japan, 235-0045

Medical Corporation Heishinkai OCROM Clinic

Suita-shi, Osaka, Japan, 565-0853

Takatsuki Red Cross Hospital

Takatsuki, Osaka, Japan, 569-1096

Senrichuo Ekimae Clinic

Toyonaka, Osaka, Japan, 560-0082

Asano Clinic

Kawagoe, Saitama, Japan, 350 0581

Kawaguchi General Hospital

Kawaguchi, Saitama, Japan, 332-8558

Wakakusa Clinic

Shimotsuke, Tochigi, Japan, 329-0433

Seiwa Clinic

Adachi-ku, Tokyo, Japan, 123 0845

Meiwa Hospital

Chiyodaku, Tokyo, Japan, 101 0041

HDC Atlas Clinic

Chiyoda, Tokyo, Japan, 102-0082

Asahi Life Foundation Adult Disease Research Center

Chuo-ku, Tokyo, Japan, 103 0002

Nihonbashi Sakura Clinic

Chuo-ku, Tokyo, Japan, 103-0025

Tokyo-Eki Center-building Clinic

Chuo-ku, Tokyo, Japan, 103-0027

Medical Corporation Chiseikai Tokyo Center Clinic

Chuo-ku, Tokyo, Japan, 103-0028

Tokyo aSBo Clinic

Chuo-ku, Tokyo, Japan, 104 0031

Fukuwa Clinic

Chuo-ku, Tokyo, Japan, 104-0031

IHL Shinagawa East One Medical Clinic

Minato-ku, Tokyo, Japan, 108-0075

Sato Medical Clinic

Ootaku, Tokyo, Japan, 143-0015

Medical Corporation Heishinkai ToCROM Clinic

Shinjuku-ku, Tokyo, Japan, 160 0008

Tomonaga Clinic

Shinjuku-ku, Tokyo, Japan, 160 0022

Shinjuku Research Park Clinic

Shinjuku, Tokyo, Japan, 169-0073

Shinei Clinic

Suginami, Tokyo, Japan, 166-0003

Ikebukuro Metropolitan Clinic

Toshima-ku, Tokyo, Japan, 171-0021

Futata Tetsuhiro Clinic

Fukuoka, Japan, 810-0006

JR Hiroshima Hospital

Hiroshima, Japan, 732-0057

Yoshimura Clinic

Kumamoto, Japan, 861-8039

Keiseikai Kajiyama Clinic

Kyoto, Japan, 6008898

Abe Clinic

Oita, Japan, 870-0039

OKAYAMA Medical Center

Okayama, Japan, 701-1192

AMC Nishiumeda Clinic

Osaka, Japan, 530-0001

Kitada Clinic

Osaka, Japan, 538-0044

Nanko Clinic

Osaka, Japan, 559-0011

Suruga Clinic

Shizuoka, Japan, 424-0855

Yokohama Minoru Clinic

Yokohama, Japan, 232-0064

Sponsors and Collaborators

Eli Lilly and Company

Investigators

• 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: Clinical Study Protocol Amendment Version (a)  [PDF] January 17, 2019

Study Protocol: Clinical Study Protocol Addendum Version (1)  [PDF] December 18, 2018

Statistical Analysis Plan: Statistical Analysis Plan Version 2  [PDF] April 7, 2021

Statistical Analysis Plan: Statistical Analysis Plan Addendum Version 2  [PDF] April 7, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03861052
• Other Study ID Numbers: 17077; I8F-JE-GPGO ( Other Identifier: Eli Lilly and Company )
• First Posted: March 4, 2019
• Results First Posted: April 14, 2022
• Last Update Posted: April 14, 2022
• Last Verified: April 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: http://www.clinicalstudydatarequest.com

• 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:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Dulaglutide; Tirzepatide; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists